Treatment methods for chronic thyroid eye disease

Abstract

A method for treating patients with chronic thyroid eye disease is provided herein, including by administering antibodies and compositions that bind to and / or antagonize IGF-1R.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 512,468, filed Jul. 7, 2023, which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in XML file format, which is hereby incorporated by reference in its entirety. The XML copy created on Jul. 3, 2024 is named VRD - 016WO1_SL and is 41,045 bytes.

Background Art

[0003] Thyroid eye disease (TED) is the autoimmune condition most widely associated with Graves' disease and hyperthyroidism, but may also be found in patients with euthyroidism or hypothyroidism. The course of the disease has been said to progress from an initial active and progressive stage ( "active TED") characterized by inflammation of orbital tissues and the tissues surrounding the external orbit to a more stable fibrotic stage. Active TED can be characterized by local inflammation of the conjunctiva, superficial vascular structures, orbital fat, eyelids, and extraocular muscles. The second stage of TED may be characterized by the waning of the autoimmune inflammation of the first stage, leaving sequelae such as hypertrophy and fibrosis of orbital tissues and dysfunction of tethered extraocular muscles, but there is evidence that these TED patients may still exhibit underlying inflammatory elements. Thus, the occurrence of this inactive stage can be indicated by the duration, severity, and / or nature of the disease symptoms. An effective treatment for TED considering the different natures of the two disease stages is still needed.

Summary of the Invention

[0004] This disclosure relates, in general, to IGF-1R antibodies and their antigen-binding fragments, including any form, variant, or derivative thereof, and to the use thereof. Certain IGF-1R antibodies and antigen-binding fragments inhibit the function of IGF-1R or block the biological function of IGF-I mediated IGF-1R signaling. Furthermore, the invention relates, in general, to methods for treating thyroid-related eye diseases (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, insufficient thyroid eye disease, autoimmune-related eye disorders associated with IGF-1R signaling, inflammatory orbital disorders associated with IGF-1R signaling, and other thyroid eye disorders, including chronic TED, which are associated with IGF-1R signaling.

[0005] In one embodiment, the present invention relates to a method for treating a patient suffering from chronic thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11. In some embodiments, the anti-IGF-1R antibody is administered in a therapeutically effective drug regimen.

[0006] In another embodiment, the present invention relates to a method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment, characterized in that the method. In some embodiments, the anti-IGF-1R antibody is administered in a drug regimen effective for treatment.

[0007] In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment with anti-IGF-1R antibodies. In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment with anti-IGF-1R antibodies. In some embodiments, the patient has one or more symptoms of thyroid eye disease associated with a clinical activity score (CAS) of 4 or higher prior to treatment with anti-IGF-1R antibodies, and such symptoms(s) have decreased in severity over time. In some embodiments, the patient has one or more symptoms of thyroid eye disease that have reached a plateau, e.g., a static plateau, prior to treatment with anti-IGF-1R antibodies. In some embodiments, the patient has one or more symptoms of thyroid eye disease associated with a clinical activity score (CAS) of 4 or higher prior to treatment with anti-IGF-1R antibodies, and such symptoms(s) have decreased in severity over time. In some embodiments, the patient has one or more symptoms of thyroid eye disease that have reached a plateau, e.g., a static plateau, prior to treatment with anti-IGF-1R antibodies.

[0008] In some embodiments, the patient suffers from one or more symptoms of TED, selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) greater than 3 mm, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia.

[0009] In some embodiments, exophthalmos exceeds the standard range for race and sex by more than 3 mm.

[0010] In some embodiments, patients had 0, 1, 2, 3, or 4 or more CAS levels prior to treatment with anti-IGF-1R antibodies.

[0011] In some embodiments, the patient had a CAS of more than 2 prior to treatment with anti-IGF-1R antibody.

[0012] In some embodiments, patients had a CAS of less than 2 prior to treatment with anti-IGF-1R antibody.

[0013] In some embodiments, patients had 2–4 CASes prior to treatment with anti-IGF-1R antibodies.

[0014] In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment with anti-IGF-1R antibody. In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment with anti-IGF-1R antibody.

[0015] In another embodiment, the present invention relates to a method for treating a patient suffering from inactive thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In the embodiment, the anti-IGF-1R antibody is administered in a drug regimen effective for treatment.

[0016] In another embodiment, the present invention relates to a method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody in a therapeutically effective drug regimen, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the patient had a clinical activity score (CAS) of 2 or less prior to treatment.

[0017] In some embodiments, the patient exhibits fibrosis.

[0018] In another embodiment, the present invention relates to a method for treating fibrosis associated with thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody to a patient in need of treatment in a therapeutically effective drug regimen, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.

[0019] In some embodiments, patients had a clinical activity score (CAS) of 0 or 1 prior to treatment with anti-IGF-1R antibodies.

[0020] In some embodiments, the patient has one or more symptoms of TED, selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) greater than 3 mm or more above the racial and sex-specific standard range, and indeterminate or constant diplopia.

[0021] In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least two years prior to treatment with anti-IGF-1R antibodies. In some embodiments, the patient has had one or more symptoms of thyroid eye disease for at least three years prior to treatment with anti-IGF-1R antibodies.

[0022] In some embodiments, an effective drug regimen for treatment involves administering a first dose to the patient ranging from approximately 3.0 mg / kg to approximately 20 mg / kg.

[0023] In some embodiments, the first dose is approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg.

[0024] In some embodiments, an effective drug regimen for treatment includes administering a subsequent dose to the patient.

[0025] In some embodiments, the subsequent dose is approximately 3.0 mg / kg to approximately 20 mg / kg.

[0026] In some embodiments, the subsequent dose is approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg.

[0027] In some embodiments, the subsequent dose is administered to the patient every two weeks, every three weeks, every four weeks, every month, every five weeks, or every six weeks.

[0028] In some embodiments, the subsequent dose is administered to the patient once every three weeks.

[0029] In some embodiments, the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

[0030] In some embodiments, the patient is administered at least four subsequent doses.

[0031] In some embodiments, the patient is administered at least 5 subsequent doses.

[0032] In some embodiments, the patient is administered a drug regimen that includes at least eight subsequent doses.

[0033] In some embodiments, administration of the drug regimen resulted in a reduction of approximately 1–3 mm, 1–2 mm, and 2–3 mm of exophthalmos from baseline within 6 weeks of the first dose, as measured by exophthalmos measurement or MRI / CT.

[0034] In some embodiments, exophthalmos, as measured by exophthalmoscopy or MRI / CT, ​​decreases by approximately 2–3 mm from baseline within 6 weeks of the first dose.

[0035] In some embodiments, the patient does not have hearing impairment, acoustotoxic changes in audiometry, or hyperglycemic levels in the patient during treatment.

[0036] In some embodiments, the light chain includes a variable region having an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain includes a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having the amino acid sequence of SEQ ID NO: 3.

[0037] In some embodiments, the light chain includes an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 11.

[0038] In some embodiments, the light chain contains an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain contains the amino acid sequence of SEQ ID NO: 10.

[0039] In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10, and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0040] In embodiments of any method described herein, the anti-IGF-1R antibody comprises an anti-IGF-1R antibody and an antigen-binding fragment thereof, comprising any form, variant, or derivative thereof of the anti-IGF-1R antibody and the antigen-binding fragment.

[0041] In some embodiments, patients achieve improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total quality of life (GO-QoL) score for Graves' ophthalmopathy, activity subscale of GO-QoL, appearance subscale of GO-QoL, visual acuity, Gorman subjective diplopia score, and the EQ-5D-5L QoL questionnaire. [Brief explanation of the drawing]

[0042] [Figure 1] This specification presents various data from patients with chronic thyroid eye disease treated with anti-IGF-1R antibodies. [Figure 2] An exemplary Phase 3 trial design schematic for evaluating VRDN-5000 in participants with chronic TED is shown. [Modes for carrying out the invention]

[0043] This specification provides antibodies that bind to IGF-1R and regulate its activity. These antibodies can be used to treat thyroid-related eye diseases (TAOs), also known as other thyroid eye disorders associated with IGF-1R signaling, such as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, autoimmune-associated eye disorders associated with IGF-1R signaling, inflammatory orbital disorders associated with IGF-1R signaling, and chronic TED.

[0044] As used herein, “thyroid-associated eye disease” (TAO), “thyroid eye disease” (TED), “Graves’ eye disease” or “Graves’ ophthalmopathy” (GO) refer to the same disorder or condition and are used interchangeably. All of these refer to some autoimmune thyroid disorder, most broadly “Graves’ disease” (GD), but in some cases associated with other diseases, such as Hashimoto’s thyroiditis, and inflammatory orbital conditions.

[0045] The terms “protosis” and “exophthalmos” (also known as exophthalmus, exophthalmia, or exorbitism) refer to an anterior projection, movement, bulge, or protrusion of an organ. As used herein, the term refers to an anterior projection, movement, bulge, or projection of the eye from the orbit. To those skilled in the art, proptosis and exophthalmos are considered to be synonymous and often interchangeable, although some consider there to be slight differences in meaning. Exophthalmos may be used by some to mean severe exophthalmos; or to mean endocrine gland-related exophthalmos. Furthermore, for example, TAO (TED or GO) may use the term exophthalmos when describing eye-related exophthalmos in a subject.

[0046] As used herein, “proptosis” and “exophthalmos” are used interchangeably and refer to the forward projection, movement, bulge, or forward protrusion of the eye from the orbit. Due to the rigid bony structure of the orbit, where the only opening that can expand is the anterior side, any increase in the volume of orbital soft tissue arising from the lateral or posterior side will cause the eyeball to move forward. Protosis or exophthalmos can be the result of several disease processes, including infection, inflammation, tumors, trauma, metastasis, endocrine lesions, vascular diseases, and extraorbital lesions. TAO (TED or GO) is currently recognized as the most common cause of proptosis in adults. Protosis can be bilateral, as is often seen in TAO (TED or GO), or unilateral, as is often seen in orbital tumors.

[0047] The degree of exophthalmos can be measured, for example, using an exophthalmosmeter, an instrument used to measure the degree of forward movement of the eye. This device allows for the measurement of the distance from the transverse rim of the orbit to the anterior cornea. Computed tomography (CT) and magnetic resonance imaging (MRI) can also be used to measure the degree of exophthalmos or proptosis. CT scanning is an excellent imaging technique for diagnosing TAO. In addition to enabling magnified imaging of the extraocular muscles, CT scans provide surgeons or clinicians with a depiction of the orbital bone anatomy when orbital decompression is required. MRI, with its multi-plane and inherent contrast capabilities, provides excellent imaging of orbital volume without the radiation exposure associated with CT scans. While MRI provides better imaging of the optic nerve, orbital fat, and extraocular muscles, CT scans provide better images of the orbital bone structure. Orbital ultrasonography can also be used for the diagnosis and evaluation of TAO because it can be performed quickly and with high reliability. High reflectivity and hypertrophy of the extraocular muscles are readily assessable, and serial ultrasound imaging can be used to evaluate the progression or stability of ocular diseases. Based on currently available or future available technologies, those skilled in the art can determine the best means for diagnosing and investigating proptosis or exophthalmos.

[0048] As used herein, the term “antibody” means any form of antibody exhibiting the desired biological activity. Therefore, the term is used in its broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single-domain antibodies. “Parental antibody” refers to an antibody obtained by exposing the immune system to an antigen before modifying the antibody for use, for example, before humanizing the antibody for use as a human therapeutic antibody.

[0049] As used herein, unless otherwise specified, "antibody fragment" or "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that maintains the ability to specifically bind to an antigen to which a full-length antibody is bound, such as a fragment that maintains one or more CDR regions. Examples of antibody-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as scFv; nanobodies; and multispecific antibodies formed from antibody fragments.

[0050] "Fab fragment" consists of one light chain and one heavy chain of C H It consists of one region and a variable region. The heavy chain of the Fab molecule cannot form disulfide bonds with other heavy chain molecules.

[0051] The "Fc" region is the C of the antibody. H 1 and C H It contains two heavy chain fragments, each containing two domains. The two heavy chain fragments are connected by two or more disulfide bonds, and C H The three domains are bound to each other through hydrophobic interactions.

[0052] In some embodiments, the antibodies or antigen fragments of this specification include an Fc region. In some embodiments, the Fc region includes a mutation that, when bound to the Fc region, extends the half-life of the antibody. In some embodiments, the Fc region includes the S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S mutation, or any combination thereof. In some embodiments, the Fc region includes the M252Y, S254T, and T256E mutations. In some embodiments, the Fc region includes the S228P and L235E mutations. In some embodiments, the antibody includes the L234F, L235E, and P331S mutations. In some embodiments, the Fc region includes the M252Y, S254T, T256E, S228P, and L235E mutations. In some embodiments, the Fc region includes the S228P, L235E, M428L, and N434S mutations. In some embodiments, the Fc region includes the M428L and N434S mutations. In some embodiments, the Fc region includes the L234F, L235E, P331S, M252Y, S254T, and T256E mutations. In some embodiments, the Fc region includes the S228P, L235E, M252Y, S254T, T256E, M428L, N434S, L234F, P331S, T250Q, L309D, Q311H, N434Y, Q311R, M428E, N434W mutations, or any combination thereof. In some embodiments, the Fc region includes the T250Q and M428L mutations. In some embodiments, the Fc region includes L309D, Q311H, and N434S mutations. In some embodiments, the Fc region includes L309D, Q311H, and N434Y mutations. In some embodiments, the Fc region includes Q311R and M428L mutations. In some embodiments, the Fc region includes Q311R, M428E, and N434W mutations. In some embodiments, the FC region includes P329G, LALA(L234A, L235A), LALAGA(L234A, L235A, G237A), YTE(M252Y / S254T / T256E), or LS(M428L / N434S) mutations.Mutations in the Fc region are also described in US2007041972A1, US20190048078A1, US20220348690A1, EP2235059B1, US Patent No. 7,365,168, US Patent No. 8,394,925, US Patent No. 11,492,415, Mueller et al. (1997) Mol.Immunol. 34(6):441-52, Schlothauer et al. (2016) Protein Eng Des Sel.; 29(10):457-466, and Damelang et al., (2024) Front.Immunol. 14:1304365 (see, for example, Table 2), each of which is referenced in whole. The numbering referred to herein, with respect to the Fc region, refers to the Kabat numbering system.

[0053] In this embodiment, the Fc region contains one or more of the following mutations: E233P; G236A[GA]; G237A; P238D; S239A; I253A; S254A; D265A; S267E; H268F; D270A; R292A; N297(A / Q / G)[NA]; S298N; K322A; S324T; K326W; A327Q; L328E; L328F; P329A; I332E; E333A; K338A; E345R[Arg345]; E380A; E430G; H433A; N434A; N435W; K439E; S440K; C221D / D222C;L234A / L235A[LALA];L234A / L235E;L234A / G237A;G236A / G237A[G AGA];G236N / H268D;G236R / L328R[RR];G236A / I332E[AE];K236W / E333S[KW ES];S239D / I332E[DE or SDIE];P247I / A339Q;M252Y / T256D[YD];T256D / T307Q[DQ];T256D / T307W[DW];P257I / Q311I[PIQI];S267E / L328F[SE / LF]; H268F / S324T[FT or HFST];S298G / T299A[Ga];K326A / E333A;K326M / E333S;K326W / E333S[WS];A330S / P331S;E380A / N434A;M428L / N434S[MN or LS] ;H433K / N434F[HN or KF];E233P / L234V / L235A;L234A / L235A / K322A;L23 4F / L235E / K322A;L234F / L235Q / K322Q[FQQ];L234A / L235A / P329G[LALAPG] ;L234F / L235E / P331S[FES];L234S / L235T / G236R;L234A / L235A / G237A;L2 34F / L235E / D265A[FEA];L234Y / G236W / S298A[YWA];L235A / G237A / E318A;G 236A / S239D / I332E[GASDIE];G236A / A330L / I332E[GAALIE];S239D / S298A / I332E;S239D / A330L / I332E[SDALIE or DLE];T250Q / M428L / N434S[QLS];M252Y / S254T / T256E[YTEもしくはMST];I253A / H310A / H435A[IHH];P257I / M428L / N434S;V259I / N315D / N434Y[C6A-74];S267E / H268F / S324T[EFT];H285D / T307Q / A378V[DQV];S298A / E333A / K334A[AAA];T307A / E380A / N434A;L309D / Q311H / N434S[DHS];A327G / A330S / P331S;I332 E / M428L / N434S;E333A / M428L / N434S[ALS];E345R / E430G / S440Y[RGY];D376V / M428L / N434S;E380A / M428L / N434S;L234A / L235A / N297A / P329G;L234A / L235A / M428L / N434S;G236A / S239D / A330L / I332E[GASDALIE];S239D / H268F / S324T / I332E;S239D / I332E / M428L / N434S[SDIE LS];P257I / Q311I / M428L / N434S[PIQI LS];S267E / L328F / M428L / N434S[SE / LF LS];H268F / S324T / M428L / N434S[HFST] LS];T307A / E380A / M428L / N434S;L235V / F243L / R292P / Y300L / P396L[VPLIL];F24 3L / R292P / Y300L / V305I / P396L[バリアント18(LPLIL)];G236A / S239D / I332E / M428L / N 434S;G236A / S267E / H268F / S324T / I332E[EFT-EA];S239D / S298A / I332E / M428L / N434S;S239D / A330L / I332E / M428L / N434S;M252Y / S254T / T256E / M428L / N434S[YTE LS];M252Y / S254T / T256E / H433K / N434F[YTE-KFもしくはMST / HN];S267E / H268F / S324T / M428L / N434 E345R / E430G / S440Y / M428L / N434S[RGY] LS];G236A / S239D / A330L / I332E / M428L / N434S;M252Y / S254T / T256Y+S239D / A330L / I332E[YTE-SDALIE];E233D / G237D / P238D / H268D / P271G / A330R[V12];E233P / L234V / L235A / DG236+A327G / A330S / P331S;G236A / S267E / H268F / S324T / I332E / M428L / N434S[EFT-EA LS];T250Q / M428L;N434Y;Q311R / M428L[PFc29];and Q311R / M428E / N434W[REW];or any combination thereof.

[0054] In this embodiment, the Fc region contains one or more of the following mutations: E380A; N434A; N435W; M252Y / T256D[YD]; T256D / T307Q[DQ]; T256D / T307W[DW]; M428L / N434S[MN or LS]; H433K / N434F[HN or KF]; M252Y / S254T / T256E[YTE or MST]; V259I / N315D / N434Y[C6A-74]; H285D / T307Q / A378V[DQV]; T307A / E380A / N434A; L309D / Q311H / N434S[DHS]; M252Y / S254T / T256E / H433K / N434F[YTE-KF or MST / HN]; N315D / A330V / N361D / A378V / N434Y[T5A-74]; M252Y / S254T / T256Y+S239D / A330L / I332E[YTE-SDALIE]; T250Q / M428L; N434Y; Q311R / M428L[PFc29]; and Q311R / M428E / N434W[REW]; or any combination thereof.

[0055] "Fab' fragment" consists of one light chain and V H Domain and C H 1 domain, and C H 1 and C HSince it also contains a part or fragment of one heavy chain that also contains the region between the two domains, an inter-chain disulfide bond can be formed between the two heavy chains of the two Fab’ fragments to form an F(ab’)2 molecule.

[0056] The "F(ab’)2 fragment" contains two light chains and two heavy chains that contain a part of the constant region between the C H 1 and C H 2 domains. Therefore, an inter-chain disulfide bond is formed between the two heavy chains. Thus, the F(ab’)2 fragment is composed of two Fab’ fragments that are linked to each other by a disulfide bond between the two heavy chains.

[0057] The "Fv region" includes variable regions derived from both the heavy and light chains but lacks the constant regions.

[0058] The term "single-chain Fv" or "scFv" antibody means an antibody fragment that contains the V H and V L domains and these domains are present within a single polypeptide chain. Generally, the Fv polypeptide further includes a polypeptide linker between the V H domain and the V L domain that enables the scFv to form the desired structure for antigen binding. For an overview of scFv, see Pluckthun (1994) The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., Springer-Verlag, New York, pp. 269 - 315. Also see International Patent Application Publication No. WO88 / 01649, as well as U.S. Patent Nos. 4,946,778 and 5,260,203.

[0059] A "domain antibody" is an immunologically functional immunoglobulin fragment that contains only the variable region of the heavy chain or only the variable region of the light chain. In some cases, two or more V HThe region covalently binds to the peptide linker, creating a bivalent domain antibody. The two Vs of the bivalent domain antibody H The region can target the same or different antigens.

[0060] A "bivalent antibody" contains two antigen-binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody may be bispecific (see below).

[0061] In certain embodiments, the monoclonal antibodies described herein also include camelized single-domain antibodies. See, for example, Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO94 / 04678; WO94 / 25591; U.S. Patent No. 6,005,079. In one embodiment, the present invention relates to two V having modifications such that a single-domain antibody is formed. H We provide single-domain antibodies containing the domain.

[0062] As used herein, the term "diabody" refers to a small antibody fragment having two antigen-binding sites, where these fragments are located within the same polypeptide chain's light chain variable domain (V L ) connected to a heavy chain variable domain (V H )(V H -V L , or V L -V HThis includes ). By using a linker that is too short to allow pairing between two domains on the same chain, a domain can be paired with a complementary domain on another chain, generating two antigen-binding sites. Diabodies are described in more detail, for example, EP404,097, WO93 / 11161, and Hollinger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448. For a review of engineered antibody variants, see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136 in general.

[0063] Typically, variant antibodies or antigen-binding fragments of the antibodies provided herein retain at least 10% of their IGF-1R binding activity (compared to the modified parent antibody) when activity is expressed on a molar basis. In some embodiments, variant antibodies (or their antigen fragments) or antigen-binding fragments of the antibodies provided herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the same IGF-1R binding affinity as the parent antibody. As described herein, the antibodies or antigen-binding fragments of the present invention are also intended to include conservative or non-conservative amino acid substitutions that do not substantially alter the biological activity of the antibody, which may also be called “conservative variants” or “functionally preserved variants.”

[0064] "Isolated antibody" refers to a bound compound in a purified state, and in this context, means that the molecule substantially does not contain other biomolecules such as nucleic acids, proteins, lipids, carbohydrates, or other substances (such as cell debris and growth media). Generally, the term "isolated" is not intended to mean the complete absence of such substances, or the absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with the experimental or therapeutic use of the bound compound described herein.

[0065] As used herein, the term “monoclonal antibody” refers to a substantially homogeneous population of antibodies, i.e., the antibody molecules constituting the population have identical amino acid sequences, except for the slight possibility of spontaneously occurring mutations. In contrast, conventional (polyclonal) antibody preparations typically contain a number of different antibodies, often specific to different epitopes, and having different amino acid sequences in their variable domains (particularly the CDR). The modifier “monoclonal” indicates a characteristic of the antibody that it is obtained from a substantially homogeneous population of antibodies, and should not be interpreted as requiring the production of the antibody by any particular method. For example, the monoclonal antibodies used in this invention may be prepared by the hybridoma method first described in Kohler et al. (1975) Nature 256:495, or by the recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0066] As used herein, a “chimeric antibody” is an antibody having a variable domain derived from a first antibody and a constant domain derived from a second antibody, wherein the first and second antibodies originate from different species (U.S. Patent No. 4,816,567, and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). Typically, the variable domain is obtained from antibodies derived from laboratory animals such as rodents ("parent antibodies"), and the constant domain sequence is obtained from human antibodies. Therefore, the resulting chimeric antibodies are less likely to induce harmful immune responses in human subjects than parent (e.g., rodent) antibodies.

[0067] As used herein, the term “humanized antibody” refers to a form of antibody that contains sequences derived from both human and non-human (e.g., mouse, rat) antibodies. Generally, a humanized antibody contains substantially all of at least one, typically two, variable domains, all or substantially all of the hypervariable loops correspond to the hypervariable loops of a non-human immunoglobulin, and all or substantially all of the framework (FR) region is the FR of a human immunoglobulin sequence. A humanized antibody may optionally contain at least a portion of the constant region (Fc) of a human immunoglobulin.

[0068] The term "fully human antibody" refers to an antibody containing only human immunoglobulin protein sequences. Fully human antibodies may contain mouse glycans when produced from mice, mouse cells, or hybridomas derived from mouse cells. Similarly, "mouse antibody" refers to an antibody containing only mouse immunoglobulin sequences. Alternatively, fully human antibodies may contain rat glycans when produced from rats, rat cells, or hybridomas derived from rat cells. Similarly, "rat antibody" refers to an antibody containing only rat immunoglobulin sequences.

[0069] Generally, the basic antibody structural unit consists of a tetramer. Each tetramer is composed of two identical polypeptide chain pairs, each pair containing one "light chain" (approximately 25 kDa) and one "heavy chain" (approximately 50-70 kDa). The amino-terminus of each chain contains a variable region of approximately 100-110 or more amino acids, primarily involved in antigen recognition. The carboxyl-terminus of the heavy chain can define a constant region primarily involved in effector function. Typically, human light chains are classified as κ and λ light chains. Furthermore, human heavy chains are usually classified as μ, δ, γ, α, or ε, defining antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are linked by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 10 or more amino acids. Generally, Fundamental Immunology See Chapter 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989)).

[0070] The variable region of each light / heavy chain pair forms an antibody binding site. Therefore, generally, an intact antibody has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites are generally identical.

[0071] Typically, both the heavy and light chain variable domains contain three hypervariable regions, also known as complementarity-determining regions (CDRs), located within a relatively conserved framework region (FR). The CDRs are usually aligned by the framework region, enabling binding to specific epitopes. Generally, from the N-terminus to the C-terminus, both the light and heavy chain variable domains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignments to each domain are generally (unless otherwise specified) from *Sequences of Proteins of Immunological Interest*, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5 th ed.;NIH Publ.No.91-3242(1991);Kabat(1978)Adv.Prot.Chem.32:1-75;Kabat, et al.,(1977)J.Biol.Chem.252:6609-6616;Chothia,et al.,(1987)J Mol.Biol.196:901-917 or according to the definition of Chothia, et al., (1989) Nature342:878-883.

[0072] As used herein, the term “hypervariable region” refers to the amino acid residues of an antibody involved in antigen binding. The hypervariable region consists of amino acid residues from the “complementarity-determining region” or “CDR” (i.e., residues 24-34 (CDRL1), 50-56 (CDRL2), and 89-97 (CDRL3) in the light chain variable domain, and residues 31-35 (CDRH1), 50-65 (CDRH2), and 95-102 (CDRH3) in the heavy chain variable domain, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of This includes these residues from Health, Bethesda, Md., and / or from the “hypervariable loop” (i.e., residues 26–32 (CDRL1), 50–52 (CDRL2), and 91–96 (CDRL3) in the light chain variable domain and residues 26–32 (CDRH1), 53–55 (CDRH2), and 96–101 (CDRH3) in the heavy chain variable domain, Chothia and Lesk (1987) J.Mol.Biol.196:901–917). Those skilled in the art will understand that different numbering schemes, such as Kabat, IMGT, Chothia, and North / Dunbrack (North), may be used to define CDRs for a given amino acid variable region sequence. As used herein, the terms “framework” or “FR” residues refer to variable domain residues other than the hypervariable region residues defined herein as CDR residues. A CDR provides the majority of the contact residues necessary for an antibody to bind to an antigen or epitope. The CDRs in question may be derived from the variable heavy chain and variable light chain sequences of a donor antibody and may include analogs of spontaneously occurring CDRs, these analogs sharing or retaining the same antigen-binding specificity and / or neutralizing ability as the donor antibody from which they are derived.

[0073] Furthermore, in some embodiments, the antibody is specified by U.S. Patent No. or Publication No. US7,417,130, US2004 / 132094, US5,831,012, US2004 / 023334, US7,250,297, US6,818,418, US2004 / 209243, US7,838,629, US7,186,524, US6,004,746, US5,475, As described in 096, US2004 / 146938, US2004 / 157209, US6,994,982, US6,794,144, US2010 / 239633, US7,803,907, US2010 / 119446, and / or US7,166,697 (the entire contents of each of these are incorporated herein by reference), full-length antibodies, single domains These can take the form of antibodies, recombinant heavy chain-only antibodies (VHH), single-chain antibodies (scFv), shark heavy chain-only antibodies (VNAR), microproteins (cysteine ​​knot protein, nottin), DARPin; tetranectin; afibody; transbody; anticarin; adonectin; afirin; microbody; peptide aptamer; alterase; plastic antibody; phylomer; stradobody; maxibody; shrimpbody; finomer, armadillo repeat protein, Kunitz domain, avimer, atrimer, probody, immunobody, triomab, trobody; peptibody; baxisbody, unibody; afimer, duobody, Fv, Fab, Fab', F(ab')2, peptimimetic molecules, or synthetic molecules. See also Storz (2011) MAbs3(3):310-317, which is incorporated herein by reference. In some embodiments, antibodies can take the form of bispecific, tripspecific, multispecific antibodies, diabodies, triabodies, tetrabodies, minibodies, sterol regulatory binding protein cleavage activating proteins (Scap), chelated recombinant antibodies, intrabodies, or small module immunoassays (SMIPs), which can be collectively referred to as antibody forms.

[0074] The term “antigen,” as used herein, means any molecule that has the ability to produce an antibody, either directly or indirectly, or that binds to an antibody. The definition of “antigen” includes protein-coding nucleic acids. “Antigen” can also refer to an antibody binding partner. In some embodiments, the antigen is an IGF-1R protein expressed on the surface of a cell. In some embodiments, the cell is an intact cell. An intact cell is a cell that has been dissolved or destroyed with a detergent or other reagent and is not open. A cell that has been treated with a surfactant or other reagent that destroys or perforates the cell membrane is not an intact cell. For example, a method for producing an antibody that binds to an IGF-1R protein is provided herein, and the method comprises culturing a cell containing a nucleic acid molecule encoding an IGF-1R antibody.

[0075] As used herein, “specific binding,” “immunospecific binding,” or “immunospecific binding” refers to an antibody that binds to a given antigen (e.g., IGF-1R) or an epitope present on that antigen. In some embodiments, the antibody is 10 -7 Dissociation constants less than or equal to M (K D ) binds, but the K when binding to a nonspecific antigen other than the specified antigen (e.g., BSA, casein, or other nonspecific polypeptides) D K, at most half of D And it binds. The phrases “antibody that recognizes IGF-1R” and “antibody that is specific to IGF-1R” are used herein to mean the same thing as “antibody that binds immunospecifically to IGF-1R.” IGF-1R may be referred to in this disclosure. The degree of specificity required for an anti-IGF-1R antibody may depend on the intended use of the antibody and in any case is defined by its suitability for use for that intended use. In some embodiments, the antibody, or the conjugate compound derived from the antigen-binding site of the antibody, of the method under consideration binds to the antigen (IGF-1R) with an affinity at least twice, at least ten times, at least twenty times, or at least 100 times greater than its affinity to any other antigen.

[0076] Methods for measuring mAb specificity and affinity by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, (1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993), and Muller (1983) Meth. Enzymol. 92:589-601, all of which are incorporated herein by reference.

[0077] The term "homologous" refers to a protein sequence having 40% to 100% sequence homology or identity with respect to a reference sequence. The percentage of identity between two peptide chains can be measured by pairwise alignment using the AlignX module (Invitrogen Corp., Carlslbad, Calif.) of Vector NTI v.9.0.0 with default settings. In some embodiments, the antibody, or its antigen-binding fragment, has at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or identity with respect to the sequences described herein. In some embodiments, the antibody has conserved substitutions compared to the sequences described herein. Exemplary conserved substitutions are shown in Table 1, and these are within the scope of the subject matter disclosed. Conservative substitutions may be located within the framework region or within the antigen-binding site, provided that they do not adversely affect the properties of the antibody. Substitutions can be added to improve the properties of the antibody, such as stability or affinity. Conservative substitutions produce molecules that have similar functional and chemical properties to the molecule to which they are modified. Exemplary amino acid substitutions are shown in the table below. [Table 1]

[0078] In some embodiments, variants of proteins and peptides provided herein are provided. In some embodiments, the variants include substitutions, deletions, or insertions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) substitutions. The substitutions described herein may be conservative substitutions. In some embodiments, the substitutions are non-conservative. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) deletions. In some embodiments, the variants include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1 to 10) insertions. In some embodiments, the substitutions, deletions, or insertions are present in the CDRs provided herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided herein.

[0079] The term "in combination with" as used herein means that the described agents may be administered to an animal or subject together with a mixture, simultaneously as monotherapy, or sequentially as monotherapy in any order.

[0080] Techniques for producing antibodies and converting them into small peptide sequences that recognize and bind to sequences, whether presented as free, conjugated, or, in the case of large proteins, as natural sequences, are well known in the art. Examples of such antibodies include mouse, mouse-human, and human-human antibodies produced by hybridoma or recombinant techniques known in the art. Antibodies can also be produced from humans, mice, sheep, rats, rabbits, sharks, llamas, or chickens. In some embodiments, antibodies are produced from chickens. Antibodies can also be produced from humans or other small animals.

[0081] The term "epitope" refers to one or more antigen-binding regions of an antibody (Ab) that are capable of being recognized and bound by the antibody. Epitopes typically consist of chemically active surface classifications of molecules, such as amino acids or sugar side chains, and possess specific three-dimensional structural and charge properties. Examples of epitopes include, but are not limited to, the residues described herein that form the IGF-1R epitope. In some embodiments, epitopes are present only in undenatured proteins. In some embodiments, epitopes are present only in denatured proteins.

[0082] In some embodiments, the source of DNA encoding non-human antibodies may be an antibody-producing cell line, such as a hybrid cell line commonly known as a hybridoma.

[0083] Hybrid cells are formed by fusing non-human antibody-producing cells, typically spleen cells from animals immunized with either native or recombinant antigens, or peptide fragments of antigen protein sequences. Alternatively, the non-human antibody-producing cells can be B lymphocytes obtained from the blood, spleen, lymph nodes, or other tissues of animals immunized with the antigen.

[0084] The second fusion partner that confers immortalization function may be lymphoblastoma cells, plasmacytoma cells, or myeloma cells, which are malignant tumor cells, even though they themselves are not antibody-producing cells. Examples of fusion partner cells include, but are not limited to, the hybridoma SP2 / 0-Ag14, abbreviated as SP2 / 0 (ATCC CRL1581), and myeloma P3X63Ag8 (ATCC TIB9), or their derivatives. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference).

[0085] Antibodies can be produced according to the examples provided herein. Once the sequence is known, antibodies can also be produced according to known methods. Antibodies can also be converted to different types, for example, to human IgG. By converting antibodies to human antibodies, human subjects should not recognize the antibodies as foreign. Converting non-human IgG antibodies to human IgG antibodies is well known and can be done routinely once the natural sequence is known. As discussed herein, antibodies can be modified according to known methods. Such methods are described, for example, in Riechmann L et al., (1988) Reshaping human antibodies for therapy Nature 332(6162):332-323; Tsurushita N et al. (2004) J. Immunol. Methods 295(1-2):9-19. Antibody-producing cells involved in the nucleotide sequence encoding the antigen-binding region of a chimeric antibody can also be produced from non-human cells such as primate cells, or by transformation of human cells. For example, antibody-producing B lymphocytes can be transformed into immortal antibody-producing cells by infecting them with a virus such as the Epstein-Barr virus (Kozbor et al., (1983) Immunol. Today 4:72 79). Alternatively, B lymphocytes can be transformed by providing a transforming gene or a transforming gene product, as is well known in the art. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference). Cell fusion is achieved by standard procedures well known to those skilled in the field of immunology. Cell lines of fusion partners, as well as methods for fusing and selecting hybridomas and screening them against mAbs, are well known in the art. See, for example, Ausubel, Harlow, and Colligan (the entire contents of these references are incorporated herein by reference).

[0086] In some embodiments, the antibody is a MAb or antibody fragment, or a form, variant, or derivative thereof, and binds to IGF-1R. In some embodiments, the antibody (e.g., MAb or antibody fragment) binds to an amino acid of the IGF-1R epitope.

[0087] In some embodiments, the antibody includes the sequence provided herein.

[0088] Human IgG antibodies can be obtained by modifying the sequence of an antibody. Other types of antibodies can be obtained by modifying the sequence transformations provided herein. CDRs can also be conjugated to other antibodies, proteins, or molecules to create antibody fragments that bind to IGF-1R. These can exist in the form of antibody-drug conjugates ("ADCs"), multispecific molecules, or chimeric antigen receptors. The CDRs and antibody sequences provided herein can be humanized or fully human according to known methods. The sequences can also be used to form chimeric antibodies described herein.

[0089] In some embodiments, the antibody comprises an amino acid sequence or a fragment thereof containing a sequence provided herein. In some embodiments, the antibody comprises one or more amino acid sequences provided herein, their antigen-binding fragments, or their human IgG variants. "Their human IgG variants" means antibodies that have been modified to become human IgG if the starting antibody is not a human IgG antibody.

[0090] As described herein, the production of antibodies using known sequences is routine and can be carried out by any method. Accordingly, in some embodiments, nucleic acids encoding an antibody or a fragment thereof are provided. In some embodiments, the nucleic acid encodes a sequence provided herein. The antibody can also be modified to become a chimeric antibody or a human antibody. The antibody can also be used in injectable pharmaceutical compositions. Also as described herein, the antibody can be an isolated antibody or a manipulated antibody.

[0091] In some embodiments, the methods described herein involve the use or administration of an anti-IGF-1R antibody and its antigen-binding fragment, comprising any form, variant, or derivative thereof of the anti-IGF-1R antibody and its antigen-binding fragment.

[0092] In some embodiments, "derivatives" of antibodies, fragments, regions, or derivatives thereof are provided (this term includes proteins encoded by cleavage- or modification genes that produce molecular species functionally similar to immunoglobulin fragments). Modifications include, but are not limited to, the addition of gene sequences encoding cytotoxic proteins such as plant and bacterial toxins. Modifications may also include reporter proteins such as fluorescent or chemiluminescent tags. Fragments and derivatives can be prepared by any method.

[0093] In some embodiments, the antibody is a derivative of an antibody that binds to IGF-1R. In some embodiments, the antibody (e.g., an antibody derivative) binds to an amino acid of the IGF-1R epitope.

[0094] In some embodiments, the antibody is an antibody variant that binds to IGF-1R. In some embodiments, the antibody variant binds to an amino acid of the IGF-1R epitope.

[0095] In some embodiments, the antibody is any form of the antibody described herein. In some embodiments, the antibody form is bound to an amino acid of the IGF-1R epitope.

[0096] Identifying these antigen-binding regions and / or epitopes recognized by the Ab described herein provides the information necessary to generate further monoclonal antibodies with similar binding properties and therapeutic or diagnostic applicability comparable to the embodiments of this application.

[0097] The nucleic acid sequences encoding antibodies described herein may be genomic DNA or cDNA, or RNA (e.g., mRNA), encoding at least one of the variable regions described herein. A convenient alternative to the use of chromosomal gene fragments as a source of DNA encoding the V-region antigen-binding segment is the use of cDNA for constructing chimeric immunoglobulin genes, as reported by Liu et al. (1987) Proc. Natl. Acad. Sci. 84:3439 and Liu et al. (1987) J. Immunology 139:3521, which are incorporated herein by reference in their entirety. The use of cDNA requires that the gene be combined with gene expression elements suitable for the host cell in order to achieve the synthesis of the desired protein. The use of cDNA sequences is advantageous over genomic sequences (containing introns) in that cDNA sequences can be expressed in bacteria or other hosts lacking a suitable RNA splicing system.

[0098] For example, cDNA encoding a V-region antigen-binding segment capable of detecting, binding to, or neutralizing the IGF-1R antigen can be provided using known methods based on the use of amino acid sequences provided herein. Because the genetic code is degenerate, two or more codons can be used to encode a specific amino acid (Watson, et al., above). Using the genetic code, two or more different oligonucleotides can be identified, each capable of encoding that amino acid. The probability that a particular oligonucleotide effectively constitutes the actual XXX coding sequence can be estimated by considering the relationships of unusual base pairing and the frequency with which a particular codon is actually used (to encode a specific amino acid) in eukaryotic or prokaryotic cells expressing the antibody or fragment. Such “codon usage rules” are disclosed by Lathe et al. (1985) J. Molec. Biol. 183:1-12. Using Lathe’s “codon usage rules,” a single oligonucleotide or set of oligonucleotides containing the theoretically “most likely” nucleotide sequence capable of encoding the variable or constant region sequence of an antibody can be identified.

[0099] The variable regions described herein can be combined with any type of constant region, including human or mouse constant regions. Antibodies, fragments, and human genes encoding the constant (C) region of the region can be obtained from human fetal liver libraries by known methods. Human C region genes can be derived from any human cells, including those produced by expressing human immunoglobulins. H The region can originate from any known class or isotype of human heavy chains, including γ, μ, α, δ, or ε and their subtypes, e.g., G1, G2, G3, and G4. Since heavy chain isotypes are responsible for various effector functions of antibodies, C H The selection of the region is guided by the desired effector function, such as complement fixation or activity in antibody-dependent cell-mediated cytotoxicity (ADCC). Preferably, CH The region originates from γ1 (IgG1), γ3 (IgG3), γ4 (IgG4), or μ (IgM). Human C L The region may be derived from either the κ or λ of the human light chain isotype. In some embodiments, the antibody contains an Fc region domain. In some embodiments, the Fc domain contains a mutation that extends the half-life of the antibody. In some embodiments, the Fc domain contains a mutation such as that described in U.S. Patent No. 7,670,600, which is incorporated herein by reference in whole. In some embodiments, the constant region contains a mutation at the position of amino acid residue 428, corresponding to the wild-type human IgG constant domain, numbered according to Kabat's EU numbering index. Although not bound by any particular theory, an antibody containing a mutation corresponding to residue 428 may have an increased half-life compared to IgG with the wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of a native residue by threonine, leucine, phenylalanine, or serine. In some embodiments, the antibody further includes one or more amino acid substitutions compared to the corresponding wild-type human IgG constant domain at one or more amino acid residues numbered according to the Kabat EU numbering index, specifically at amino acid residues 251–256, 285–290, 308–314, 385–389, and 429–436. Specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is incorporated herein by reference in its entirety.

[0100] Genes encoding the human immunoglobulin C region can be obtained from human cells using standard cloning techniques (Sambrook et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987))). Human C region genes can be readily obtained from known clones containing two classes of light chains, five classes of heavy chains, and genes exhibiting these subclasses. Chimeric antibody fragments such as F(ab')2 and Fab can be prepared by designing appropriately cleaved chimeric heavy chain genes. For example, a chimeric gene encoding the heavy chain portion of the F(ab')2 fragment produces a cleavage molecule by including the CH1 domain and hinge region of the heavy chain, followed by a DNA sequence encoding a translation termination codon.

[0101] In some embodiments, the antibodies, mouse, human, humanized, or chimeric antibodies, antibody fragments, and regions described herein are cloned DNA segments encoding the H and L chain antigen-binding regions of IGF-1R antigen-specific antibodies, and these DNA segments are respectively C H and C L It is produced by binding it to a DNA segment that codes for a region, thereby generating a mouse, human, or chimeric immunoglobulin-coding gene.

[0102] Therefore, in some embodiments, a fusion chimeric gene is created that includes a first DNA segment encoding at least a non-human antigen-binding region, such as a functionally rearranged V region having a binding (J) segment, which is bound to a second DNA segment encoding at least a portion of the human C region.

[0103] Therefore, methods for producing antibodies according to some of the embodiments described herein, including cDNA encoding the V and C regions of antibodies, may involve several steps as illustrated below: 1. Isolating and cloning messenger RNA (mRNA) derived from an optional additional antibody, which is derived from a cell line producing an anti-IGF-1R antigen antibody and which gives rise to heavy chain constant regions and light chain constant regions, and producing cDNA therefrom; 2. Preparing a full-length cDNA library from purified mRNA in which appropriate V and / or C region gene segments of the L and H chain genes can be (i) identified with an appropriate probe, (ii) sequenced, and (iii) made compatible with a chimeric antibody with a C or V gene segment derived from another antibody; 3. Constructing a complete H or L chain coding sequence by ligating the cloned specific V region gene segment to the cloned C region gene as described above; and 4. Providing mouse-mouse, human-mouse, human-human, or human-mouse antibodies by expression and production of the L and H chains in a selected host, including prokaryotic and eukaryotic cells.

[0104] Two coding DNA sequences are said to be "operably ligated" if the ligation results in a continuous, translatable sequence without altering or interrupting the triplet reading frame. A DNA coding sequence is operably ligated to a gene expression element if the ligation results in the proper function of that gene expression element and leads to the expression of the coding sequence.

[0105] As used herein, and unless otherwise specified, the term “approximately” is intended to mean ±5% of the value it modifies. Thus, approximately 100 means between 95 and 105.

[0106] In some embodiments, the antibody described herein is used to detect the presence of the antigen. The antibody can be used with any device or method to detect the presence of the antigen.

[0107] The term "purified" when referring to antibodies means that they substantially contain other substances associated with the molecule in their natural environment. For example, purified protein substantially contains no cellular material or other proteins from the cells or tissues from which it originates. This term refers to preparations in which the isolated protein is pure enough to be analyzed, e.g., at least 70%–80% (w / w) pure, at least 80%–90% (w / w) pure, 90–95% pure; or at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure. In some embodiments, antibodies are purified.

[0108] Instead of preparing monoclonal antibody-secreting hybridomas, monoclonal antibodies against polypeptides can be identified and isolated by screening recombinant combinatorial immunoglobulin libraries (e.g., antibody-phage display libraries) with the polypeptides described herein, thereby isolating immunoglobulin library members that bind to the polypeptides. Techniques for generating and screening phage display libraries, and commercially available kits, are well known to those skilled in the art. Furthermore, examples of methods and reagents particularly suitable for generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Thus, other antibodies that can be used for therapeutic, diagnostic, or investigational purposes can be screened using the epitopes described herein.

[0109] Antibody conjugate

[0110] The antibodies provided herein may also be conjugated with a chemical moiety. The chemical moiety may, among other things, be a polymer, a radionuclide, or a cytotoxic factor. In some embodiments, this may be referred to as an antibody-drug conjugate. In some embodiments, the chemical moiety is a polymer that increases the antibody molecule's antibody content in the body of the subject. Suitable polymers include, but are not limited to, polyethylene glycol (PEG) (e.g., PEG with molecular weights of 2 kDa, 5 kDa, 10 kDa, 12 kDa, 20 kDa, 30 kDa, or 40 kDa), dextran, and monomethoxypolyethylene glycol (mPEG). Lee et al. (1999) (Bioconj.Chem.10:973-981) disclose PEG-conjugated single-chain antibodies. Wen et al. al. (2001) (Bioconj.Chem. 12:545-553) discloses the conjugation of antibodies with PEG conjugated to a radioactive metal chelator (diethylenetriaminepentaacetic acid (DTPA)). Examples of chemical components include, but are not limited to, antimitotic substances such as calicheamycin (e.g., ozogamicin), monomethyl auristatin E, and meltansine. Other examples include, but are not limited to, biologically active microtubule inhibitors, alkylating agents, and DNA sulcus binding agents. Further examples are shown herein and below. The chemical portion can be conjugated to an antibody via a linking group (maleimide), a cathepsin-cleaving linker (valine-citrulline), and, in some embodiments, one or more spacers (e.g., para-aminobenzylcarbamate). Although not bound by any particular theory, when the antibody conjugate binds to IGF-1R, the antibody conjugate can be internalized, and the chemical portion can kill cells or, in other cases, inhibit cell proliferation. In some embodiments, the cells are thyroid cells.

[0111] The antibodies and antibody fragments of the present invention are 99 Tc, 90 Y, 111 In,32 P, 14 C, 125 I, 3 H, 131 I, 11 C, 15 O, 13 N, 18 F, 35 S, 51 Cr, 57 To, 226 Ra, 60 Co, 59 Fe, 57 Se, 152 EU, 67 CU, 217 Carbon, 211 At, 212 Pb, 47 Sc, 109 Pd, 234 Th, as well as 40 K, 157 Gd, 55 Mn, 52 Tr and 56 It is also possible to conjugate the material using labels such as Fe.

[0112] Antibodies and antibody fragments include rare earth element chelates, fluorescein and its derivatives, rhodamine and its derivatives, isothiocyanates, phylcoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde, fluoresamine, 152 It is also possible to conjugate with fluorescent or chemiluminescent labels, including Eu, dansyl, umbelliferone, luciferin, luminal labels, isoluminal labels, aromatic acridinium ester labels, imidazole labels, acridimium salt labels, oxalate ester labels, aequorin labels, 2,3-dihydrophthalazinedione, biotin / avidin, spin labels, and fluorophores such as stable free radicals.

[0113] Antibody molecules can also be conjugated to cytotoxic factors such as diphtheria toxin, Pseudomonas aeruginosa exotoxin A chain, lysine A chain, abrin A chain, modesine A chain, alpha-sarcin, Aleurites fordii protein and composition (e.g., fatty acids), diansine protein, Phytoiacca americana protein PAPI, PAPII, and PAP-S, momordica charantia inhibitors, curcin, crotin, saponaria officinalis inhibitors, mitogen, restrictosin, phenomycin, and enomycin.

[0114] Any method known in the art for conjugating the antibody molecule of the present invention to various parts can be used, including the methods described by Hunter, et al., (1962) Nature 144:945; David, et al., (1974) Biochemistry 13:1014; Pain, et al., (1981) J. Immunol. Meth. 40:219; and Nygren, J., (1982) Histochem. and Cytochem. 30:407. Methods for conjugating antibodies are conventional and well known in the art.

[0115] Chimeric antigen receptor

[0116] The antibodies provided herein can, for example, be incorporated into a chimeric antigen receptor ("CAR") usable in CAR-T cells. In some embodiments, the extracellular domain of the CAR may be the antibody provided herein. In some embodiments, the antibody is in scFv form. CAR-T cells are a type of treatment in which a patient's T cells are modified to attack cells expressing IGF-1R. The cells are collected from the patient's blood. A special receptor that binds to a specific protein on the patient's cells is then added in the laboratory. In some embodiments, the receptor binds to IGF-1R using the binding region of the antibody provided herein. CAR-T cells containing the IGF-1R antibody can then be used to treat medical conditions such as those provided herein.

[0117] Anti-IGF-1R antibody In some embodiments, an antibody (e.g., an anti-IGF-1R antibody) is provided herein. In some embodiments, the antibody is a recombinant antibody that binds to the IGF-1R protein. In some embodiments, the IGF-1R protein is a human IGF-1R protein. In some embodiments, the IGF-1R protein recognized by the antibody is in its natural conformation (non-denatured conformation). In some embodiments, the antibody does not specifically bind to the denatured IGF-1R protein. As used herein, the term “recombinant antibody” means an antibody that does not exist naturally. In some embodiments, the term “recombinant antibody” means an antibody that has not been isolated from a human subject.

[0118] In some embodiments, the antibody comprises one or more peptides, or variants thereof, having the following sequence: [Table 2-1] [Table 2-2] [Table 2-3]

[0119] The VH and VL sequences may be in any form, but are not limited to, including the scFv form in which the VH and VL regions are linked by a peptide linker. An example of a peptide linker that can be used to link the various peptides provided herein is (GGGGS). n (Sequence ID 12); (GGGGA) n Examples include, but are not limited to, (SEQ ID NO: 13), or any combination thereof (where each n is independently 1 to 5). In some embodiments, the peptide linker is (GGGGS) n (Sequence ID 12), (GGGGA) n (Sequence ID 13), (GSTSGSGKPGSGEGSTKG) n The antibody comprises (SEQ ID NO: 26) or any combination thereof (where each n is independently 1 to 8). In some embodiments, the variable region is not linked by a peptide linker. In some embodiments, the antibody comprises or consists of polypeptides represented by SEQ ID NOs: 10 and 11. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 3, 4, 5, 6, 7, 8, and 9. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 27, 28, 6, 29, 30, and 31. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 4, 5, 6, 32, 33, and 9. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 4, 34, 6, 35, 36, and 31. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 18, 19, 20, 21, 22, and 23. In some embodiments, the antibody comprises polypeptides comprising SEQ ID NOs: 37, 28, 20, 38, 39, and 40. In some embodiments, the antibody comprises polypeptides including SEQ ID NOs. 18, 19, 20, 41, 42, and 23. In some embodiments, the antibody comprises polypeptides including SEQ ID NOs. 18, 43, 20, 44, 45, and 40. In some embodiments, an antibody or an antigen-binding fragment thereof is provided, where the antibody or antibody fragment comprises a peptide selected from the following table. [Table 3] [Table 4] [Table 5] [Table 6]

[0120] In some embodiments, the antibody comprises one or more peptides, or variants thereof, having the following sequence, each containing one or more variable domains (italicized) CDRs (italicized bold according to the Kabat numbering scheme) and a human IgG1 / kappa constant domain (underlined): [Table 7-1] [Table 7-2]

[0121] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs. 10 and 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO. 10. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 10. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 10. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 7, 8, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 29, 30, and / or 31 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 32, 33, and / or 9 as described above.In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 10 include the CDRs of sequence numbers 35, 36, and / or 31 as described above.

[0122] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 11. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 11. In some embodiments, sequences that are 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 5, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 5, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 27, 28, and / or 6 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 11 include the CDRs of sequence numbers 4, 34, and / or 6 as described above.

[0123] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 4, 5, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 7, 8, or 9.

[0124] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 4, LCDR2 has the sequence of SEQ ID NO: 5, and LCDR3 has the sequence of SEQ ID NO: 6.

[0125] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 7, HCDR2 has the sequence of SEQ ID NO: 8, and HCDR3 has the sequence of SEQ ID NO: 9.

[0126] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 27, 28, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 29, 30, or 31.

[0127] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 27, LCDR2 has the sequence of SEQ ID NO: 28, and LCDR3 has the sequence of SEQ ID NO: 6.

[0128] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 29, HCDR2 has the sequence of SEQ ID NO: 30, and HCDR3 has the sequence of SEQ ID NO: 31.

[0129] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 32, 33, or 9.

[0130] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 32, HCDR2 has the sequence of SEQ ID NO: 33, and HCDR3 has the sequence of SEQ ID NO: 9.

[0131] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 4, 34, or 6. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 35, 36, or 31.

[0132] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 4, LCDR2 has the sequence of SEQ ID NO: 34, and LCDR3 has the sequence of SEQ ID NO: 6.

[0133] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 35, HCDR2 has the sequence of SEQ ID NO: 36, and HCDR3 has the sequence of SEQ ID NO: 31.

[0134] Different CDR motifs can be combined in any combination, including those not shown in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0135] In some embodiments, the antibody or its antigen-binding fragment includes (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: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, 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: 7, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 9, or any of the above variants.

[0136] In some embodiments, the antibody or its antigen-binding fragment includes (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: 27, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, 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: 29, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 30, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31, or any of the above variants.

[0137] In some embodiments, the antibody or its antigen-binding fragment includes (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: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, 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: 9, or any of the above variants.

[0138] In some embodiments, the antibody or its antigen-binding fragment includes (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: 4, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 34, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 6, 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: 35, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 36, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 31, or any of the above variants.

[0139] In some embodiments, the antibody or its antigen-binding fragment is a light chain variable region comprising (i) light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 4, the light chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5, and the light chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 7, the heavy chain CDR2 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 8, and the heavy chain CDR3 sequence has an amino acid sequence that is 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 9, or any of the aforementioned variants.

[0140] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 7 The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 8; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 9. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0141] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 27, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 28 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 29. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 30; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 31. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0142] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 5 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 32. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 33; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 9. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0143] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 4, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 34 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 6. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 35. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 36; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 31. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0144] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs: 14 and 15. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO: 14. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 14. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 7, 8, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 29, 30, and / or 31 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 32, 33, and / or 9 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 14 include the CDRs of sequence numbers 35, 36, and / or 31 as described above.

[0145] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 15. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 15. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 15 include the CDRs of sequence numbers 4, 5, and / or 6 as described above.

[0146] In some embodiments, the antibody or its antigen-binding fragment or protein is specified to contain a peptide having the sequence described in any of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36.

[0147] In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy or light chain having the sequences of SEQ ID NOs. 24 and 25. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having the sequence of SEQ ID NO. 24. In some embodiments, the antibody or its antibody-conjugated fragment includes a heavy chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO. 24. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 21, 22, and / or 23 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 38, 39, and / or 40 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 41, 42, and / or 23 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 24 include the CDRs of sequence numbers 44, 45, and / or 40 as described above.

[0148] In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having the sequence of SEQ ID NO: 25. In some embodiments, the antibody or its antibody-conjugated fragment includes a light chain having a sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of SEQ ID NO: 25. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 18, 19, and / or 20 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 37, 28, and / or 20 as described above. In some embodiments, sequences that are 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the sequence of sequence number 25 include the CDRs of sequence numbers 18, 43, and / or 20 as described above.

[0149] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0150] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, wherein LCDR1 has the sequence of SEQ ID NO: 18, LCDR2 has the sequence of SEQ ID NO: 19, and LCDR3 has the sequence of SEQ ID NO: 20.

[0151] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 21, HCDR2 has the sequence of SEQ ID NO: 22, and HCDR3 has the sequence of SEQ ID NO: 23.

[0152] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 19, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 21, 22, or 23.

[0153] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 37, LCDR2 has the sequence of SEQ ID NO: 28, and LCDR3 has the sequence of SEQ ID NO: 20.

[0154] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 38, HCDR2 has the sequence of SEQ ID NO: 39, and HCDR3 has the sequence of SEQ ID NO: 40.

[0155] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 41, 42, or 23.

[0156] In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 41, HCDR2 has the sequence of SEQ ID NO: 42, and HCDR3 has the sequence of SEQ ID NO: 23.

[0157] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain CDR having the sequence of SEQ ID NO: 18, 43, or 20. In some embodiments, the antibody or its antibody-conjugated fragment comprises a heavy chain CDR having the sequence of SEQ ID NO: 44, 45, or 40.

[0158] In some embodiments, the antibody or its antibody-conjugated fragment comprises a light chain having LCDR1, LCDR2, and LCDR3, where LCDR1 has the sequence of SEQ ID NO: 18, LCDR2 has the sequence of SEQ ID NO: 43, and LCDR3 has the sequence of SEQ ID NO: 20.

[0159] In some embodiments, the antibody or antibody-conjugated fragment comprises a heavy chain having HCDR1, HCDR2, and HCDR3, where HCDR1 has the sequence of SEQ ID NO: 44, HCDR2 has the sequence of SEQ ID NO: 45, and HCDR3 has the sequence of SEQ ID NO: 40.

[0160] Different CDR motifs can be combined in any combination, including those not shown in the table above. For example, the following embodiments are provided as non-limiting examples of such combinations.

[0161] In some embodiments, the antibody or its antigen-binding fragment includes (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: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 19, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, 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: 21, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 22, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23, or any of the above variants.

[0162] In some embodiments, the antibody or its antigen-binding fragment includes (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: 37, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, 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 any of the above variants.

[0163] In some embodiments, the antibody or its antigen-binding fragment includes (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: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 19, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, 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: 41, the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 42, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 23, or any of the above variants.

[0164] In some embodiments, the antibody or its antigen-binding fragment includes (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: 18, the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 43, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 20, 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: 40, or any of the above variants.

[0165] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 18, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 19 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 21. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 22; the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 23; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 23. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0166] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 37, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 28 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 38. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 39; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 40. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0167] In some embodiments, the antibody or its antigen-binding fragment (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 37, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 28 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 41. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 42; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 23. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0168] In some embodiments, the antibody or its antigen-binding fragment is (i) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence that is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical to the amino acid sequence of SEQ ID NO: 43, and the light chain CDR2 has an amino acid sequence that is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 43 It has an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the light chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 20. (ii) a light chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and (ii) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 44. The amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR2 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 45; the amino acid sequences are 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, and the heavy chain CDR3 sequence is 80%, 81%, 82%, 83% identical to the amino acid sequence of SEQ ID NO: 40. A heavy chain variable region having an amino acid sequence that is 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or substantially 100% identical, or includes any of the aforementioned variants.

[0169] In some embodiments, the antibody or its antigen-binding fragment or protein is specified to contain a peptide having the sequence described in any of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 28, 37, 38, 39, 40, 41, 42, 43, 44, or 45.

[0170] In some embodiments, the methods described herein involve the use or administration of an anti-IGF-1R antibody and its antigen-binding fragment, comprising any form, variant, or derivative thereof of the anti-IGF-1R antibody and its antigen-binding fragment.

[0171] In some embodiments, the antibody or its antigen-binding fragment comprises one of the sequences or variants thereof described above.

[0172] In some embodiments, the anti-IGF-1R antibody includes the anti-IGF-1R antibody disclosed in WO2023 / 122714 (which is incorporated herein by reference in its entirety), or a variant thereof.

[0173] In some embodiments, the anti-IGF-1R antibody includes the anti-IGF-1R antibody disclosed in WO2023 / 133485 (which is incorporated herein by reference in its entirety), or a variant thereof.

[0174] In some embodiments, the anti-IGF-1R antibody includes the anti-IGF-1R antibody disclosed in WO2023 / 133486 (which is incorporated herein by reference in its entirety), or a variant thereof.

[0175] Pharmaceutical composition In some embodiments, an anti-IGF-1R antibody, or other proteins provided herein, or an antigen-binding fragment thereof, or other proteins provided herein, are mixed with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical or sterile composition of the antibody or other proteins provided herein. See, for example, Remington's Pharmaceutical Sciences and USPharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0176] Formulations of therapeutic and diagnostic agents can be prepared by mixing them with acceptable carriers, excipients, or stabilizers in the form of, for example, lyophilized powders, slurries, aqueous solutions, or suspensions (e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse See Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY. In some embodiments, the antibody is diluted to an appropriate concentration in a sodium acetate solution (pH 5-6), and NaCl or sucrose is added for tonicity. Additional active agents such as polysorbate 20 or polysorbate 80 may be added to improve stability.

[0177] The toxicity and therapeutic effects of antibody compositions administered alone or in combination with other active agents are, for example, LD 50 (50% lethal dose in the population) and ED 50 The dose effective for treatment in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index (LD50). 50 / ED 50 ) In certain embodiments, antibodies exhibiting a high therapeutic index are desirable. Data obtained from these cell culture assays and animal studies can be used to formulate a wide range of doses for use in humans. Such compound doses are preferably little to no toxicity and ED 50 It is within the circulating concentration range, including [the specified substance]. Depending on the dosage form and route of administration used, the dose may vary within this range.

[0178] In some embodiments, the composition of the present invention is administered to a subject in accordance with Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0179] Various methods of administration are possible. Preferred routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, transnasal, intraocular, aspiration, inhalation, topical, cutaneous, transdermal, or intraarterial.

[0180] In some embodiments, antibodies or their antigen-binding fragments may be administered by invasive routes such as injection. In some embodiments, antibodies or their antigen-binding fragments, or their pharmaceutical compositions, are administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly (e.g., into arthritis-affected joints), or by aspiration, aerosol delivery. Administration by non-invasive routes (e.g., orally, e.g., pills, capsules, or tablets) is also within the scope of these embodiments.

[0181] In some embodiments, the anti-IGF-1R antibody, or its antigen-binding fragment, is administered in combination with at least one additional therapeutic agent, such as any therapeutic agent used to treat thyroid eye disease, but is not limited to those described above. For example, in some embodiments, the anti-IGF-1R antibody, or its antigen-binding fragment, is administered in combination with at least one additional therapeutic agent, such as a therapeutic agent used to treat thyroid eye disease or symptoms associated with thyroid eye disease, but is not limited to those described above. Examples of such treatments and medications include antithyroid drugs, antidiabetic drugs, beta-blockers, immunosuppressants, propylthiouracil, methimazole, propranolol, atenolol, metoprolol, nadolol, corticosteroids, metformin, sulfonylurea, meglitinide, thiazolidinedione, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, regular insulin, insulin aspart, insulin glulisinide, insulin lispro, insulin isofen, insulin degludec, insulin detemir, insulin glargine, acarbose, miglitol, acebutrol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, nebivolol, penbutrol, pindolol, propranolol, sotalol, timolol, timolol ophthalmic drops. The solution may include, but is not limited to, sitagliptin, saxagliptin, linagliptin, alogliptin, dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, canagliflozin, dapagliflozin, empagliflozin, or any combination thereof.

[0182] The composition can be administered using medical devices known in the art. For example, the pharmaceutical composition of the present invention can be administered by injection using a subcutaneous needle, such as a pre-filled syringe or an auto-injector.

[0183] The pharmaceutical compositions may also be administered using needle-free subcutaneous injection devices, such as those disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824, or 4,596,556.

[0184] Pharmaceutical compositions can also be administered by intravenous infusion. Examples of well-known implant and module forms for administering pharmaceutical compositions include U.S. Patent No. 4,487,603, disclosing an implantable microinfusion pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,447,233, disclosing a drug infusion pump for delivering a drug at a precise infusion rate; U.S. Patent No. 4,447,224, disclosing a flow-changeable implantable infusion device for continuous drug delivery; and U.S. Patent No. 4,439,196, disclosing a permeable drug delivery system having multiple chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0185] Alternatively, antibodies can be administered locally rather than systemically, for example, by direct injection into the arthritis joint or pathogen-induced lesions identified by immunopathology, often in depot or sustained-release formulations. Furthermore, antibodies can be administered via targeted drug delivery systems within liposomes coated with tissue-specific antibodies that target, for example, the arthritis joint or pathogen-induced lesions identified by immunopathology. The liposomes are targeted to the affected tissue and selectively taken up by the affected tissue.

[0186] IGF-1R-related conditions and thyroid eye diseases As used herein, IGF-1R-related conditions refer to conditions resulting from changes in IGF-1R. These conditions include, but are not limited to, thyroid eye diseases and other conditions provided herein.

[0187] In some embodiments, methods are provided for treating, inhibiting, or relieving IGF-1R-related conditions. In some embodiments, the methods include administering an antibody or pharmaceutical composition described herein to a target to treat, inhibit, or relieve an IGF-1R-related condition. In some embodiments, the condition is as described herein. In some embodiments, IGF-1R-related conditions include thyroid-associated eye disease (TAO), also known as thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, thyroid dysfunction eye disease, autoimmune-associated eye disorders related to IGF-1R signaling, or inflammatory orbital disorders related to IGF-1R signaling. In some embodiments, IGF-1R-related conditions include thyroid eye disease (TED). In some embodiments, the condition is as described herein. In some embodiments, the IGF-1R-related condition is fibrosis.

[0188] For example, the methods described herein may be beneficial for the treatment of thyroid eye disease in patients (e.g., patients with chronic thyroid disease, patients with one or more symptoms of thyroid eye disease for at least 12 months, patients with inactive thyroid disease, or patients with a clinical activity score of 2 or less prior to treatment). Other exemplary methods described herein include the treatment of fibrosis.

[0189] thyroid eye disease In some embodiments, antibodies are provided for use in the treatment of subjects requiring treatment for thyroid-related eye diseases. In some embodiments, anti-IGF-1R antibodies are provided for use in the treatment of subjects requiring treatment for thyroid-related eye diseases.

[0190] In some embodiments, the patient has a moderate to severe thyroid eye disease. The severity of the disease can be measured in the following non-limiting embodiments. For example, for eyelid opening, the distance between the eyelid margins is measured (in mm) in the patient sitting relaxed and fixating on a distant object in the first eye position. Eyelid retraction can be assessed by measuring the eyelid opening (distance from the center of the pupil to the upper eyelid margin) along the midline of the pupil in the patient sitting relaxed and fixating on a distant object in the first eye position. For eyelid swelling, the measurement / assessment is either "absent / uncertain," "moderate," or "severe." Eyelid redness is either absent or present. Conjunctival redness is either absent or present. In some embodiments, conjunctival edema is either absent or present. In some embodiments, inflammation of the carncle or folds is either absent or present. In some embodiments, spontaneous posterior eye pain is either absent or present. In some embodiments, pain when attempting to move the eyes (e.g., gazing upwards, sideways, and downwards) is either absent or present. Exophthalmos is measured in millimeters for each individual patient using the same Hertel exophthalmosmeter and the same angular distance. Subjective diplopia is scored on a scale of 0 to 3 (0 = no diplopia; 1 = intermittent, i.e., diplopia in the first gaze position when tired or first waking up; 2 = indeterminate, i.e., diplopia in extreme gaze; 3 = constant, i.e., continuous diplopia in the first gaze position or reading gaze position). With respect to extraocular muscle infiltration, pull is measured in angles. Corneal infiltration is either absent / punctate or keratopathy / ulceration. Regarding optic nerve infiltration, i.e., most severe visual acuity, color vision, optic disc, and relative concentric pupillary impairment, the condition may be absent or present. In addition, if optic nerve compression is suspected, the visual field should be examined. In some embodiments, patients can be classified according to the following severity classification: for example, thyroid eye disease threatening the visual field: patients with optic neuropathy due to thyroid dysfunction (DON) and / or corneal damage. This category warrants immediate intervention.Moderate to severe thyroid eye disease: Patients who do not have visual field-threatening conditions that significantly impact their daily life, thus justifying the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe thyroid eye disease typically have one of the following: eyelid retraction of 2 mm or more, moderate or severe soft tissue infiltration, proptosis of 3 mm or more that is above average for their race and sex, or irregular or constant diplopia. Mild thyroid eye disease: Patients whose thyroid eye disease features have only a minimal impact on their daily life, and are not sufficient to justify immunosuppression or surgical treatment. These patients typically have only one or more of the following: slight eyelid retraction (<2 mm), mild soft tissue infiltration, proptosis less than 3 mm above average for their race and sex, transient or absent diplopia, and corneal exposure that responds to lubricants.

[0191] Active and inactive thyroid eye diseases Thyroid eye diseases can be described as “active” thyroid eye diseases or “inactive” thyroid diseases. In some embodiments, “active” and “inactive” thyroid diseases are based on differences in the Clinical Activity Score (CAS) values.

[0192] As used herein, the term Clinical Activity Score (CAS) refers to the protocol described and scored according to Table 8. According to this protocol, one point is awarded for the presence of each parameter evaluated in the following table. The sum of all points defines clinical activity and provides the CAS, where 0 or 1 represents inactive disease, and 7 represents severe active ophthalmopathy. [Table 8]

[0193] As shown in Table 8, CAS consists of seven components: spontaneous posterior ocular pain, pain when attempting to move the eye (up, side to side, and down), conjunctival redness, eyelid redness, conjunctival edema, carncle / fold swelling, and eyelid swelling. Each component is scored as present (1 point) or absent (0 points). The score in each efficacy assessment is the sum of all present items and is given on a range of 0 to 7, where 0 or 1 is inactive disease and 7 is severe active ophthalmopathy. A change of 2 points or more is considered clinically significant. In some embodiments, the subject's score improves by at least 2, 3, or 4 points. In some embodiments, the subject's score improves within 3 weeks from the first dose. In some embodiments, the subject's score improves within 6 weeks from the first dose.

[0194] Item 1, spontaneous orbital pain, involves pain or a feeling of pressure in or behind the eyeball. This pain may be caused by increased intraorbital pressure as the volume of orbital tissue increases due to excessive extracellular matrix synthesis, fluid retention, and cellular infiltration and swelling. Item 2, gaze-induced orbital pain, can be intraocular pain when looking up, down, or to the side, or when attempting to look; i.e., pain associated with upward, downward, or horizontal eye movements, or when attempting to move the eyes. This type of pain may be caused by stretching of inflamed muscles, particularly when attempting to gaze upward. A "stretching pain" is not likely to be caused by pressing on the eyeball, as it is predicted to be a sign of increased intraorbital pressure. Both types of pain may be relieved after anti-inflammatory treatment. Therefore, these types of pain are directly related to autoimmune inflammation in the orbit and are thus considered useful in evaluating TED activity.

[0195] Swelling in TED manifests as conjunctival edema (swelling of the conjunctiva), as well as swelling of the caruncle and / or crescent folds, as listed in item 6 of Table 8. Both are signs of TED activity. Swollen eyelids may be due to edema, prolapse of fat through the orbital septum, or fibrotic degeneration. In addition to swelling, other symptoms indicating active TED include redness and / or pain of the conjunctiva, eyelids, caruncle, and / or crescent folds.

[0196] In some embodiments, the patient has a clinical activity score (CAS) of approximately 0 to approximately 7. In some embodiments, the patient has a CAS of 2 or higher. In some embodiments, the patient has a CAS of 3 or higher. In some embodiments, the patient has a CAS of 4 or higher. In some embodiments, the patient has a CAS of 5 or higher. In some embodiments, the patient has a CAS of 6 or higher. In some embodiments, the patient has a CAS of 7. In some embodiments, the patient had a CAS of 0, 1, 2, 3, or 4 or higher before treatment. In some embodiments, the patient had a CAS of less than 2 before treatment. In some embodiments, the patient had a CAS of 2 to 4 before treatment. In some embodiments, the patient had a clinical activity score (CAS) greater than 3 before treatment.

[0197] In some embodiments, the subject had a CAS of 0, 1, 2, 3, or more than 4, or about 2 to about 4, before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2, 3, or 4 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 2 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 3 or more before administration of the pharmaceutical composition. In some embodiments, the subject had a CAS of 4 or more before administration of the pharmaceutical composition.

[0198] In some embodiments, the patient has exophthalmos (proptosis) of 3 mm or more and a CAS of about 0 to about 7.

[0199] In some embodiments, patients with thyroid eye disease (TED) also have inactive thyroid eye disease (TED). In some embodiments, patients with inactive thyroid eye disease (TED) had a clinical activity score (CAS) of 2 or less prior to treatment. In some embodiments, patients with inactive thyroid eye disease (TED) had a clinical activity score (CAS) of 0 or 1 prior to treatment.

[0200] In some embodiments, patients with thyroid eye disease (TED) had active thyroid eye disease (TED). In some embodiments, patients with thyroid eye disease (TED) had a clinical activity score (CAS) of 0, 1, 2, 3, or greater than 4, or about 2 to about 4. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) greater than 2 before treatment. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) greater than 3 before treatment. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) greater than 4 before treatment. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) greater than 5 before treatment. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) greater than 6 before treatment. In some embodiments, patients with active thyroid eye disease (TED) had a clinical activity score (CAS) of approximately 2 to 4 prior to treatment.

[0201] In some embodiments, patients with thyroid eye disease (TED) have one or more symptoms of TED. In some embodiments, one or more of the symptoms of TED are selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) of 3 mm or more, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia. In some embodiments, patients with TED have eyelid retraction greater than 2 mm. In some embodiments, patients with TED have exophthalmos (proptosis) of 3 mm or more. In some embodiments, patients with TED have exophthalmos (proptosis) that is 3 mm or more above the standard range for race and sex. In some embodiments, patients with thyroid eye disease (TED) have a clinical activity score (CAS) of approximately 0 to approximately 7. In some embodiments, patients with thyroid eye disease (TED) have indeterminate or constant diplopia. In some embodiments, patients with thyroid eye disease (TED) have indeterminate diplopia. In some embodiments, patients with thyroid eye disease (TED) have indeterminate diplopia. In some embodiments, patients with thyroid eye disease (TED) have indeterminate diplopia. In some embodiments, patients exhibit fibrosis.

[0202] chronic thyroid eye disease Thyroid eye disease has traditionally been described as progressing from an active and progressive stage (characterized by inflammation of orbital and external periorbital tissues) to a more stable, fibrous, chronic stage. Active TED is characterized by local inflammation of the conjunctiva, superficial vascular structures, orbital fat, eyelids, and extraocular muscles. The duration of active TED can be variable, sometimes lasting 1 to 3 years. Chronic TED develops when the autoimmune inflammation weakens, leaving sequelae such as orbital tissue hypertrophy and fibrosis and dysfunction of the tethered extraocular muscles. However, there is evidence that even patients with chronic TED may exhibit underlying inflammatory elements. Therefore, chronic TED may be characterized by the duration of symptoms (e.g., time since the first onset of symptoms) and / or by the severity of the disease based on one or more of the following criteria: (i) mild eyelid retraction of less than 2 mm (mild) or eyelid retraction of 2 mm or more (moderate to severe); (ii) mild soft tissue infiltration (mild) or moderate / severe soft tissue infiltration (moderate to severe); (iii) proptosis less than 3 mm above the racial and sex standard (mild) or proptosis 3 mm or more above the racial and sex standard (moderate to severe); (iv) no diplopia, or intermittent diplopia and lubricant-responsive corneal exposure (mild), or indeterminate or constant diplopia (moderate to severe); or optic neuropathy and / or corneal damage due to thyroid dysfunction that threatens the visual field (severe). Furthermore, chronic TED may be characterized by a fibrous component to the disease. However, patients with chronic TED may still experience inflammation. Therefore, patients with chronic TED may be further classified into active chronic TED (e.g., clinical activity score ≥ 3) or inactive chronic TED (e.g., clinical activity score < 3) based on the activity of the underlying disease.

[0203] In some embodiments, the patient suffers from chronic thyroid eye disease (TED). In some embodiments, the patient suffers from fibrosis associated with TED.

[0204] In some embodiments, a method for treating a patient with chronic thyroid eye disease is provided. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 12 months prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 1 year prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for more than 1 year prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 15 months prior to treatment. In some embodiments, the patient with thyroid eye disease has had one or more symptoms for at least 2 years prior to treatment.

[0205] In some embodiments, the patient has had one or more symptoms of thyroid eye disease for 2, 3, 4, 5, 6, or 7 years or for 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, or about 7 to about 8 years prior to administration of the first dose of the pharmaceutical composition provided herein. In some embodiments, the patient has had one or more symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 or 13 months prior to administering the dose of the pharmaceutical composition provided herein.

[0206] In some embodiments, the patient has inactive chronic TED. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of less than 2 prior to treatment. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of 1 or less prior to treatment. In some embodiments, the patient with inactive chronic TED had a clinical activity score (CAS) of 0 or 1 prior to treatment.

[0207] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 12 months (1 year) before initiating treatment according to the method described herein.

[0208] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 15 months, prior to initiating treatment according to the method described herein.

[0209] In the embodiments, the patient has a baseline CAS of 1 or less, and / or demonstrated signs and symptoms that have persisted for more than 2 years, prior to initiating treatment according to the method herein.

[0210] In some embodiments, the patient had active chronic TED. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 2 or higher before treatment. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 3 or higher before treatment. In some embodiments, the patient had inactive chronic TED had a clinical activity score (CAS) of 4 or higher before treatment.

[0211] In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than 12 months (1 year) prior to initiating treatment according to the method herein.

[0212] In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than 15 months before initiating treatment according to the method herein. In the embodiments, the patient has two or more baseline CASs and demonstrated signs and symptoms that have persisted for more than 15 months before initiating treatment according to the method herein. In the embodiments, the patient has two or more baseline CASs and / or demonstrated signs and symptoms that have persisted for more than 2 years before initiating treatment according to the method herein. In the embodiments, the patient has two or more baseline CASs and demonstrated signs and symptoms that have persisted for more than 2 years before initiating treatment according to the method herein.

[0213] Treatment methods using IGF-1R inhibitors The administration regimen is determined by several factors, including the serum or tissue metabolic rate of the therapeutic antibody, the severity of the symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of target cells within the biological matrix. Preferably, the administration regimen delivers enough therapeutic antibody to bring about improvement in the target condition while simultaneously minimizing undesirable side effects. Therefore, the amount of biological agent delivered is determined in part by the specific therapeutic antibody and the severity of the condition being treated. Guidance is available for selecting the appropriate dose of therapeutic antibodies (e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl.J.Med.344:783-792;Beniaminovitz et al.(2000)New Engl.J.Med.342:613-619;Ghosh et al.(2003)New Engl.J.Med.348:24-32;Lipsky et al.(2000)New Please refer to Engl.J.Med.343:1594-1602).

[0214] The determination of the appropriate dose is made by the clinician, for example, using parameters or factors known or suspected in the art to affect the treatment. Generally, the dose is started at a level somewhat below the optimal dose and then increased in small increments until the desired or optimized effect is achieved, relative to any negative side effects. Important diagnostic indicators include, for example, indicators of inflammatory symptoms or the amount of inflammatory cytokines produced. Generally, it is desirable that the biological agent used is derived from the same species as the animal being targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized, and fully human antibodies may be desirable.

[0215] Antibodies or antigen-binding fragments, including any form, variant, or derivative, can be provided by continuous infusion or in doses administered, for example, daily, 1 to 7 times a week, once a week, once every two weeks, once a month, once every two months, once every three months, once every six months, once a year, etc. Doses may be provided, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by aspiration. The total weekly dose is generally at least 0.05 μg / kg of body weight, more commonly at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / 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 (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. Neurosurg. Psych. 67:451-456; Portielji et al. (2003) Cancer See Immunol.Immunother.52:133-144). Doses may also be provided to achieve a predetermined target concentration of the antibody in the serum of the subject, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / ml or higher. In other embodiments, the fully human antibody is administered subcutaneously or intravenously on a basis of once a week, once every two weeks, "every four weeks", once a month, once every two months, or once every three months, at doses of 10, 20, 50, 80, 100, 200, 500, 1000, or 2500 mg / subject, or as otherwise provided herein.

[0216] As used herein, “inhibit,” “treat,” or “cure” includes slowing the progression of symptoms associated with a disorder and / or reducing the severity of symptoms of such disorder. These terms further include relieving existing, uncontrolled, or undesirable symptoms, preventing further symptoms, and relieving or preventing the underlying causes of such symptoms, including, for example, slowing or preventing the progression of the associated disease. Thus, these terms indicate that beneficial results are achieved in vertebrate subjects that have, or are likely to develop, a disorder, disease, or symptoms.

[0217] As used herein, the terms “therapeutic dose,” “therapeutic dosage,” and “effective dose” refer to the amount of an antibody or its antigen-binding fragment that, when administered alone or in combination with additional therapeutic agents to a cell, tissue, or subject, is effective in causing a measurable improvement in one or more symptoms of a disease or condition, or in the progression of such disease or condition. A therapeutic dose further refers to the amount of the binding compound sufficient to result in at least partial remission of symptoms, e.g., treatment, cure, prevention or remission of the associated condition, or acceleration of treatment, cure, prevention or remission of such condition, or prevention or delay of the progression of the associated condition. When applied to an individual active ingredient administered alone, a therapeutic dose refers to that ingredient only. When applied to a combination, a therapeutic dose refers to the combined amount of the active ingredients that produce a therapeutic effect, regardless of whether the combination is administered sequentially or simultaneously. In some embodiments, an effective dose of a therapeutic agent results in an improvement of at least 10%; typically at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably at least 50% in a diagnostic indicator or parameter. An effective amount can also result in an improvement in subjective indicators when assessing the severity of a disease using subjective indicators. In some embodiments, an effective therapeutic amount is an amount that can be used to treat or alleviate the medical condition provided herein.

[0218] The term “subject” as used throughout includes animals, including mammals (e.g., rats, mice, dogs, cats, rabbits), and any living organism, such as humans. A subject may also be referred to as a patient. In some embodiments, a subject is a “requiring” subject. A “requiring” subject is one that is identified as needing treatment for a medical condition requiring treatment, and whose treatment is for such a condition for a specific purpose. A medical condition may be, for example, any of the medical conditions described herein.

[0219] On the other hand, any isolated antibody or antigen-binding fragment capable of binding to the IGF-1R protein or an epitope on other proteins described herein and exhibiting inhibitory or therapeutic activity against IGF-1R in vitro and / or in vivo, thereby inhibiting IGF-1R function, is suitable as a therapeutic agent for treating IGF-1R-related conditions in humans and animals. These conditions include thyroid eye disease (TED), Graves' eye disease or ophthalmopathy (GO), thyroid-toxic exophthalmos, insufficient thyroid eye disease, autoimmune-related eye disorders associated with IGF-1R signaling, inflammatory orbital disorders associated with IGF-1R signaling, and thyroid-associated eye diseases (TAO), also known as other thyroid eye disorders, including chronic TED, which are associated with IGF-1R signaling. Therefore, methods for treating such conditions are also provided, comprising administering an antibody or antigen-binding fragment, including any form, variant, or derivative, to a subject having such a condition.

[0220] In some embodiments, the method includes administering an effective amount of one or more monoclonal antibodies or antigen-binding fragments of antibodies described herein to a susceptible subject or a subject exhibiting a condition in which IGF-1R is known or suspected to be the cause of the observed pathological condition. Any active form of antibody, including but not limited to scFV, Fab, and F(ab')2 fragments, and other forms of antibodies provided herein, may be administered.

[0221] In some embodiments, the antibody used is compatible with the recipient species so that the immune response to the antibody does not result in an unacceptably short circulating half-life, or does not induce an unacceptably strong immune response to the antibody in the subject.

[0222] Treatment of an individual may include administering a therapeutically effective amount of the antibodies described herein. The antibodies may be supplied in kits, such as those provided herein. The antibodies may be used or administered alone or in combination with other therapeutic agents, analgesics, or diagnostic agents, such as those provided herein. When a patient is provided with an antibody or fragment thereof that can bind to IGF-1R, or an antibody that can protect against IGF-1R, the disease state in the recipient patient and the dose of the active agent administered will vary depending on factors such as the patient's age, weight, height, sex, general condition, and medical history.

[0223] Antibodies capable of treating conditions related to IGF-1R activity, or usable to treat IGF-1R-related conditions, are intended to be provided to subjects in amounts sufficient to influence the alleviation, resolution, or remission of IGF-1R-related symptoms or conditions. Examples of such conditions include thyroid eye disease.

[0224] Accordingly, in some embodiments, methods are provided for treating subjects with IGF-1R-mediated disorders. In some embodiments, the method involves administering a pharmaceutical composition comprising an antibody or its antigen-binding fragment, including any form, variant, or derivative, as provided herein. In some embodiments, the disorder is thyroid eye disease (TED). As provided herein, the antibody or its antigen-binding fragment can be administered together with other therapeutic agents. These can be administered simultaneously or sequentially.

[0225] In some embodiments, an antibody, or its antigen-binding fragment, may be used to treat thyroid eye disease (also known as thyroid-associated eye disease (TAO) or Graves' eye disease or ophthalmopathy (GO)). In some embodiments, an antibody or its antigen-binding fragment can be used to treat thyroid-associated eye disease (TAO) or its symptoms, or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0226] In some embodiments, antibodies or their antigen-binding fragments can be used to treat toxic exophthalmos. In some embodiments, antibodies or their antigen-binding fragments can be used to treat toxic exophthalmos or its symptoms, or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0227] In some embodiments, antibodies or their antigen-binding fragments can be used to treat thyroid dysfunction ophthalmopathy. In some embodiments, antibodies or their antigen-binding fragments can be used to treat thyroid dysfunction ophthalmopathy or its symptoms, or to reduce its severity. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0228] In some embodiments, an antibody or its antigen-binding fragment can be used to treat autoimmune-related ocular disorders associated with IGF-1R signaling. In some embodiments, an antibody or its antigen-binding fragment can be used to treat or reduce the severity of autoimmune-related ocular disorders or their symptoms associated with IGF-1R signaling. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0229] In some embodiments, an antibody or its antigen-binding fragment can be used to treat inflammatory orbital disorders associated with IGF-1R signaling. In some embodiments, an antibody or its antigen-binding fragment can be used to treat or reduce the severity of inflammatory orbital disorders or their symptoms associated with IGF-1R signaling. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0230] In some embodiments, an antibody or its antigen-binding fragment can be used to treat IGF-1R signaling-related thyroid eye disorders, including chronic TED. In some embodiments, an antibody or its antigen-binding fragment can be used to treat or reduce the severity of IGF-1R signaling-related thyroid eye disorders (including chronic TED) or their symptoms. In some embodiments, the method involves using any form, variant, or derivative of the antibody or its antigen-binding fragment.

[0231] In some embodiments, methods or uses are provided for reducing exophthalmos in the eye in subjects with thyroid-associated eye disease (TAO).

[0232] In some embodiments, the subject is a subject that has been previously treated with an antibody different from those provided herein.

[0233] In some embodiments, methods or uses are provided for a clinical activity score (CAS) in subjects who have or are suspected of having thyroid-associated eye disease (TAO).

[0234] In some embodiments, a method or use is provided to reduce exophthalmos by at least 2 mm. In some embodiments, a method or use is provided to reduce exophthalmos by at least 3 mm. In some embodiments, a method or use is provided to reduce exophthalmos by at least 2-3 mm or 2-4 mm. In some embodiments, exophthalmos is reduced by at least 2, 3, or 4 mm. In some embodiments, the reduction in exophthalmos is observed within 3 weeks of administration of the first dose. In some embodiments, the reduction in exophthalmos is observed within 6 weeks of administration of the first dose.

[0235] In some embodiments, the subjects have a reduced clinical activity score (CAS) in subjects with thyroid-associated eye disease (TAO).

[0236] In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 2 mm. In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 3 mm. In some embodiments, the subject to be treated has exophthalmos that is reduced by at least 4 mm.

[0237] In some embodiments, the clinical activity score (CAS) of the treated subject decreases by at least 2 points. In some embodiments, the clinical activity score (CAS) of the subject decreases to (1). In some embodiments, the clinical activity score (CAS) of the subject decreases to zero (0).

[0238] In some embodiments, methods are provided for treating or reducing the severity of thyroid-associated eye disease (TAO) in a subject, wherein the treatment with the antibody (i) reduces proptosis in one eye by at least 2 mm; (ii) without worsening of 2 mm or more in the other eye; and (iii) reduces the CAS in the subject to 1 or 0.

[0239] In some embodiments, methods are provided to improve the quality of life in subjects with thyroid-associated eye disease (TAO, also known as Graves' eye disease). In some embodiments, quality of life is measured by the Graves' eye disease quality of life (GO-QoL) survey, or by either its visual functioning subscale or appearance subscale. In some embodiments, treatment results in an improvement of 8 points or more on the GO-QoL. In some embodiments, treatment results in an improvement on the GO-QoL functioning subscale. In some embodiments, treatment results in an improvement on the GO-QoL appearance subscale.

[0240] In some embodiments, a method for treating diplopia in subjects suffering from thyroid-associated eye disease (TAO), or a method for reducing the severity of TAO, is provided. In some embodiments, the diplopia is constant diplopia. In some embodiments, the diplopia is non-constant diplopia. In some embodiments, the diplopia is intermittent diplopia. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 20 weeks after discontinuation of antibody administration. In some embodiments, the improvement or reduction in the severity of diplopia lasts for at least 50 weeks after discontinuation of antibody administration. In some embodiments, the diplopia improves in subjects within 3 weeks or 6 weeks from the first dose.

[0241] In some embodiments, patients can be characterized by a Graves' Eye Disease Quality of Life (GO-QoL) score. In addition to exophthalmos (or proptosis) and CAS, quality of life is also investigated using the GO-QoL questionnaire. This questionnaire is designed to measure improved quality of life after treatment by the methods disclosed herein. In some embodiments, the questionnaire can measure the reduction or absence of side effects after treatment with antibodies or their antigen-binding fragments according to the methods disclosed herein, compared to treatment with glucocorticoids. GO-QoL is a 16-item self-administered questionnaire divided into two subsets, used to assess the perceived effects of TED by the subject in (i) their daily physical activity (as this activity relates to visual function) and (ii) psychosocial functioning. Quality of life is investigated using the GO-QoL questionnaire. The GO-QoL questionnaire [CBTerwee et al, 1998] is completed on day 1 of the treatment period, as well as at weeks 6, 12, and 24 (or PW), and at months 7 and 12 (or PW) during the follow-up period. The GO-QoL is a 16-item self-management questionnaire divided into two self-assessment subscales: one covering the impact of visual function on daily activities, and another assessing the impact on one's perceived appearance. The visual functioning subscale covers activities such as driving, walking outdoors, reading, and watching television. The appearance subscale asks questions such as whether the eye disease has altered the appearance of objects, whether it has caused others to react negatively to objects, whether it has caused social isolation, and whether it has caused objects to try to conceal their appearance. Each subscale has eight questions to be answered with "yes (strongly agree)," "yes (somewhat agree)," or "no (strongly disagree)." Each question was scored on a scale of 0 to 2, and the sum of these scores was then mathematically converted to a scale of 0 to 100, where 0 represents the greatest negative impact on quality of life and 100 represents no impact. A change of 8 points or more on the 0-100 scale has been shown to be clinically significant.The combined score utilizes the raw scores from both subscales and converts them back to a single 0-100 scale. The questionnaire has two self-assessment subscales. Each subscale has eight questions to be answered with (i) yes (strongly agree), (ii) yes (somewhat agree), or (iii) no (strongly disagree). Each question is scored from 0 to 2, and the sum of the raw scores is then mathematically converted to a 0-100 scale, where 0 represents the greatest negative impact on quality of life and 100 represents no impact. On the 0-100 scale, a change of more than 8 points is considered clinically significant. The combined score utilizes the raw scores from both subscales and converts them back to a single 0-100 scale.

[0242] Patients can also assess their diplopia based on the Gorman grading system. The subjective Gorman grading of diplopia includes four categories: no diplopia (absent), diplopia when the patient is tired or waking (intermittent), diplopia during extreme staring (undefined), and continuous diplopia in the primary or reading position (constant). Patients score according to the degree of diplopia they experience. An improvement of one degree or more is considered clinically significant.

[0243] Fibrosis In some embodiments, the methods described herein can treat fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the alleviation of fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the reversal of fibrosis (e.g., ocular fibrosis). In some embodiments, the therapeutic benefit is the prevention of fibrosis (e.g., ocular fibrosis) or the prevention of further fibrosis. In some embodiments, the therapeutic benefit of alleviation and / or reversal of ocular fibrosis is improved visual acuity. In some embodiments, the therapeutic benefit of alleviation and / or reversal of ocular fibrosis is the absence of further vision loss or worsening of symptoms (e.g., maintenance of visual acuity or the absence of further vision loss or impairment). In embodiments, treatment of ocular fibrosis results in improvement of diplopia and / or proptosis (e.g., as described herein). In embodiments, fibrosis (e.g., ocular fibrosis) is related to or caused by inflammation. In embodiments, fibrosis (e.g., ocular fibrosis) is related to or caused by an autoimmune disorder. In embodiments, fibrosis (e.g., ocular fibrosis) is associated with or resulting from thyroid eye disease. In embodiments, ocular fibrosis is fibrosis occurring around the extraocular muscles. In embodiments, fibrosis (e.g., ocular fibrosis) follows the inflammatory period of TED (e.g., fibrosis following active TED or fibrosis after inflammatory relapse in patients with chronic and / or inactive TED). Those skilled in the art will understand that various methods well known in the art may be used to assess changes in fibrosis (e.g., ocular fibrosis), including via biopsy and subsequent staining, or imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)). Further methods for diagnosing and / or characterizing fibrosis (e.g., ocular fibrosis) include dye-based angiography, optical coherence tomography (OCT), and OCT angiography (OCTA). Fibrosis may also be assessed using levels of inflammatory or fibrotic factors. In some embodiments, fibrosis is assessed through one or more of the following analyses: adenosine monophosphate-activated protein kinase (AMPK), fibronectin, alpha-SMA, and collagen staining.

[0244] A dosing regimen effective for treatment In some embodiments, the method comprises administering to a patient an IGF-1R inhibitor (e.g., an antibody such as those provided herein) in a dosing regimen effective for treatment. Exemplary dosages and dosing regimens effective for treatment are described herein.

[0245] In embodiments, the antibody is administered at a dosage of about 3.0 - 20.0 mg / kg (e.g., at a dosage of about 3.0 - 10.0 or about 10.0 - 20.0 mg / kg). In embodiments, the antibody is administered at a dosage of about 3.0 - 10.0 mg / kg. In embodiments, the antibody is administered at a dosage of about 3.0 - 20.0 mg / kg. In embodiments, the antibody is administered at a dosage of about 10.0 - 20.0 mg / kg.

[0246] In embodiments, the antibody is administered at a dosage of about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg. In embodiments, the antibody is administered at a dosage of about 3.0 mg / kg. In embodiments, the antibody is administered at a dosage of about 5.0 mg / kg. In embodiments, the antibody is administered at a dosage of about 10 mg / kg. In embodiments, the antibody is administered at a dosage of about 20 mg / kg.

[0247] In embodiments, the antibody is administered at a dosage of at least about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg. In embodiments, the antibody is administered at a dosage of at least about 3.0 mg / kg. In embodiments, the antibody is administered at a dosage of at least about 5.0 mg / kg. In embodiments, the antibody is administered at a dosage of at least about 10 mg / kg. In embodiments, the antibody is administered at a dosage of at least 20 mg / kg.

[0248] In embodiments, the antibody is administered at a dose of about 3.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, or about 20 mg / kg or less. In embodiments, the antibody is administered at a dose of about 3.0 mg / kg or less. In embodiments, the antibody is administered at a dose of about 5.0 mg / kg or less. In embodiments, the antibody is administered at a dose of about 10 mg / kg or less. In embodiments, the antibody is administered at a dose of about 20 mg / kg or less.

[0249] In some embodiments, the pharmaceutical composition comprising the antibody is administered at a dose of about 10 mg / kg. In some embodiments, the pharmaceutical composition administered at a dose of about 10 mg / kg is administered to the patient every 21 days. In some embodiments, the pharmaceutical composition is administered at a dose of about 10 mg / kg and a total of about 4 to about 8 doses, about 4, about 5, about 6, about 7, or about 8 doses are administered to the patient every 21 days.

[0250] In some embodiments, the pharmaceutical composition comprising the antibody is administered at a dose of about 3 mg / kg. In some embodiments, the pharmaceutical composition administered at a dose of about 3 mg / kg is administered to the patient every 21 days. In some embodiments, the pharmaceutical composition is administered at a dose of about 3 mg / kg and a total of about 4 to about 8 doses, about 4, about 5, about 6, about 7, or about 8 doses are administered to the patient every 21 days.

[0251] In embodiments, a therapeutically effective dosing regimen comprises administration of one or more doses (e.g., one or more doses of the antibodies described herein) to a patient.

[0252] In embodiments, a therapeutically effective dosing regimen comprises administration of a first dose (e.g., any dose of the antibodies described herein) to a patient. In embodiments, a therapeutically effective dosing regimen comprises administration of subsequent dose(s) (e.g., any dose of the antibodies described herein) to a patient. In embodiments, the first dose is the same amount as the subsequent dose. In embodiments, the first dose is a different amount than the subsequent dose. In embodiments, the first dose is a greater amount than the subsequent dose. In embodiments, the first dose is a lesser amount than the subsequent dose.

[0253] In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 2 to 6 weeks. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 1 month, once every 5 weeks, or once every 6 weeks. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 2 weeks. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 3 weeks. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 4 weeks. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 1 month. In the embodiments, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every 5 weeks. In the embodiment, the subsequent dose (for example, of the antibody described herein) is administered to the patient once every six weeks.

[0254] In some embodiments, the method includes administering a dose to the patient approximately every 21 days. In some embodiments, the patient is administered at least five consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days. In some embodiments, the dose is administered every 21 days. In some embodiments, the patient is administered at least five consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days or every 21 days. In some embodiments, the patient is administered at least eight consecutive doses of the pharmaceutical composition, each dose administered approximately every 21 days, including every 21 days.

[0255] In one embodiment, the patient is administered at least 3 to 10 subsequent doses. In another embodiment, the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses. In one embodiment, the patient is administered at least 3 subsequent doses. In another embodiment, the patient is administered at least 4 subsequent doses. In another embodiment, the patient is administered at least 5 subsequent doses. In another embodiment, the patient is administered at least 6 subsequent doses. In another embodiment, the patient is administered at least 7 subsequent doses. In another embodiment, the patient is administered at least 8 subsequent doses. In another embodiment, the patient is administered at least 9 subsequent doses. In another embodiment, the patient is administered at least 10 subsequent doses.

[0256] In the embodiment, the patient is administered a subsequent dose of 3 to 10. In the embodiment, the patient is administered a subsequent dose of 3, 4, 5, 6, 7, 8, 9, or 10. In the embodiment, the patient is administered a subsequent dose of 3. In the embodiment, the patient is administered a subsequent dose of 4. In the embodiment, the patient is administered a subsequent dose of 5. In the embodiment, the patient is administered a subsequent dose of 6. In the embodiment, the patient is administered a subsequent dose of 7. In the embodiment, the patient is administered a subsequent dose of 8. In the embodiment, the patient is administered a subsequent dose of 9. In the embodiment, the patient is administered a subsequent dose of 10.

[0257] In the embodiment, a total dose of at least 3 to 10 (of the antibodies described herein, for example, 5 to 10 or 5 to 8) is administered to the patient. In the embodiment, a total dose of at least 3, 4, 5, 6, 7, 8, 9, or 10 (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of at least 4 to 8 (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of at least 5 to 8 (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of 4, 5, 6, 7, 8, 9, or 10 or less (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of 3, 4, 5, 6, 7, 8, 9, or 10 (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of 5, 6, 7, 8, 9, or 10 or less (of the antibodies described herein) is administered to the patient. In the embodiment, a total dose of 3, 4, 5, 6, 7, 8, 9, or 10 (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 4 to 8 or less (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 5 to 8 or less (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 4 to 8 (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 5 to 8 (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 5 (of the antibody described herein) is administered to the patient. In the embodiment, a total dose of 8 (of the antibody described herein) is administered to the patient.

[0258] In embodiments, an effective therapeutic regimen includes the administration of a first dose (e.g., of the antibody described herein) and subsequent doses 3 to 7 (e.g., of the antibody described herein) so that a total dose of 4 to 8 (e.g., of the antibody described herein) is administered to the patient. In embodiments, an effective therapeutic regimen includes the administration of a first dose (e.g., of the antibody described herein) and subsequent doses 4 to 7 (e.g., of the antibody described herein) so that a total dose of 5 to 8 (e.g., of the antibody described herein) is administered to the patient. In embodiments, the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg, and / or subsequent doses (e.g., each of the subsequent doses 3 to 7) are 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg. In this embodiment, the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg, and / or the subsequent doses (e.g., each of the subsequent doses 4-7) are 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg. In this embodiment, the first dose of the antibody described herein is 10 mg / kg, and / or the subsequent doses of the antibody described herein (e.g., each of the subsequent doses 3-7) are 10 mg / kg or 20 mg / kg. In this embodiment, the first dose of the antibody described herein is 10 mg / kg, and / or the subsequent doses of the antibody described herein (e.g., each of the subsequent doses 4-7) are 10 mg / kg or 20 mg / kg.

[0259] In some embodiments, the antibody is administered as a first dose in a dose of 1 mg / kg to approximately 5 mg / kg. In some embodiments, the antibody is administered as a first dose in a dose of 5 mg / kg to approximately 10 mg / kg. In some embodiments, the antibody is administered as a subsequent dose in a dose of 5 mg / kg to 20 mg / kg. In some embodiments, the antibody is administered as a first dose of 10 mg / kg and as a subsequent dose of 10 mg / kg. In some embodiments, the antibody is administered as a first dose of 10 mg / kg and as a subsequent dose of 20 mg / kg.

[0260] In this embodiment, the first dose of the antibody described herein is 10 mg / kg, and the subsequent doses of the antibody described herein (e.g., each of the subsequent doses 3 to 7) are 10 mg / kg.

[0261] In this embodiment, the first dose of the antibody described herein is 10 mg / kg, and the subsequent doses of the antibody described herein (e.g., each of the subsequent doses 4 to 7) are 10 mg / kg.

[0262] In some embodiments, the first dose of the antibody described herein is 10 mg / kg, and the subsequent doses of the antibody described herein (e.g., each of the subsequent doses 4-7) are 20 mg / kg. In some embodiments, the subsequent doses are administered every 3 weeks for at least 12 weeks.

[0263] The doses described herein may be administered according to methods known in the art. Exemplary routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, transnasal, intraocular, aspiration, inhalation, topical, cutaneous, transdermal, or intra-arterial. In some embodiments, the subsequent dose is administered every three weeks for at least 12 weeks. In some embodiments, the subsequent dose is administered every three weeks for at least 21 weeks.

[0264] In some embodiments, the dose is administered by intravenous fluid, intravenous, or subcutaneous administration. In some embodiments, the dose is administered intravenously, such as by intravenous fluid.

[0265] In some embodiments, the method comprises administering an anti-IGF-1R antibody at a dose of 10 mg / kg intravenously to a subject regularly for a period sufficient to alleviate one or more symptoms associated with a thyroid eye disease (e.g., chronic thyroid eye disease), wherein the anti-IGF-1R antibody comprises a heavy chain containing HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and a light chain containing LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. In some embodiments, the anti-IGF-1R antibody comprises a light chain and a heavy chain, wherein the light chain comprises a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain comprises a variable region having the amino acid sequence of SEQ ID NO: 3. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 10, and the light chain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-IGF-1R antibody is administered by intravenous infusion. In some embodiments, the anti-IGF-1R antibody is administered every three weeks. In some embodiments, the anti-IGF-1R antibody is administered for a sufficient period of time to reach four doses. In some embodiments, the anti-IGF-1R antibody is administered for a sufficient period of time to reach five doses. In some embodiments, the anti-IGF-1R antibody is administered for a sufficient period of time to reach eight doses. In some embodiments, the anti-IGF-1R antibody is administered for a period of time selected from three weeks, six weeks, nine weeks, twelve weeks, fifteen weeks, eighteen weeks, twenty-one weeks, twenty-four weeks, or longer.

[0266] Effectiveness The methods described herein may provide therapeutic benefits to patients. In embodiments, the therapeutic benefits are evaluated in comparison to a baseline (e.g., evaluated before initiating a therapeutically effective drug regimen, as described herein). For example, non-limiting therapeutic effects of the claimed methods include treatment of exophthalmos (proptosis), treatment of diplopia, and / or reduction of clinical activity score (CAS).

[0267] In embodiments, therapeutic advantages are observed for one or more of proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total score of quality of life in Graves' ophthalmopathy (GO-QoL), activity subscale of GO-QoL, appearance subscale of GO-QoL, visual acuity (VA), and Gorman subjective diplopia score (diplopia score).

[0268] In embodiments, the degree of thyroid eye disease (e.g., proptosis) is a comparison to the standard range by race and gender.

[0269] In embodiments, a patient has one or more of the following symptoms of thyroid eye disease: eyelid retraction of more than 2 mm, exophthalmos (proptosis) of 3 mm or more, clinical activity score (CAS) of about 0 to about 7, variable or constant diplopia, or any combination thereof.

[0270] In some embodiments, exophthalmos (proptosis) exceeds the standard range by race and gender by 3 mm or more.

[0271] In embodiments, the methods described herein provide a therapeutic advantage for one or more of the components of CAS.

[0272] In embodiments, a patient has a reduction in exophthalmos of 2 mm or more from baseline (e.g., in the most proptotic eye). In embodiments, the reduction is measured by exophthalmometry or MRI / CT. In embodiments, the reduction is determined at week 15 from baseline. In embodiments, week 15 from baseline is also 3 weeks after the 5th total dose in the dosing regimen. In embodiments, a patient has a reduction in exophthalmos of 2 mm or more from baseline in the most proptotic eye. In embodiments, the reduction in exophthalmos in the most proptotic eye occurs without a corresponding increase of 2 mm or more in the other eye.

[0273] In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–3 mm, 1–2 mm, and 2–3 mm of exophthalmos from baseline (as measured, for example, by exophthalmos measurement or MRI / CT).

[0274] In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.2 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.3 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.4 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.5 mm to approximately -2 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.3 mm to approximately -1.8 mm. In some embodiments, patients with chronic TED and a CAS of 0 or 1 have a reduction in exophthalmos of approximately -1.1 mm, -1.2 mm, -1.3 mm, -1.4 mm, -1.5 mm, -1.6 mm, -1.7 mm, -1.8 mm, -1.9 mm, or -2.0 mm. In some embodiments, the reduction occurs within 6 weeks of administration of the first dose. In some embodiments, the reduction occurs after the patient has received two doses. In some embodiments, the dose is approximately 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each of the doses administered to the patient is the same.

[0275] In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–3 mm, 1–2 mm, and 2–3 mm of exophthalmos from baseline within 6 weeks of the first dose (as measured, for example, by exophthalmos measurement or MRI / CT). In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–3 mm of exophthalmos from baseline within 6 weeks of the first dose (as measured, for example, by exophthalmos measurement or MRI / CT). In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–2 mm of exophthalmos from baseline within 6 weeks of the first dose (as measured, for example, by exophthalmos measurement or MRI / CT). In the embodiment, administration of an effective drug regimen results in a reduction of approximately 2–3 mm of exophthalmos from baseline within 6 weeks of the first dose (as measured, for example, by exophthalmos measurement or MRI / CT).

[0276] In the embodiment, administration of an effective drug regimen results in a reduction of approximately 1–3 mm, 1–2 mm, and 2–3 mm of exophthalmos from baseline within 6 weeks of the first dose, as measured by exophthalmoscopy or MRI / CT. In the embodiment, exophthalmos decreases by approximately 2–3 mm from baseline within 6 weeks of the first dose, as measured by exophthalmoscopy or MRI / CT.

[0277] In some embodiments, exophthalmos in subjects with chronic thyroid eye disease decreases by approximately 1–3 mm, 1–2 mm, or 2–3 mm from baseline, as measured by exophthalmoscopy or MRI / CT. In some embodiments, exophthalmos decreases by approximately 2–3 mm from baseline, as measured by exophthalmoscopy or MRI / CT. In some embodiments, the decrease is observed within or after 6 weeks following the administration of the first dose. In some embodiments, the decrease is observed after the administration of two doses. In some embodiments, the dose is approximately 3 mg / kg or 10 mg / kg, or other doses as provided herein. In some embodiments, each of the doses administered to the patient is the same.

[0278] In embodiments, administration of a therapeutically effective drug regimen results in the therapeutic benefit of no worsening of CAS from baseline. In embodiments, non-worsening occurs without a corresponding increase of 2 points or more in the other eye. In embodiments, administration of a therapeutically effective drug regimen results in a decrease in CAS from baseline (e.g., a decrease in CAS, or 1, 2, or 3). In embodiments, the decrease occurs without a corresponding increase of 2 points or more in the other eye. In embodiments, administration of a therapeutically effective drug regimen results in the therapeutic benefit of no worsening of CAS from baseline, with a baseline CAS of 0 or 1. In embodiments, administration of a therapeutically effective drug regimen results in the therapeutic benefit of a CAS of 0. In embodiments, administration of a therapeutically effective drug regimen results in the therapeutic benefit of a CAS of 1. In embodiments, administration of a therapeutically effective drug regimen results in the therapeutic benefit of a CAS decrease of 2 or more from baseline.

[0279] In this embodiment, the administration of a therapeutically effective medication regimen provides the therapeutic benefit of treating diplopia. In this embodiment, the treatment of diplopia is evaluated using a change in the Gorman subjective diplopia score (diplopia score), which ranges from 0 to 3 and includes the following four categories: • No double vision (not present, scored as 0) • Participants exhibiting diplopia (intermittent, scored as 1) in the primary gaze position when tired or waking up. • Double vision during extreme staring (undefined, scored as 2) • Continuous diplopia in the primary or reading eye position (constant, scored as 3).

[0280] In the embodiment, a patient having a baseline diplopia score greater than 0 will have their diplopia score reduced to 0 after initiation of treatment according to the method described herein.

[0281] In the embodiment, the therapeutic benefit is a change of 8 points or more in the total score on the Graves' Eye Disease Quality of Life (GO-QoL) questionnaire, on a scale of 0 to 100 or on an individual subscale (e.g., the GO-QoL activity subscale or the GO-QoL appearance subscale).

[0282] In the embodiment, therapeutic benefits are observed with respect to one or more of the following: extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, and visual acuity (VA).

[0283] In some embodiments, the patient achieves improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total score of Graves' ophthalmopathy quality of life (GO-QoL), GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and the EQ-5D-5L QoL questionnaire. In some embodiments, the patient achieves improvement in at least two or more parameters. In some embodiments, the patient achieves improvement in at least three or more parameters. In some embodiments, the patient achieves improvement in at least four or more parameters.

[0284] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are realized within 3 to 52 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are realized within 6, 9, 12, 15, 18, 21, 24, 36, or 52 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are realized at 6, 9, 12, 15, 18, 21, 24, 36, or 52 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within or within 6 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within or within 9 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within or within 12 weeks from the start of treatment (baseline). In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within 15 weeks of the start of treatment (baseline) or within 15 weeks. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within 18 weeks of the start of treatment (baseline) or within 18 weeks.In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within 21 weeks from the start of treatment (baseline), or at 21 weeks. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within 24 weeks from the start of treatment (baseline), or at 24 weeks. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are obtained within 36 weeks from the start of treatment (baseline), or at 36 weeks. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are delivered within 52 weeks from the start of treatment (baseline).

[0285] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the first dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) are brought about after subsequent doses. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the second total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the third total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the fourth total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the fifth total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the sixth total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear after the seventh total dose. In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia, as described herein) appear after the eighth total dose.

[0286] In embodiments, the therapeutic benefit (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appears after the final dose in an effective drug regimen. In embodiments, the final dose is the fourth total dose. In embodiments, the final dose is the fifth total dose. In embodiments, the final dose is the sixth total dose. In embodiments, the final dose is the seventh total dose. In embodiments, the final dose is the eighth total dose. In embodiments, the therapeutic benefit appears 15 weeks after baseline.

[0287] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia, as described herein) appear from baseline at 9 weeks or after 9 weeks.

[0288] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia, as described herein) appear from baseline to 12 weeks or after 12 weeks.

[0289] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia, as described herein) appear from baseline to 15 weeks or after 15 weeks.

[0290] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia, as described herein) appear from baseline to 21 weeks or after 21 weeks.

[0291] In embodiments, the therapeutic benefits (for example, in exophthalmos (proptosis), CAS, and / or diplopia as described herein) appear from baseline to 24 weeks or after 24 weeks.

[0292] In some embodiments, the subject's clinical activity score decreases after the first dose of the antibody. In some embodiments, the subject's clinical activity score decreases after the second dose of the antibody.

[0293] In some embodiments, subjects with chronic thyroid eye disease do not experience any serious adverse events after administration of the antibody. In some embodiments, subjects with chronic thyroid eye disease do not experience any serious adverse events resulting from the administration of the antibody. In some embodiments, patients do not experience any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition. In some embodiments, patients do not experience any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events resulting from the administration of the pharmaceutical composition.

[0294] In some embodiments, the patient does not experience any adverse events related to IV infusion after administration of the pharmaceutical composition. In some embodiments, the patient does not experience any adverse events related to IV infusion resulting from the administration of the pharmaceutical composition.

[0295] In some embodiments, patients do not experience any adverse events such as muscle spasms after administration of the pharmaceutical composition. In some embodiments, patients do not experience any adverse events such as muscle spasms resulting from the administration of the pharmaceutical composition.

[0296] In some embodiments, the patient does not experience any gastrointestinal adverse events (e.g., diarrhea or exacerbation of pre-existing inflammatory bowel disease (IBD)) after administration of the pharmaceutical composition.

[0297] In some embodiments, the antibody is administered in a pharmaceutical composition such as those provided herein. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically active compounds for the treatment of TAO. In some embodiments, the pharmaceutical composition further comprises a corticosteroid; rituximab or other anti-CD20 antibody; tocilizumab or other anti-IL-6 antibody; or selenium, infliximab or other anti-TNF-alpha antibody, or a thyroid-stimulating hormone receptor (TSHR) inhibitor.

[0298] Kits useful for carrying out the embodiments described herein are also provided. These kits include a first container containing, or packaged with, the antibody described above. The kit may also include another container containing, or packaged with, any associated solutions necessary or convenient for carrying out the embodiments. The containers may be made of glass, plastic, or foil, and may be vials, bottles, pouches, tubes, bags, etc. The kit may also include written information, such as procedures or analytical information for carrying out the embodiments, including the amount of reagent contained in the first container. The kit may also include a delivery device and instructions for using the delivery device. The containers, along with the written information, may be contained in another container device, such as a box or bag.

[0299] A kit for detecting the IGF-1R protein in biological samples is provided in yet another aspect of this specification. The kit includes a container holding one or more antibodies that bind to the epitope of the IGF-1R protein, and instructions for using the antibodies to bind to the IGF-1R protein to form an immunological complex, and for detecting the formation of the immunological complex such that the presence or absence of the immunological complex correlates with the presence or absence of the IGF-1R protein in the sample. An example of a container is a multiwell plate that allows for the simultaneous detection of the IGF-1R protein in multiple samples.

[0300] In some embodiments, an antibody that binds to the IGF-1R protein is provided. In some embodiments, the antibody is isolated. In some embodiments, the antibody binds specifically. In some embodiments, the antibody binds to a properly folded IGF-1R protein. In some embodiments, the antibody is specific to a particular IGF-1R conformational state (open or closed). In some embodiments, the antibody binds to the IGF-1R protein in the cell membrane. In some embodiments, the antibody binds to the IGF-1R protein in the cell membrane within an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of the IGF-1R protein. As used herein, the term “neutralizes” means that the activity or function of the protein is inhibited. The inhibition may be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The inhibition rate may be relative to the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits glucose transport facilitated by IGF-1R. In some embodiments, the antibody inhibits the internalization of the IGF-1R protein.

[0301] In some embodiments, the antibody comprises a sequence provided herein or an antigen-binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR described herein or an antigen-binding fragment thereof. The heavy chain may be one or more heavy chains described herein. In some embodiments, the antibody comprises a light chain as described herein or an antigen-binding fragment thereof.

[0302] In some embodiments, a method is provided for detecting the presence or absence of IGF-1R in a sample, comprising contacting the sample with one or more antibodies described herein and detecting the binding of the antibodies to the IGF-1R antigen. In some embodiments, detection of binding indicates the presence of the IGF-1R antigen, or the absence of detection of binding to the IGF-1R antigen indicates the absence of the IGF-1R antigen. Detection can be performed using any known method, such as a biosensor, ELISA, or sandwich assay. However, in some embodiments, the method includes detecting the presence of the protein under non-denaturing conditions. Using non-denaturing conditions allows the protein of interest to be detected in its native or properly folded form.

[0303] In some embodiments, a method is provided for identifying a test antibody that binds to an epitope on the IGF-1R protein, the method comprising contacting the test antibody with the epitope on the IGF-1R protein and detecting whether the test antibody binds to the epitope. In some embodiments, the detection includes detecting whether the test antibody binds to the protein and is competitively inhibited by an antibody containing a sequence provided herein. In some embodiments, the detection includes mutating one or more residues of the epitope or protein and measuring the binding of the test antibody to the mutated epitope, wherein the test antibody is considered to be bound to the epitope if the mutation reduces the binding of the test antibody compared to an undenatured epitope.

[0304] In some embodiments, a method is provided for monitoring the internalization of IGF-1R from the cell surface. In some embodiments, the method includes contacting cells with an anti-IGF-1R antibody provided herein and detecting the presence of IGF-1R inside or on the cell surface. Differences in expression on the cell surface can be measured, and internalization can be monitored and measured. This can be used to measure the effect of another molecule, such as a test agent, on controlling the internalization of the IGF-1R protein. Thus, using the antibody provided herein, test agents that control (increase or decrease) the internalization of the IGF-1R protein can be identified. Test molecules that increase internalization, measured as a decrease in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the method provided herein. Test molecules that decrease internalization, measured as an increase in the binding of the anti-IGF-1R antibody to the IGF-1R protein on the cell surface, can be identified according to the method provided herein. Surface expression can be measured by fluorescence emission, which can be performed using a secondary antibody that recognizes the IGF-1R antibody, or by labeling with the anti-IGF-1R antibody provided herein.

[0305] In some embodiments, subjects are administered the composition at a dose of approximately 3 mg / kg of antibody and have a Cmax of approximately 80 μg / mL to approximately 95 μg / mL or approximately 85 μg / mL to approximately 95 μg / mL on day 1. In some embodiments, the Cmax on day 1 is 90 μg / mL to approximately 95 μg / mL. In some embodiments, Cmax is measured or observed approximately 2 hours or within 2 hours after dose administration to the patient. In some embodiments, the median time to Cmax occurred approximately 2 hours later.

[0306] In some embodiments, subjects are administered the composition at a dose of approximately 3 mg / kg of antibody and have a Cmin of approximately 5 μg / mL to approximately 10 μg / mL or approximately 5 μg / mL to approximately 6 μg / mL on day 21.

[0307] In some embodiments, subjects are administered the composition at a dose of approximately 10 mg / kg of antibody and have a Cmax of approximately 250 μg / mL to approximately 350 μg / mL, approximately 275 μg / mL to approximately 325 μg / mL, or approximately 285 μg / mL to approximately 315 μg / mL on day 1. In some embodiments, Cmax is measured or observed approximately 2 hours or within 2 hours after dose administration to the patient. In some embodiments, the median time to Cmax occurred approximately 2 hours later.

[0308] In some embodiments, subjects are administered the composition at a dose of approximately 10 mg / kg of antibody and have a Cmin of approximately 30 μg / mL to approximately 50 μg / mL, approximately 40 μg / mL to approximately 50 μg / mL, or approximately 45 to approximately 50 μg / mL on day 21.

[0309] In some embodiments, the embodiments provided herein include, but are not limited to, the following: A first set of exemplary embodiments

[0310] 1. A method for treating patients suffering from moderate to severe chronic thyroid eye disease such as TED, comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg. The antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. The method wherein, prior to the administration of the first dose, the patient has had symptoms of thyroid eye disease for at least one year or more than one year, and has one or more of the following: eyelid retraction greater than 2 mm, moderate to severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, a clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia.

[0311] 2. The method according to Embodiment 1, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0312] 3. The method according to Embodiment 1 or 2, wherein the patient has exophthalmos of 3 mm or more and a CAS of about 0 to about 7 greater than 2.

[0313] 4. The method according to any one of Embodiments 1 to 3, wherein the patient had been diagnosed with a thyroid eye disease at least one year prior to being administered the pharmaceutical composition.

[0314] 5. The method according to Embodiment 1, wherein the pharmaceutical composition is administered intravenously or subcutaneously by infusion.

[0315] 6. The method according to Embodiment 1 or 2, comprising administering a dose to the patient approximately every 21 days.

[0316] 7. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least five consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0317] 8. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least five consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0318] 9. The method according to any one of Embodiments 1 to 3, wherein the patient is administered at least 8 consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0319] 10. The method according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition containing the antibody is administered at a dose of about 10 mg / kg.

[0320] 11. The method according to Embodiment 10, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0321] 12. The method according to Embodiment 10, wherein the pharmaceutical composition is administered to the patient in a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses every 21 days.

[0322] 13. The method according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition containing the antibody is administered at a dose of approximately 3 mg / kg.

[0323] 14. The method according to Embodiment 13, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0324] 15. The method according to Embodiment 13, wherein the pharmaceutical composition is administered to the patient in a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses every 21 days.

[0325] 16. The method according to any one of Embodiments 1 to 15, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 1 to 3 mm, approximately 1 to 2 mm, or approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

[0326] 17. The method according to any one of Embodiments 1 to 16, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

[0327] 18. The method according to Embodiment 16 or 17, wherein the subject had a CAS of 0, 1, 2, 3, or greater than 4, or about 2 to about 4, before administration of the pharmaceutical composition.

[0328] 19. The method according to any one of Embodiments 1 to 18, wherein the subject is administered the composition at a dose of about 3 mg / kg and has a Cmax of about 80 μg / mL to about 95 μg / mL or about 85 μg / mL to about 95 μg / mL on day 1.

[0329] 20. The method according to Embodiment 19, wherein the subject is administered the composition at a dose of approximately 3 mg / kg and has a Cmin of approximately 5 μg / mL to approximately 10 μg / mL or approximately 5 μg / mL to approximately 6 μg / mL on the 21st day.

[0330] 21. The method according to any one of Embodiments 1 to 18, wherein the subject is administered the composition at a dose of about 10 mg / kg and has a Cmax of about 250 μg / mL to about 350 μg / mL or about 275 μg / mL to about 325 μg / mL on day 1.

[0331] 22. The method according to Embodiment 21, wherein the subject is administered the composition at a dose of about 10 mg / kg and has a Cmin of about 30 μg / mL to about 50 μg / mL, about 40 μg / mL to about 50 μg / mL, or about 45 to about 50 μg / mL on day 21.

[0332] 23. The method according to any one of Embodiments 1 to 22, wherein the patient has had symptoms of thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years prior to the administration of the first dose, or for 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, or about 7 to about 8 years.

[0333] 24. The method according to any one of Embodiments 1 to 22, wherein the patient has had symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months prior to the administration of the first dose.

[0334] 25. The method according to any one of Embodiments 1 to 24, wherein the patient does not experience any hearing impairment, acoustotoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition.

[0335] 26. The method according to any one of Embodiments 1 to 24, wherein the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events caused by the administration of the pharmaceutical composition.

[0336] 27. The method according to any one of Embodiments 1 to 26, wherein the light chain includes a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having the amino acid sequence of SEQ ID NO: 3.

[0337] 28. The method according to any one of Embodiments 1 to 27, wherein the light chain comprises the amino acid sequence of Sequence ID No. 11.

[0338] 29. The method according to any one of Embodiments 1 to 28, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10.

[0339] 30. The method according to any one of Embodiments 1 to 27, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0340] 31. The method according to any one of Embodiments 1 to 30, wherein the clinical activity score of the subject decreases after a first dose of the antibody.

[0341] 32. The method according to any one of Embodiments 1 to 30, wherein the clinical activity score of the subject decreases after two doses of the antibody.

[0342] 33. The method according to any one of Embodiments 1 to 32, wherein the pharmaceutical composition containing the antibody comprises at least one pharmaceutically acceptable excipient, and the pharmaceutical composition contains the antibody at a concentration of 20 mg / mL to about 30 mg / mL.

[0343] 34. The method according to Embodiment 33, wherein the pharmaceutical composition contains the antibody at a concentration of about 25 mg / mL.

[0344] A second set of exemplary embodiments

[0345] 1. A method for treating a patient suffering from an eye disorder, comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg to approximately 10 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg. The antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprises LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11. The patient, before receiving the first dose of the pharmaceutical composition, (a) Having had one or more of the above-mentioned eye disorders for at least 12 months, (b) Having one or more of the above-mentioned eye disorders for at least 15 months, (c) Having one or more of the aforementioned eye disorders associated with a clinical activity score (CAS) of 4 or higher, and the severity of such symptoms(s) has decreased over time. (d) Having one or more symptoms of the eye disorder that have reached a plateau, for example, a static plateau, (e) Having one or more of the following for at least one year or more than one year: eyelid retraction greater than 2 mm, moderate or severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, clinical activity score (CAS) of approximately 0 to approximately 7, and unspecified or constant diplopia. (f) Having one or more of the following for at least 15 months or longer: eyelid retraction greater than 2 mm, moderate or severe soft tissue infiltration, exophthalmos (proptosis) greater than 3 mm, clinical activity score (CAS) of approximately 0 to approximately 7, and undefined or constant diplopia, (g) The method comprising one or more of each of (a) to (f).

[0346] 2. The method according to Embodiment 1, wherein the eye disorder is an autoimmune-related eye disorder associated with IGF-1R signaling.

[0347] 3. The method according to Embodiment 1, wherein the eye disorder is an inflammatory orbital disorder related to IGF-1R signaling.

[0348] 4. The method according to Embodiment 1, wherein the eye disorder is a thyroid eye disorder related to IGF-1R signaling.

[0349] 5. The method according to Embodiment 1, wherein the eye disorder is toxic exophthalmos.

[0350] 6. The method according to Embodiment 1, wherein the eye disorder is thyroid dysfunction eye disease.

[0351] 7. The method according to Embodiment 1, wherein the eye disorder is thyroid-associated eye disease (TAO), thyroid eye disease (TED), or Graves' eye disease or ophthalmopathy (GO).

[0352] 8. The method according to Embodiment 7, wherein the eye disorder is chronic TED.

[0353] 9. The method according to any one of the prior embodiments, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are determined using the numbering scheme of Kabat, IMGT, Chothia, or North.

[0354] 10. A method for treating patients suffering from moderate to severe chronic thyroid eye disease such as TED, comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in doses of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg to approximately 10 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg. The antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6. The method wherein, prior to the administration of the first dose of the pharmaceutical composition, the patient has had symptoms of thyroid eye disease for at least one year or more than one year, and has one or more of the following: eyelid retraction of more than 2 mm, moderate to severe soft tissue infiltration, exophthalmos (proptosis) of 3 mm or more, a clinical activity score (CAS) of about 0 to about 7, and undefined or constant diplopia.

[0355] 11. The method according to any one of the prior embodiments, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0356] 12. The method according to any one of the prior embodiments, wherein the patient has proptosis of 3 mm or more and a CAS of about 0 to about 7 greater than 2.

[0357] 13. The method according to any one of the prior embodiments, wherein the patient had been diagnosed with thyroid eye disease at least one year prior to being administered the pharmaceutical composition.

[0358] 14. The method according to any one of the prior embodiments, wherein the pharmaceutical composition is administered intravenously or subcutaneously by infusion.

[0359] 15. The method according to any one of the prior embodiments, wherein the pharmaceutical composition is administered via a subcutaneous needle, a pre-filled syringe, or an auto-injector.

[0360] 16. The method according to any one of the prior embodiments, comprising administering a dose to the patient approximately every 21 days.

[0361] 17. The method according to any one of the prior embodiments, wherein the patient is administered at least four or five consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0362] 18. The method according to any one of the prior embodiments, wherein the patient is administered at least six or seven consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0363] 19. The method according to any one of the prior embodiments, wherein the patient is administered at least eight consecutive doses of the pharmaceutical composition, the doses being administered approximately every 21 days.

[0364] 20. The method according to any one of the prior embodiments, wherein the anti-IGF-1R antibody is provided as an antigen-binding fragment, form, variant, or derivative of the anti-IGF-1R antibody.

[0365] 21. The method according to any one of Embodiments 1 to 20, wherein the pharmaceutical composition containing the antibody is administered in a dose of about 3.0 mg / kg to about 10 mg / kg.

[0366] 22. The method according to Embodiment 21, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0367] 23. The method according to Embodiment 21, wherein the pharmaceutical composition is administered to the patient in a total of about 4 to about 8 doses, about 4, about 5, about 6, about 7, or about 8 doses every 21 days.

[0368] 24. The method according to any one of Embodiments 1 to 20, wherein the pharmaceutical composition containing the antibody is administered at a dose of about 10 mg / kg.

[0369] 25. The method according to Embodiment 24, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0370] 26. The method according to Embodiment 24, wherein the pharmaceutical composition is administered to the patient in a total of about 4 to about 8 doses, about 4, about 5, about 6, about 7, or about 8 doses every 21 days.

[0371] 27. The method according to any one of Embodiments 1 to 20, wherein the pharmaceutical composition containing the antibody is administered at a dose of about 3 mg / kg.

[0372] 28. The method according to Embodiment 27, wherein the pharmaceutical composition is administered to the patient every 21 days.

[0373] 29. The method according to Embodiment 27, wherein the pharmaceutical composition is administered to the patient in a total of about 5 to about 8 doses, about 5, about 6, about 7, or about 8 doses every 21 days.

[0374] 30. The method according to any one of the prior embodiments, comprising administering a subsequent dose at a dose of approximately 3.0 mg / kg to approximately 20 mg / kg, approximately 3.0 mg / kg to approximately 10 mg / kg, approximately 3.0 mg / kg, approximately 5.0 mg / kg, approximately 10 mg / kg, or approximately 20 mg / kg.

[0375] 31. The method according to any one of the prior embodiments, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 1 to 3 mm, approximately 1 to 2 mm, or approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

[0376] 32. The method according to any one of the prior embodiments, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2-3 mm from baseline within 6 weeks from the first dose.

[0377] 33. The method according to Embodiment 31 or 32, wherein the subject had a CAS of 0, 1, 2, 3, or greater than 4, or about 2 to about 4, before administration of the pharmaceutical composition.

[0378] 34. The method according to any one of the prior embodiments, wherein the subject is administered the composition at a dose of approximately 3 mg / kg and has a Cmax of approximately 80 μg / mL to approximately 95 μg / mL or approximately 85 μg / mL to approximately 95 μg / mL on day 1.

[0379] 35. The method according to Embodiment 34, wherein the subject is administered the composition at a dose of approximately 3 mg / kg and has a Cmin of approximately 5 μg / mL to approximately 10 μg / mL or approximately 5 μg / mL to approximately 6 μg / mL on day 21.

[0380] 36. The method according to any one of the prior embodiments, wherein the subject is administered the composition at a dose of about 10 mg / kg and has a Cmax of about 250 μg / mL to about 350 μg / mL or about 275 μg / mL to about 325 μg / mL on day 1.

[0381] 37. The method according to Embodiment 36, wherein the subject is administered the composition at a dose of approximately 10 mg / kg and has a Cmin of approximately 30 μg / mL to approximately 50 μg / mL, approximately 40 μg / mL to approximately 50 μg / mL, or approximately 45 to approximately 50 μg / mL on day 21.

[0382] 38. The method according to any one of the prior embodiments, wherein the patient has had symptoms of an eye disorder or thyroid eye disease for more than 2, 3, 4, 5, 6, or 7 years prior to the administration of the first dose of the pharmaceutical composition, or for 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, about 1 to about 2 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, about 2 to about 3 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 5 years, about 3 to about 4 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, about 4 to about 5 years, about 5 to about 8 years, about 5 to about 7 years, about 5 to about 6 years, about 6 to about 8 years, or about 7 to about 8 years.

[0383] 39. The method according to any one of the prior embodiments, wherein the patient has had symptoms of thyroid eye disease for a period of 63 months, 60 months, 48 ​​months, 36 months, 24 months, or 12 months prior to the administration of the first dose.

[0384] 40. The method according to any one of the prior embodiments, wherein the patient does not experience any hearing impairment, acoustotoxic changes in audiometry, or hyperglycemic events after administration of the pharmaceutical composition.

[0385] 41. The method according to any one of the prior embodiments, wherein the patient does not have any hearing impairment, ototoxic changes in audiometry, or hyperglycemic events resulting from the administration of the pharmaceutical composition.

[0386] 42. The method according to any one of the prior embodiments, wherein the clinical activity score of the subject decreases after a first dose of the antibody.

[0387] 43. The method according to any one of the prior embodiments, wherein the clinical activity score of the subject decreases after two doses of the antibody.

[0388] 44. The method according to any one of the prior embodiments, wherein the pharmaceutical composition containing the antibody comprises at least one pharmaceutically acceptable excipient, and the pharmaceutical composition contains the antibody at a concentration of 20 mg / mL to about 30 mg / mL.

[0389] 45. The method according to Embodiment 33, wherein the pharmaceutical composition contains the antibody at a concentration of about 25 mg / mL.

[0390] 46. ​​A method for treating a patient suffering from chronic thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprises LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11.

[0391] 47. A method for treating a patient suffering from inactive thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody in a therapeutically effective drug regimen, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11.

[0392] 48. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment. The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprises LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11, and the patient has one or more symptoms of eye disorders associated with a clinical activity score (CAS) of 4 or higher prior to administration of a first dose of the pharmaceutical composition, and the severity of such symptoms(s) decreases over time.

[0393] 49. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11, wherein the patient has one or more symptoms of an eye disorder that has reached a plateau, for example, a static plateau, prior to administration of a first dose of the pharmaceutical composition.

[0394] 50. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprises LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11. The method wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0395] 51. The method according to any one of embodiments 46 to 49, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

[0396] 52. The method according to any one of embodiments 46 to 51, wherein the patient suffers from one or more symptoms of TED selected from the group consisting of eyelid retraction greater than 2 mm, exophthalmos (proptosis) of 3 mm or more, a clinical activity score (CAS) of about 0 to about 7, and unspecified or constant diplopia.

[0397] 53. The method according to Embodiment 52, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

[0398] 54. The method according to any one of embodiments 46 to 53, wherein the patient had 0, 1, 2, 3, or 4 or more CAS prior to treatment.

[0399] 55. The method according to any one of embodiments 46 to 54, wherein the patient had more than 2 CAS before treatment.

[0400] 56. The method according to any one of embodiments 46 to 55, wherein the patient had a CAS of less than 2 prior to treatment.

[0401] 57. The method according to any one of embodiments 46 to 55, wherein the patient had 2 to 4 CAS prior to treatment.

[0402] 58. The method according to any one of embodiments 46 to 57, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

[0403] 59. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition comprising an anti-IGF-1R antibody in a drug regimen effective for treatment, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 11, and the patient having a clinical activity score (CAS) of 2 or less prior to treatment.

[0404] 60. The method according to any one of embodiments 46 to 59, wherein the patient exhibits fibrosis.

[0405] 61. A method for treating fibrosis associated with thyroid eye disease (TED), comprising administering an anti-IGF-1R antibody to a patient in need of treatment in a therapeutically effective drug regimen, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 10, and the light chain comprising LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 116.

[0406] 62. The method according to any one of embodiments 59 to 61, wherein the patient had a clinical activity score (CAS) of 0 or 1 prior to treatment.

[0407] 63. The method according to any one of embodiments 59 to 62, wherein the patient has one or more symptoms of TED selected from the group consisting of eyelid retraction of more than 2 mm, exophthalmos (proptosis) that is 3 mm or more above the standard range for race and sex, and indeterminate or constant diplopia.

[0408] 64. The method according to any one of embodiments 46 to 63, wherein the patient has had one or more symptoms of thyroid eye disease for at least two years prior to treatment.

[0409] 65. The method according to any one of embodiments 46 to 64, wherein the drug regimen effective for the treatment includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

[0410] 66. The method according to Embodiment 65, wherein the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0411] 67. The method according to any one of embodiments 46 to 66, wherein the drug regimen effective for the treatment comprises administering a subsequent dose to the patient.

[0412] 68. The method according to Embodiment 67, wherein the subsequent dose is 3.0 mg / kg to 20 mg / kg.

[0413] 69. The method according to Embodiment 68, wherein the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

[0414] 70. The method according to any one of embodiments 68 to 69, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.

[0415] 71. The method according to Embodiment 70, wherein the subsequent dose is administered to the patient once every three weeks.

[0416] 72. The method according to any one of embodiments 67 to 71, wherein the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

[0417] 73. The method according to Embodiment 72, wherein the patient is administered at least four subsequent doses.

[0418] 74. The method according to Embodiment 72, wherein the patient is administered at least 5 subsequent doses.

[0419] 75. The method according to Embodiment 72, wherein the patient is administered at least 8 subsequent doses.

[0420] 76. The method according to any one of embodiments 46 to 75, wherein the administration of the drug regimen effective for the treatment results in a reduction of approximately 1 to approximately 3 mm, approximately 1 to approximately 2 mm, and approximately 2 to approximately 3 mm from baseline within 6 weeks from the first dose, as measured by exophthalmoscopy or MRI / CT.

[0421] 77. The method according to Embodiment 76, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2-3 mm from baseline within 6 weeks from the first dose.

[0422] 78. The method according to any one of embodiments 46 to 77, wherein the patient does not have hearing impairment, ototoxic changes in audiometry, or high blood glucose levels in the patient during the treatment.

[0423] 79. The method according to any one of embodiments 46 to 78, wherein the light chain includes a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having the amino acid sequence of SEQ ID NO: 3.

[0424] 80. The method according to any one of the prior embodiments, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0425] 81. The method according to any one embodiment, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10.

[0426] 82. The method according to any one embodiment, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO: 11.

[0427] 83. The method according to any one of the prior embodiments, wherein the heavy chain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.

[0428] 84. The method according to any one of Embodiments 1 to 82, wherein the heavy chain comprises HCDR1 of SEQ ID NO: 29, HCDR2 of SEQ ID NO: 30, and HCDR3 of SEQ ID NO: 31, and the light chain comprises LCDR1 of SEQ ID NO: 27, LCDR2 of SEQ ID NO: 28, and LCDR3 of SEQ ID NO: 6.

[0429] 85. The method according to any one of Embodiments 1 to 82, wherein the heavy chain comprises HCDR1 of SEQ ID NO: 32, HCDR2 of SEQ ID NO: 33, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6.

[0430] 86. The method according to any one of embodiments 1 to 82, wherein the heavy chain comprises HCDR1 of SEQ ID NO: 35, HCDR2 of SEQ ID NO: 36, and HCDR3 of SEQ ID NO: 31, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 34, and LCDR3 of SEQ ID NO: 6.

[0431] 87. The method according to any one of the prior embodiments, wherein the patient achieves improvement in one or more parameters selected from the following: proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total score of Graves' ophthalmopathy quality of life (GO-QoL), GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and EQ-5D-5L QoL questionnaire.

[0432] 88. The method according to embodiment 87, wherein the patient achieves improvement in at least two parameters.

[0433] 89. The method according to embodiment 87, wherein the patient achieves improvement in at least three parameters.

[0434] 90. The method according to Embodiment 87, wherein the patient achieves improvement in at least four parameters.

[0435] The subject matter is described here with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the claims should not be construed as being limited to these embodiments, but rather as encompassing any and all modifications that become apparent as a result of the teachings provided herein. Those skilled in the art will readily recognize that there are various less important parameters that can be changed or modified to produce essentially similar results. [Examples]

[0436] Example 1. VRDN-5000 effectively treats patients with chronic thyroid eye disease. Patients with chronic thyroid eye disease (protrusion of the eyeball ≥ 3 mm above the racial and sex standard, clinical activity score (CAS) 0-7, onset of thyroid eye disease symptoms ≥ 12 months prior to treatment) were randomized in a double-blind, placebo-controlled clinical trial and administered either two doses of the antibody at 3 mg / kg every 3 weeks (n=7), two doses of the antibody at 10 mg / kg every 3 weeks (n=7), or placebo (n=2 in the 10 mg / kg cohort, n=3 in the 3 mg / kg cohort). The table below shows the baseline patient characteristics of patients who received two infusions. [Table 9]

[0437] The following represents the data available from the trial as of May 30, 2023, and is preliminary.

[0438] No safety signals were observed after administration, including no adverse events related to hearing impairment, no changes in auditory toxicity in audiometry, or no hyperglycemic events.

[0439] In the 10 mg / kg dose cohort, only after two doses was a 50% proptosis response rate observed at week 6. Measured by proptosis measurement, the mean change in proptosis from baseline was -1.8 mm at week 6. Measured by MRI / CT, ​​the mean change in proptosis from baseline was -1.5 mm at week 6. Patients who participated in the study with a CAS score greater than 0 showed a decrease of -2.8 in their CAS score.

[0440] In the 3 mg / kg dose cohort, only after two doses was there a 33% proptosis response rate at week 6. Measured by proptosis measurement, the mean change in proptosis from baseline was -1.5 mm at week 6. Measured by MRI / CT, ​​the mean change in proptosis from baseline was -2.6 mm at week 6. Patients who participated in the study with a CAS score greater than 0 showed a decrease of -2.0 in their CAS score.

[0441] In both the 3 mg / kg and 10 mg / kg cohorts, as measured by MRI / CT, ​​there was a mean reduction of 2.0 mm from baseline in exophthalmos at week 6 (n=8) compared to a placebo response of -0.2 mm (n=5).

[0442] In patients with baseline proptosis exceeding 24 mm, a greater change in proptosis from baseline to week 6 was observed.

[0443] However, in the 10 mg / kg cohort, exophthalmos was observed despite the relative floor effect of low baseline exophthalmos.

[0444] In patients with a CAS score of 0 or 1, a reduction in proptosis was observed compared to placebo. The data is summarized in the table below. [Table 10]

[0445] The data for patients with chronic thyroid eye disease is summarized in a table, as shown in Figure 15.

[0446] These results, observed within six weeks of treatment for patients with chronic thyroid eye disease, were surprising and unpredictable. In Example 2, VRDN-5000 treated at doses of 3 mg / kg and 10 mg / kg in patients with active and chronic thyroid eye disease showed consistent PK levels across the cohort. When Cmax and Cmin were measured in patients with active or chronic thyroid eye disease treated with either 3 mg / kg or 10 mg / kg of VRDN-5000, Cmax and Cmin were found to be similar between both cohorts. The median time to Cmax occurred approximately 2 hours after infusion of the pharmaceutical composition containing VRDN-5000. The data are illustrated in the table below. [Table 11]

[0447] As the data show, chronic subjects, on average, had a reduction or improvement in proptosis or other symptoms of thyroid eye disease as measured by the CAS score, which was not observed in the placebo cohort. These data demonstrate the unexpected result that VRDN-5000 can achieve therapeutic effects so rapidly, even in chronic TED patients, which was unpredictable.

[0448] Example 3. VRDN-5000 effectively treats patients with symptoms of thyroid eye disease that began more than 15 months prior to the present. This example describes a phase 3 randomized, double-masking, placebo-controlled trial to investigate the safety, tolerability, and efficacy of VRDN-5000 in participants with chronic TED. In this trial, participants with chronic TED who showed rapid and significant improvement in proptosis and CAS at week 6 after receiving two infusions of VRDN-5000 at either 3 mg / kg or 10 mg / kg will continue the previous trial.

[0449] This study consists of an initial screening period followed by a 12-week double-masking treatment period and a 40-week double-masking follow-up period (Figure 2). Participants with chronic TED were randomized in a 2:1 ratio to either the treatment group or the placebo group, receiving either 10 mg / kg of VRDN-5000 or placebo intravenously every 3 weeks for 5 times. Participants who did not achieve a reduction of 2 mm or more from baseline in proptosis (measured by MRI / CT) in the most protruding eye three weeks after the 5th IV infusion (i.e., week 15) were defined as non-responders. Participants who were non-responders at week 15 could be enrolled in an open-label treatment trial to receive a further 12 weeks of VRDN-5000 IV infusions every 3 weeks for a total of 5 more times.

[0450] Selection Criteria All participants in the exam must meet all of the following criteria: 1. You understand the examination procedures and associated risks, and you are willing to provide written informed consent before any initial examination-related activities. 2. Participants must be adult males or females aged 18 to under 75. 3. The patient has a clinical diagnosis of TED and has one of the following CASes (0-7): 4. When measured with an exophthalmoscopy device, the principal investigator has, in their opinion, exophthalmos that is 3 mm or more above the racial and sex-specific standard values, and has moderate to severe chronic TED (i.e., significantly impacting daily life) with exophthalmos of 17 mm or more in the study eye at pre-dose baseline (-1 day or 1 day) when measured with an exophthalmoscopy device. 5. There is recorded evidence of ocular symptoms or signs associated with chronic TED that began more than 15 months prior to the trial screening. 6. VRDN-5000 can be initiated simultaneously with an attempt to achieve normal thyroid function. The underlying thyroid condition is not a selection criterion. 7. For no reason whatsoever, the research eye does not require immediate ophthalmic or orbital surgery. 8. VRDN-5000 may be used with caution in participants with diabetes mellitus. Diabetic participants must be monitored by a general practitioner or other appropriately trained person, and their glycated hemoglobin (HbA1c) must be less than 8.5% at the time of study participation. 9. In the case of women, the serum pregnancy test must be negative at the time of screening, and the urine pregnancy test must also be negative immediately before administration of each investigational drug. If a participant is a woman of childbearing potential (including those who are less than two years past menopause or who are not surgically infertile due to hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), such participant must agree to use an acceptable method of contraception, such as condoms, and a second, highly effective method of contraception from screening until 100 days after the final dose of the study drug (including day 100). If a participant has started hormonal contraception at the time of screening or within one cycle on day 1, the participant must agree to use a double-barrier method of contraception until one cycle of hormonal contraception is completed. Acceptable double-barrier combinations are condoms with either a diaphragm or a sponge containing spermicide. 10. You have been surgically infertile at least six weeks prior to this date, or you agree to use an acceptable method of contraception, such as condoms, and a second, highly effective method of contraception, from screening until 100 days after the final dose of the study drug (including day 100). 11. Having the willingness and ability to comply with all protocol requirements throughout the entire duration of the examination.

[0451] Exclusion criteria All participants in the exam must not meet any of the following criteria: 1. The patient has received prior treatment with another anti-IGF-1R therapy. 2. Within two weeks prior to the first dose of the study drug, the patient has received systemic corticosteroids containing TED or selenium for any of the following conditions (eye drops containing selenium or topical steroids containing multivitamins are permitted). Periocular (including intraorbital) or intraocular administration of corticosteroids within three months prior to the first dose of the study drug, or more than three periocular or intraocular corticosteroid injections at any given time, is also excluded. 3. Within 8 weeks prior to the first dose of the study drug, the patient has received rituximab, tocilizumab, secukinumab, satralizumab, or other immunosuppressants including anti-FcRn for any condition (including TED), or has received intraorbital administration of such other immunosuppressants at any point in time. 4. Having received any other treatment for TED within 8 weeks prior to the first dose of the study drug (artificial tears are permitted). 5. The patient has received the investigational drug for any of the following conditions within 8 weeks prior to the first dose of the investigational drug. 6. Patients with TED's compressive optic neuropathy who are expected to require surgical decompression in the near future. 7. A research eye with corneal decompensation that does not respond to medical management. 8. For participants with a CAS score of 2 or higher at screening, the CAS score decreased by 2 points or more in the study eye between the screening evaluation and day -1. 9. Between the screening evaluation and day 1, the exophthalmos in either eye has decreased by 2 mm or more as measured by an exophthalmoscopy device. 10. Previously undergone orbital irradiation of TED into the orbit of a research eye, or decompression surgery with fat removal for TED in the orbit of a research eye. 11. The research eye has a pre-existing ophthalmological condition that, in the principal investigator's opinion, could confuse the interpretation of the trial results. 12. The patient has a history of a significant ear condition, related ear surgery, or hearing loss (as determined by the principal investigator), or has had an audiometric evaluation at the time of such screening. 13. Having inflammatory bowel disease (e.g., confirmed by biopsy or clinical evidence of inflammatory bowel disease). 14. A woman who is pregnant or breastfeeding. 15. The patient is a regular user of alcohol or illegal drugs, or is considered by the principal investigator to be at high risk of relapse. 16. You have a known allergy to either the VRDN-5000 or placebo formulation, or you have previously experienced allergic reactions to monoclonal antibodies (mAbs). 17. Having any condition that, in the opinion of the principal investigator, would prevent participation in the trial. 18. Tested positive for human immunodeficiency virus (HIV-1 and HIV-2). 19. Test positive for active hepatitis B or hepatitis C infection. 20. Have previously participated in either this study or the VRDN-5000 study. 21. The patient has received radioactive iodine (RAI) therapy for any of the following conditions within 8 weeks prior to the first dose of the study drug.

[0452] A history of bone-only thyroidectomy, radioactive iodine (RAI) therapy, or orbital decompression surgery is not excluded. (If fat resection is performed in conjunction with orbital decompression, participants will be excluded as described in the exclusions above.)

[0453] Effectiveness evaluation items The primary efficacy endpoints to be evaluated are the proptosis responder rate and the clinical activity responder rate in the most prominent eye. The proptosis responder rate is evaluated as a decrease of 2 mm or more from baseline in proptosis at 3 weeks after the 5th IV infusion (i.e., week 15) (without a corresponding increase of 2 mm or more in the other eye). The clinical activity responder rate is evaluated as no deterioration of CAS from baseline at 3 weeks after the 5th IV infusion (i.e., week 15) (without a corresponding increase of 2 points or more in the other eye).

[0454] Important secondary outcome measures include: • Change from baseline in the most protruding eye at week 15 • Percentage of individuals with the most exophthalmos when measured with an exophthalmosmeter at week 15. • Change from baseline in the most exophthalmos measured with a proptophthalmometer at 15 weeks. • Clinical activity response rate in the most prominent eye at week 15 • Overall responder rate in the most prominent eye at week 15 • Diplopia resolution rate at week 15 (i.e., for participants with a baseline diplopia score greater than 0, the decrease from baseline to 0 in the Gorman subjective diplopia score)

[0455] The exploratory efficacy endpoints further include: • Percentage of proptosis responders in the most protruding eye at week 24 (12 weeks after the 5th IV infusion), week 36 (24 weeks after the 5th IV infusion), and week 52. • Exophthalmos response rate in the other eye at weeks 15, 24, 36, and 52 (i.e., reduction of 2 mm or more of exophthalmos from baseline) • Persistence of exophthalmos in the most protruding eye at weeks 24, 36, and 52. • Time to the first exophthalmos in the most protruding eye • Clinical activity response rate in the most prominent eyes at weeks 24, 36, and 52 • Clinical activity response rate in the other eye at weeks 15, 24, 36, and 52 • Overall responder rate in the most prominent eyes at weeks 24, 36, and 52 • Overall responder rate in the other eye at weeks 15, 24, 36, and 52 • Rate of resolution of double vision at weeks 24, 36, and 52 • Changes from baseline in the most prominent eye and the other eye at weeks 15, 24, 36, and 52, corresponding to the following parameters: ·proptophthalmia CAS ·Extraocular muscle mass ·Orbital fat amount Manual measurement of eyelid retraction • Total score of the quality of life (GO-QoL) for Graves' ophthalmopathy GO-QoL Activity Subscale GO-QoL exterior subscale ·Visual acuity (VA) Gorman Subjective Diplopia Score EQ-5D-5L QoL Questionnaire • VRDN-5000, IGF-1, and anti-drug antibodies (ADA) at various time points before and after IV infusion.

[0456] Safety evaluation items Adverse events (AEs) and serious adverse events (SAEs) will be monitored and recorded throughout the study period. All clinically significant changes in other safety measures will be recorded as AEs.

[0457] All references cited herein are invoked by reference to the same extent as when each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent is specifically and individually indicated as being invoked by reference. This use of reference is intended to be explicitly identified by the applicants in accordance with 37 CFR §1.57(b)(1) and all individual publications, database entries (e.g., Genbank sequence or GeneID entry), patent applications, or patents, even if such references are not directly adjacent to the specific use of reference indicated by reference, in accordance with 37 CFR §1.57(b)(2). Any inclusion of specific use of reference indicated by reference within this specification, where present, does not in any way diminish this general statement regarding use of reference by reference. The references made herein are not intended to imply that such references refer to appropriate prior art, nor do they constitute any endorsement of the content or date of such publications or documents.

[0458] This embodiment is not limited to the scope of the specific embodiments described herein. In fact, various modifications beyond those described herein will be obvious to those skilled in the art from the prior description and the accompanying drawings. Such modifications are intended to be included within the embodiments and any of the accompanying claims.

[0459] This specification is considered sufficient to enable those skilled in the art to carry out the embodiments. In addition to those shown and described herein, various modifications will be apparent to those skilled in the art from the foregoing description and are included in the scope of this disclosure and any of the appended claims.

Claims

1. A method for treating patients suffering from chronic thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO:

6.

2. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO:

6. The method wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

3. The method according to claim 1, wherein the patient has had one or more symptoms of thyroid eye disease for at least 12 months prior to treatment.

4. The method according to any one of the prior claims, wherein the patient suffers from one or more symptoms of TED selected from the group consisting of eyelid retraction of more than 2 mm, exophthalmos (proptosis) of 3 mm or more, a clinical activity score (CAS) of about 0 to about 7, and unspecified or constant diplopia.

5. The method according to claim 4, wherein the exophthalmos exceeds the standard range for race and sex by 3 mm or more.

6. The method according to any one of the prior claims, wherein the patient had 0, 1, 2, 3, or 4 or more CAS before treatment.

7. The method according to any one of the prior claims, wherein the patient had more than two CASs before treatment.

8. The method according to any one of claims 1 to 6, wherein the patient had a CAS score of less than 2 prior to treatment.

9. The method according to any one of claims 1 to 7, wherein the patient had 2 to 4 CASs before treatment.

10. The method according to any one of the prior claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least 15 months prior to treatment.

11. A method for treating a patient suffering from inactive thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO:

6.

12. A method for treating a patient suffering from thyroid eye disease (TED), comprising administering a pharmaceutical composition containing an anti-IGF-1R antibody in a drug regimen effective for treatment, The antibody comprises a heavy chain and a light chain, the heavy chain comprising HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprising LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO:

6. The method wherein the patient had a clinical activity score (CAS) of 2 or less before treatment.

13. The method according to any one of the prior claims, wherein the patient exhibits fibrosis.

14. A method for treating fibrosis associated with thyroid eye disease (TED), comprising an effective drug regimen, in which an anti-IGF-1R antibody is administered to a patient in need of treatment. The method wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, and HCDR3 of SEQ ID NO: 9, and the light chain comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO:

6.

15. The method according to any one of claims 11 to 14, wherein the patient had a clinical activity score (CAS) of 0 or 1 prior to treatment.

16. The method according to any one of claims 11 to 15, wherein the patient has one or more symptoms of TED selected from the group consisting of eyelid retraction of more than 2 mm, exophthalmos (proptosis) that is 3 mm or more above the standard range for race and sex, and indeterminate or constant diplopia.

17. The method according to any one of the prior claims, wherein the patient has had one or more symptoms of thyroid eye disease for at least two years prior to treatment.

18. The method according to any one of the prior claims, wherein the drug regimen effective for the aforementioned treatment includes administering a first dose of 3.0 mg / kg to 20 mg / kg to the patient.

19. The method according to claim 18, wherein the first dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

20. The method according to any one of the prior claims, wherein the drug regimen effective for the aforementioned treatment includes administering a subsequent dose to the patient.

21. The method according to claim 20, wherein the subsequent dose is 3.0 mg / kg to 20 mg / kg.

22. The method according to claim 21, wherein the subsequent dose is 3.0 mg / kg, 5.0 mg / kg, 10 mg / kg, or 20 mg / kg.

23. The method according to any one of claims 20 to 22, wherein the subsequent dose is administered to the patient once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, or once every six weeks.

24. The method according to claim 23, wherein the subsequent dose is administered to the patient once every three weeks.

25. The method according to any one of claims 20 to 24, wherein the patient is administered at least 3, 4, 5, 6, 7, 8, 9, or 10 subsequent doses.

26. The method according to claim 25, wherein the patient is administered at least 5 subsequent doses.

27. The method according to claim 25, wherein the patient is administered at least 8 subsequent doses.

28. The method according to any one of the prior claims, wherein the administration of the drug regimen effective for the aforementioned treatment results in a reduction of approximately 1 to approximately 3 mm, approximately 1 to approximately 2 mm, and approximately 2 to approximately 3 mm from baseline within 6 weeks from the first dose, as measured by exophthalmoscopy or MRI / CT.

29. The method according to claim 28, wherein the exophthalmos, when measured by exophthalmos measurement or MRI / CT, ​​decreases by approximately 2 to 3 mm from baseline within 6 weeks from the first dose.

30. The method according to any one of the prior claims, wherein the patient does not have hearing impairment, auditory toxic changes in audiometry, or hyperglycemic levels in the patient during treatment.

31. The method according to any one of the prior claims, wherein the light chain includes a variable region having the amino acid sequence of SEQ ID NO: 2, and the heavy chain includes a variable region sequence having the amino acid sequence of SEQ ID NO:

3.

32. The method according to any one of the prior claims, wherein the light chain comprises the amino acid sequence of SEQ ID NO:

11.

33. The method according to any one of the prior claims, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:

10.

34. The method according to any one of the prior claims, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID NO:

11.

35. The method according to any one of the prior claims, wherein the patient achieves improvement in one or more parameters selected from proptosis, CAS, extraocular muscle mass, orbital fat mass, manual measurement of eyelid retraction, total quality of life (GO-QoL) score for Graves' ophthalmopathy, GO-QoL activity subscale, GO-QoL appearance subscale, visual acuity, Gorman subjective diplopia score, and the EQ-5D-5L QoL questionnaire.

36. The method according to claim 35, wherein the patient achieves improvement in at least two, three, four, or more parameters.

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