Anti-IGF-1R antibody composition

Abstract

The present disclosure generally relates to pharmaceutical compositions comprising anti-IGF-1R antibodies and methods of making and using such compositions. In certain embodiments, such compositions exhibit low viscosity and high stability and can thus be delivered conveniently with reduced discomfort to a subject in need thereof. Anti-IGF-1R antibodies having a heavy chain that includes a charged amino acid at its C-terminus are also provided herein. In certain aspects, provided herein is a pharmaceutical composition comprising (a) at least 75 mg / ml of an anti-IGF-1R antibody; (b) 20-30 mM histidine; and (c) 4%-6% sugar, and having a pH range of 5.5-6.5. 1

Description

Background Art

[0001] Background Thyroid eye disease (TED), also known as Graves' ophthalmopathy, is an autoimmune inflammatory disorder of the orbit and peripheral tissues characterized by upper eyelid retraction, lid lag, swelling, erythema, conjunctivitis, and proptosis. It most commonly occurs in individuals with Graves' disease, rarely in individuals with Hashimoto's thyroiditis or those with normal thyroid function. It is part of a systemic process that manifests variably in the eye, thyroid, and skin and is caused by autoantibodies that bind to tissues of these organs. The autoantibodies target fibroblasts in the eye muscles, and these fibroblasts can differentiate into fat cells (adipocytes). The fat cells and muscles enlarge and become inflamed. Veins are compressed and unable to drain fluid, which causes edema.

[0002] Current treatments for hyperthyroidism due to Graves' disease are incomplete because there is no treatment that targets the specific underlying pathogenic autoimmune mechanisms of this disease. The treatment of moderate to severe active TED is even more complex. Although there has been a better understanding of its pathogenesis in recent years, there remain therapeutic challenges and dilemmas in TED. Therefore, there is a large unmet need for the treatment of patients with TED and its related symptoms.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Summary There is an unmet need for the development of treatments for the treatment of TED that result in a deeper and more persistent response. In addition, currently available treatments for the treatment of TED have side effects including hearing loss. These side effects, reported in a significant proportion of patients receiving currently available treatments, limit the treatment of patients with TED.

Means for Solving the Problems

[0004] In certain embodiments, pharmaceutical compositions comprising anti-IGF-1R antibodies, as well as methods of using and making such pharmaceutical compositions, are provided herein. In certain embodiments, the pharmaceutical composition of the present invention is an IGF-1R antibody solution. In certain embodiments, the pharmaceutical compositions provided herein comprise a high concentration of anti-IGF-1R antibody solution (e.g., higher than 75 mg / ml, or higher than 100 mg / ml, etc.), but exhibit high drug stability and low viscosity. Therefore, such compositions are suitable for subcutaneous delivery, including self-delivery, to patients suffering from thyroid ophthalmopathy and other diseases and disorders in which anti-IGF-1R antibodies may provide a therapeutic benefit. Furthermore, the high antibody concentration with the low viscosity of the compositions provided herein allows for delivery of a lower volume of the composition to patients with a thinner needle, resulting in reduced patient discomfort and further facilitating self-delivery.

[0005] In certain embodiments, provided herein is a pharmaceutical composition comprising (a) at least 75 mg / ml of an anti-IGF-1R antibody; (b) 20-30 mM histidine; and (c) 4%-6% sugar, and having a pH range of 5.5-6.5. In some embodiments, the sugar is D-sorbitol.

[0006] In certain embodiments, the anti-IGF-1R antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In some embodiments, the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In certain embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain further comprising a charged amino acid (e.g., a C-terminal arginine, histidine, lysine, aspartic acid, or glutamic acid) at its C-terminus. In some embodiments, the charged amino acid is a positively charged amino acid (e.g., arginine, histidine, or lysine). In some embodiments, the charged amino acid is a negatively charged amino acid (e.g., aspartic acid or glutamic acid). In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11, 12, 13, 14, or 15. In some embodiments, the antibody comprises a human IgG1 heavy chain constant domain and a human kappa light chain constant domain. In certain embodiments, the anti-IGF-1R antibody is lonigutamab.

[0007] Lonigutamab is a humanized monoclonal antibody against IGF-1R. Lonigutamab has high affinity and specificity for IGF-1R. Specifically, lonigutamab has picomolar affinity for IGF-1R. In certain preferred embodiments, lonigutamab has a k D of about 30 pM for the binding epitope of IGF-1R. When lonigutamab binds to IGF-1R, it induces receptor internalization, as a result of which the signal from IGF-1R is blocked, and the therapeutic effect of lonigutamab can thereby occur. IGF-1R internalization can occur within minutes after administration of a pharmaceutical composition comprising lonigutamab. In certain preferred embodiments, the therapeutic effective serum concentration of lonigutamab can be reached about 1 hour after administration of a pharmaceutical composition comprising lonigutamab to a patient.

[0008] Lonigutamab has unique and beneficial pharmacological properties. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization at a level greater than about 70%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization at a level greater than about 80%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization at a level greater than about 85%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization at a level greater than about 90%.

[0009] In certain embodiments, the pharmaceutical composition comprises at least 75 mg / ml of an anti-IGF-1R antibody. In some embodiments, the pharmaceutical composition comprises at least 100 mg / ml, at least 125 mg / ml, at least 150 mg / ml, at least 175 mg / ml, at least 200 mg / ml, or at least 250 mg / ml of an anti-IGF-1R antibody. In certain embodiments, the pharmaceutical composition comprises 75 mg / ml to 300 mg / ml, 100 mg / ml to 300 mg / ml, or 125 mg / ml to 250 mg / ml of an anti-IGF-1R antibody. In some embodiments, the pharmaceutical composition comprises about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, or about 250 mg / ml of an anti-IGF-1R antibody.

[0010] In some embodiments, the pharmaceutical composition comprises 20 to 30 mM histidine. In certain embodiments, the pharmaceutical composition comprises about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM or about 30 mM histidine.

[0011] In some embodiments, the pharmaceutical composition comprises 4% to 6% sugar (e.g., D-sorbitol). In certain embodiments, the pharmaceutical composition comprises about 4%, 5% or 6% sugar (e.g., D-sorbitol).

[0012] In some embodiments, the pharmaceutical composition has a pH of 5.5 to 6.5. In certain embodiments, the pharmaceutical composition has a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0013] In some embodiments, the pharmaceutical composition does not contain polysorbate 80. In some embodiments, the pharmaceutical composition contains a small amount of polysorbate 80 (e.g., less than 0.05%). In certain embodiments, the pharmaceutical composition contains 0.05% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.02% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.01% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.005% or less of polysorbate 80. In certain embodiments, the pharmaceutical composition contains 0.002% to 0.05% of polysorbate 80. In some embodiments, the pharmaceutical composition contains about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045% or about 0.05% of polysorbate 80.

[0014] In some embodiments, the pharmaceutical composition does not contain poloxamer 188 (P188). In some embodiments, the pharmaceutical composition contains a small amount of poloxamer 188 (e.g., less than 0.1%). In certain embodiments, the pharmaceutical composition contains 0.1% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.05% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.02% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.01% or less of poloxamer 188. In some embodiments, the pharmaceutical composition further contains 0.01% - 0.1% of poloxamer 188. In certain embodiments, the pharmaceutical composition contains about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09% or about 0.1% of poloxamer 188.

[0015] In certain embodiments, the weight osmolality of the pharmaceutical composition is within the physiological weight osmolality range of 250 - 400 mOsm / kg.

[0016] In certain embodiments, the viscosity of the pharmaceutical composition is 30 cP or less at 21°C. In certain embodiments, the viscosity of the pharmaceutical composition is 15 cP or less at 21°C. In certain embodiments, the viscosity of the pharmaceutical composition is about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 21 cP, about 22 cP, about 23 cP, about 24 cP, about 25 cP, about 26 cP, about 27 cP, about 28 cP, about 29 cP, or about 30 cP at 21°C.

[0017] In certain embodiments, the pharmaceutical composition is stable for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, or longer. In some embodiments, the pharmaceutical composition is stable at a temperature of -70°C to 8°C (e.g., at about -70°C, at about -20°C, at about 4°C) during such a period.

[0018] In some embodiments, a syringe or a syringe containing a pharmaceutical composition provided herein is provided herein. In some embodiments, the syringe includes a delivery volume of 2 ml or less (e.g., 1.5 ml or less, 1 ml or less). In some embodiments, the syringe comprises a needle sized 24G or less (e.g., 25G, 26G). In certain embodiments, the syringe is an automated reusable fixed-dose device. In some embodiments, the syringe is an automated reusable variable-dose device. In some embodiments, the syringe is an automated disposable fixed-dose self-injector.

[0019] In certain embodiments, an anti-IGF-1R antibody comprising CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6, wherein the heavy chain of the antibody comprises a charged amino acid (e.g., c-terminal arginine, histidine, lysine, aspartic acid or glutamic acid) at its c-terminus, is provided herein. In some embodiments, the charged amino acid is a positively charged amino acid (e.g., arginine, histidine or lysine). In some embodiments, the charged amino acid is a negatively charged amino acid (e.g., aspartic acid or glutamic acid). In some embodiments, the antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11, 12, 13, 14 or 15. In some embodiments, a pharmaceutical composition comprising an anti-IGF-1R antibody is provided herein.

[0020] In certain embodiments, provided herein is a method of treating a disease or disorder, the method comprising administering the pharmaceutical composition and / or antibody provided herein. In some embodiments, the pharmaceutical composition is administered using the syringe provided herein. In certain embodiments, the disease or disorder is thyroid eye disease (TED). In some embodiments, the disease or disorder is stroke, acromegaly, diabetic nephropathy (diabetic kidney disease), idiopathic pulmonary fibrosis, interstitial lung disease, obesity, type 2 diabetes, juvenile idiopathic arthritis (JIA), diffuse cutaneous systemic sclerosis, Sjogren's syndrome with calcinosis and vasculitis, cachexia and sarcopenia, diabetic macular edema, atherosclerosis, peripheral arterial disease (PAD), myocardial infarction and stroke, diabetic foot and skin lesions, rheumatoid arthritis, neurofibromatosis type 1, neurofibromatosis type 2, polycystic kidney disease, multiple hepatic cysts, polycystic ovary syndrome, Alzheimer's disease, cognitive decline, dementia, depression and anxiety, asthma, aging, thyroid eye disease, idiopathic orbital inflammation, human type 2 lipodystrophy and related cardiomyopathy, autosomal dominant polycystic kidney disease (ADPKD), NASH, Graves' disease, and / or Hashimoto's thyroiditis.

[0021] In certain embodiments, the pharmaceutical composition and / or antibody provided herein is used in the treatment of a disease or disorder. In some embodiments, the disease or disorder is thyroid eye disease (TED). In some embodiments, the disease or disorder is stroke, acromegaly, diabetic nephropathy (diabetic kidney disease), idiopathic pulmonary fibrosis, interstitial lung disease, obesity, type 2 diabetes, juvenile idiopathic arthritis (JIA), diffuse cutaneous systemic sclerosis, Sjogren's syndrome with calcinosis and vasculitis, cachexia and sarcopenia, diabetic macular edema, atherosclerosis, peripheral arterial disease (PAD), myocardial infarction and stroke, diabetic foot and skin lesions, rheumatoid arthritis, neurofibromatosis type 1, neurofibromatosis type 2, polycystic kidney disease, multiple hepatic cysts, polycystic ovary syndrome, Alzheimer's disease, cognitive decline, dementia, depression and anxiety, asthma, aging, thyroid eye disease, idiopathic orbital inflammation, human type 2 lipodystrophy and related cardiomyopathy, autosomal dominant polycystic kidney disease (ADPKD), NASH, Graves' disease, and / or Hashimoto's thyroiditis.

[0022] In certain embodiments of the compositions and methods provided herein, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is administered subcutaneously. In certain embodiments, the pharmaceutical composition is formulated for intramuscular administration. In certain embodiments, the pharmaceutical composition is administered intramuscularly. In some embodiments, the pharmaceutical composition is formulated for suborbital, intravitreal, intraocular, subconjunctival, retrobulbar, peribulbar, and / or intrathecal administration. In certain embodiments, the pharmaceutical composition is administered by suborbital, intravitreal, intraocular, subconjunctival, retrobulbar, peribulbar, and / or intrathecal injection.

[0023] In certain embodiments, the pharmaceutical composition is administered with a delivery volume of 3 ml, 2.5 ml, 2 ml, 1.5 ml, or 1 ml or less. In some embodiments, the pharmaceutical composition is administered with a delivery volume of 2 ml or less.

[0024] In certain embodiments, the pharmaceutical composition is administered with a needle sized 24G, 25G, or 27G or less. In some embodiments, the pharmaceutical composition is administered with a 24G needle, 25G needle, or 27G needle.

[0025] In certain embodiments, the pharmaceutical composition is administered with a jet output of 14N, 13N, 12N, 11N, 10N, 9N, 8N, 7N, or 6N or less. In some embodiments, the pharmaceutical composition is administered with a jet output of 12N or less. In certain embodiments, the pharmaceutical composition is administered with a jet output of about 4N, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N, or about 12N.

[0026] In certain embodiments, the methods provided herein treat and / or prevent one or more diseases or disorders. In some embodiments, the disease or disorder is thyroid eye disease (TED). In some embodiments, the disease or disorder is stroke, acromegaly, diabetic nephropathy (diabetic kidney disease), idiopathic pulmonary fibrosis, interstitial lung disease, obesity, type 2 diabetes, juvenile idiopathic arthritis (JIA), diffuse cutaneous systemic sclerosis, Sjogren's syndrome with calcinosis and vasculitis, cachexia and sarcopenia, diabetic macular edema, atherosclerosis, peripheral artery disease (PAD), myocardial infarction and stroke, diabetic foot and skin lesions, rheumatoid arthritis, neurofibromatosis type 1, neurofibromatosis type 2, polycystic kidney disease, polycystic liver disease, polycystic ovary syndrome, Alzheimer's disease, cognitive decline, dementia, depressive and anxiety states, asthma, aging, thyroid eye disease, idiopathic orbital inflammation, human type 2 lipodystrophy and related cardiomyopathy, autosomal dominant polycystic kidney disease (ADPKD), NASH, Graves' disease, and / or Hashimoto's thyroiditis.

[0027] In certain embodiments, the method reduces the severity of thyroid eye disease (TED). The method reduces proptosis in the eyes of a subject having thyroid eye disease (TED). In some embodiments, the proptosis is reduced by at least 2 mm, at least 3 mm, or at least 4 mm.

[0028] In some embodiments, the methods provided herein reduce the clinical activity score (CAS) of thyroid eye disease (TED). In some embodiments, the clinical activity score (CAS) is reduced by at least 2 points. In certain embodiments, the clinical activity score (CAS) is reduced to one (1). In certain embodiments, the clinical activity score (CAS) of the subject is reduced to zero (0).

[0029] In some embodiments, the methods provided herein improve the European Group on Graves' Orbitopathy Clinical Activity Score (EUGOGO CAS) for a subject with Graves' orbitopathy by (at least 1, 2, or 3). In certain embodiments, the method improves the Clinical Myopathy Severity Scale Score (CMSS) for pa by (e.g., at least 1, 2, or 3).

[0030] In certain embodiments, the methods provided herein improve the quality of life of a subject. In some embodiments, the quality of life is measured by the Quality of Life in Graves' Ophthalmopathy (GO-QoL) assessment. In certain embodiments, the quality of life is measured by the visual function or its appearance subscale. In some embodiments, the quality of life is measured by the European Group on Graves' Orbitopathy (EUGOGO) guidelines for Graves' orbitopathy. In certain embodiments, the methods provided herein reduce the severity of diplopia (e.g., constant diplopia, non-constant diplopia, intermittent diplopia).

[0031] In certain aspects, the present invention provides a method of administering a pharmaceutical composition comprising rontigumab. These pharmaceutical compositions can be administered to patients suffering from thyroid eye disease (TED). In certain embodiments, the pharmaceutical compositions of the present invention can be administered intravenously. The method of the present invention provides for intravenous infusion of a pharmaceutical composition comprising rontigumab at up to about 3.0 mg / kg to a patient. In certain embodiments, the method of the present invention provides for administration as an intravenous infusion of a pharmaceutical composition comprising about 0.1, 0.3, 1.0, or 3.0 mg / kg of rontigumab. The present invention further provides that the intravenous infusion can be performed over a period of about 15 minutes to about 120 minutes. In certain preferred embodiments, the intravenous infusion is performed for about 60 minutes.

[0032] In certain embodiments, the invention provides for administration of a pharmaceutical composition comprising lonigutamab by subcutaneous injection. In certain embodiments, the method of the invention provides for subcutaneous administration of up to about 250 mg of lonigutamab. In certain embodiments, the pharmaceutical composition for subcutaneous administration comprises about 20 mg, 40 mg, 125 mg or 250 mg of lonigutamab. The pharmaceutical composition for subcutaneous administration may comprise a volume of from about 0.1 mL to about 3 mL. In certain embodiments, the pharmaceutical composition for subcutaneous administration may comprise a volume of from about 0.5 mL to about 3 mL. In preferred embodiments, the volume administered is up to about 2 mL. Advantageously, subcutaneous administration is within the tolerable volume, so that the pharmaceutical composition could be administered in an outpatient setting or the pharmaceutical composition of the invention could be self-administered by the patient. This leads to a convenient and efficient method for administration of a pharmaceutical composition comprising lonigutamab. In particular, subcutaneous administration of the pharmaceutical composition is beneficial compared to intravenous administration due to the ease of administration of the pharmaceutical composition. Further, as demonstrated by the pharmacokinetic data provided herein, subcutaneous administration of a pharmaceutical composition comprising lonigutamab results in favorable pharmacokinetic and pharmacodynamic characteristics of lonigutamab. Specifically, subcutaneous administration of a pharmaceutical composition comprising lonigutamab results in higher therapeutic effective serum concentrations of lonigutamab over a longer period of time.

[0033] In certain embodiments of the present invention, administration of a pharmaceutical composition comprising lonigutamab results in a maximal IGF-1R receptor occupancy by an anti-IGF-1R antibody. This maximal occupancy of IGF-1R can be achieved at any time after administration of the pharmaceutical composition comprising lonigutamab. In certain embodiments, this is achieved at about 12 hours after administration of the pharmaceutical composition comprising lonigutamab. In certain embodiments, the pharmaceutical composition to be administered can comprise from about 10 mg to about 500 mg of lonigutamab. In certain embodiments, the pharmaceutical composition to be administered can comprise from about 20 mg to about 400 mg of lonigutamab. In preferred embodiments, the pharmaceutical composition to be administered can comprise from about 100 mg to about 300 mg of lonigutamab. In preferred embodiments, the pharmaceutical composition to be administered can comprise about 20 mg or about 40 mg of lonigutamab. In preferred embodiments, the pharmaceutical composition can comprise about 125 mg or about 250 mg of lonigutamab. Notably, the maximal IGF-1R receptor occupancy can be maintained for up to several months after a single administration. In preferred embodiments, the IGF-1R receptor occupancy is maintained for at least about 4 weeks after a single administration of the pharmaceutical composition comprising lonigutamab. The maximal receptor occupancy level can be maintained after a single subcutaneous injection or intravenous infusion of the pharmaceutical composition comprising lonigutamab.

[0034] In certain aspects, the serum concentration required for maximal IGF-1R internalization is a lonigutamab concentration of at least about 3 μg / mL. Thus, the therapeutically effective serum concentration of lonigutamab is at least about 1 μg / mL. In certain preferred embodiments, the therapeutically effective serum concentration of lonigutamab is at least about 3 μg / mL. Importantly, the pharmaceutical compositions of the present invention provide a therapeutically effective serum concentration of lonigutamab to a patient.

[0035] In certain aspects of the present invention, a pharmaceutical composition comprising lonigutamab administered to a patient is safe and well tolerated. Furthermore, there are few adverse events associated with the pharmaceutical compositions of the present invention.

[0036] In certain embodiments, the present invention provides a method for treating thyroid eye disease (TED), the method comprising the step of subcutaneously administering a pharmaceutical composition comprising from about 10 mg to about 500 mg of rontatamab. In certain embodiments, the pharmaceutical composition comprises about 20 mg of rontatamab. In certain embodiments, the pharmaceutical composition comprises about 40 mg of rontatamab. In certain embodiments, the pharmaceutical composition comprises about 125 mg of rontatamab. In certain embodiments, the pharmaceutical composition comprises about 250 mg of rontatamab.

[0037] In certain embodiments, the pharmaceutical composition comprising rontatamab is administered once a week. In certain embodiments, the pharmaceutical composition comprising rontatamab is administered twice a week. In certain embodiments, the pharmaceutical composition comprising rontatamab is administered three times a week. In certain embodiments, the pharmaceutical composition comprising rontatamab is administered every other day, i.e., once every two days. In certain preferred embodiments, the pharmaceutical composition comprising rontatamab is administered once every two (2) weeks. In certain preferred embodiments, the pharmaceutical composition comprising rontatamab is administered once every three (3) weeks. In certain preferred embodiments, the pharmaceutical composition comprising rontatamab is administered once every four (4) weeks. In certain embodiments, the pharmaceutical composition comprising rontatamab is administered once every five (5) weeks. In certain embodiments, the pharmaceutical composition comprising rontatamab is administered once every six (6) weeks.

[0038] In certain preferred embodiments, the pharmaceutical composition comprising rontatamab is administered on day 1 and day 14. In other preferred embodiments, the pharmaceutical composition comprising rontatamab is administered on day 1 and day 21. In other preferred embodiments, the pharmaceutical composition comprising rontatamab is administered on day 1 and day 28.

[0039] In certain preferred embodiments, the pharmaceutical composition containing lonigutamab is administered subcutaneously on day 1 and day 14. In other preferred embodiments, the pharmaceutical composition containing lonigutamab is administered subcutaneously on day 1 and day 21. In other preferred embodiments, the pharmaceutical composition containing lonigutamab is administered subcutaneously on day 1 and day 28.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0060] Detailed Description General Provided herein are novel pharmaceutical compositions comprising antibodies, particularly monoclonal antibodies, that can bind to IGF-1R, as well as methods of making and using such pharmaceutical compositions. In one aspect, provided herein are novel pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof that can bind to IGF-1R and is internalized into cells by inducing internalization of IGF-1R. Also provided herein are certain anti-IGF-1R antibodies that contain a positively charged amino acid (e.g., C-terminal arginine, histidine or lysine) at their C-terminus. Also provided herein is the use of said pharmaceutical compositions and / or antibodies for preventing, reducing the risk of developing or treating IGF-1R-related diseases such as thyroid ophthalmopathy.

[0061] Certain aspects of the present disclosure relate to pharmaceutical compositions and methods for preventing, reducing the risk of developing, or treating thyroid eye disease. Thyroid eye disease is a condition in which the eye muscles, eyelids, lacrimal glands, and adipose tissue behind the eyes become inflamed. This can cause the eyes and eyelids to become red, swollen, and uncomfortable, and may push the eyes forward ("staring" eyes, or "bulging" eyeballs). In some cases, there is swelling and stiffness of the muscles that move the eyes, such that the eyes no longer move in coordination with each other, which can cause double vision. Rarely, TED can cause vision loss due to pressure on the nerves behind the eyes, or ulcers may form on the front of the eyes if the eyelids cannot fully close.

[0062] TED - also known as Graves ophthalmopathy or orbitopathy - is an autoimmune condition. It occurs when the body's immune system attacks the tissues around the eyes, causing inflammation in the tissues around and behind the eyes. In most patients, the same autoimmune condition that causes TED also affects the thyroid, resulting in Graves' disease. Graves' disease most commonly causes hyperthyroidism (overactive thyroid), but rarely can also cause hypothyroidism (underactive thyroid). TED can occur in people when their thyroid is overactive, underactive, or functioning normally. It can also occur after treatment for Graves' disease. People with TED need to be seen by an eye specialist (ophthalmologist) and a thyroid specialist (endocrinologist).

[0063] Current treatments available for the treatment of TED have side effects, including hearing loss. These side effects, reported in a significant proportion of patients receiving current available treatments, limit the viable treatment options for patients with TED. Therefore, there is an unmet need for the development of treatments for TED that have a deeper and more persistent response. Definitions

[0064] As used herein in the present application, "a" or "an" can mean one or more. As used in the claims of the present application, when used in conjunction with the word "comprising", the word "a" or "an" can mean one or more than one. For example, a reference to "an antibody" is a reference to one antibody to many antibodies. As used in the present application, "another" can mean at least a second or higher order.

[0065] The term "immunoglobulin" (Ig) is used interchangeably herein with "antibody". The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies), antibody fragments, and antibody derivatives, provided that they exhibit biological activity. The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. V H and V LBy pairing, a single antigen-binding site is formed. For the structures and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. Light chains from any vertebrate species can be assigned to one of two distinct types called kappa ("κ") and lambda ("λ") based on the amino acid sequence of their constant domains. Immunoglobulins can be assigned to different classes or isotypes depending on the amino acid sequence of their heavy chain constant domains (CH). There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The γ and α classes are further divided into subclasses (isotypes) based on relatively small differences in CH sequence and function. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional arrangements of different classes of immunoglobulins are well known and are generally described, for example, in Abbas et al., Cellular and Molecular Immunology, 4 th ed. (W.B. Saunders Co., 2000).

[0066] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains are designated "V H " and "V Lcan be referred to as "". These domains are generally the most variable parts of the antibody (compared to other antibodies of the same class) and contain the antigen-binding site. The variable domain mediates antigen binding and defines the specificity of that particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain variable domain and the heavy-chain variable domain. The more highly conserved parts of the variable domain are called framework regions (FRs). The variable domains of the native heavy and light chains each contain four FR regions, which predominantly adopt a beta-sheet arrangement connected by and in some cases forming loops that connect beta-sheet structures and are connected by three HVRs. The HVRs in each chain are held together in close proximity by the FR regions and, together with the HVRs from the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not directly involved in the binding of the antibody to the antigen but exhibit various effector functions such as the antibody's involvement in antibody-dependent cell cytotoxicity.

[0067] As used herein, the term "CDR" or "complementary determining region" is intended to mean the discontinuous antigen-binding sites found within the variable regions of both the heavy chain polypeptide and the light chain polypeptide. CDRs are described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991) (also referred to herein as Kabat 1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987) (also referred to herein as Chothia 1987); and MacCallum et al., J. Mol. Biol. 262:732-745 (1996), and these definitions, when compared to each other, include overlapping or subsets of amino acid residues. Nevertheless, the application of any of the definitions for referring to the CDRs of an antibody or a grafted antibody or a variant thereof is intended to be within the scope of the terms defined and used herein. As used herein, the terms "CDR-L1", "CDR-L2", and "CDR-L3" refer to the first, second, and third CDRs, respectively, in the light chain variable region. As used herein, the terms "CDR-H1", "CDR-H2", and "CDR-H3" refer to the first, second, and third CDRs, respectively, in the heavy chain variable region. As used herein, the terms "CDR-1", "CDR-2", and "CDR-3" refer to the first, second, and third CDRs, respectively, in the variable region of either chain.

[0068] Multiple HVR and CDR descriptions are used and are included herein. The HVRs that are Kabat complementarity determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia instead refers to the positions of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on the analysis of available complex crystal structures. Residues from each of these HVRs are described below. Loop Kabat AbM Chothia Contact L1 L24~L34 L24~L34 L26~L32 L30~L36 L2 L50~L56 L50~L56 L50~L52 L46~L55 L3 L89~L97 L89~L97 L91~L96 L89~L96 H1 H31~H35B H26~H35B H26~H32 H30~H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H53-H55 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101

[0069] HVRs can include the following "extended HVRs": 24~36 or 24~34 (L1), 46~56 or 50~56 (L2), and 89~97 or 89~96 (L3) in VL, and 26~35 (H1), 50~65 or 49~65 (preferred embodiment) (H2), and 93~102, 94~102, or 95~102 (H3) in VH. Variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0070] The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the immunoglobulin heavy chain (e.g., the EU index reported in Kabat et al., supra). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies. Unless otherwise stated herein, references to residue numbers in the variable domain of an antibody mean residue numbering according to the Kabat numbering system. Unless otherwise stated herein, references to residue numbers in the constant domain of an antibody mean residue numbering according to the EU numbering system (see, e.g., U.S. Patent Application Publication No. 2010-280227).

[0071] As used herein, the expression "IGF-1R antibody" should be construed in the same manner as "anti-IGF-1R antibody" and means an antibody capable of binding to IGF-1R. In embodiments of the present application, the epitope of the antibody is located in the extracellular domain of human IGF-1R (also referred to as IGF-1R ECD). In certain embodiments, the antibody, or any antigen-binding fragment thereof, is between 10×10 -10 ~1×10 -10 and, more preferably, between 8×10 -10 ~2×10 -10 M and can bind to IGF-1R in EC 50 .

[0072] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies in the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. A monoclonal antibody is highly specific and is an antibody directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is an antibody directed against a single determinant on an antigen.

[0073] An "antibody fragment" or "antigen-binding fragment" or "functional fragment" of an antibody includes a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody, or the F region of an antibody that retains or has modified FcR-binding ability. Examples of antibody fragments include Fab, Fab’, F(ab’)2 and Fv fragments; diabodies; and linear antibodies (see, e.g., U.S. Patent No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)). Additional examples of antibody fragments include antibody derivatives formed from antibody fragments, e.g., single-chain antibody molecules, monovalent antibodies, and multispecific antibodies.

[0074] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. The boundaries of the Fc region of an immunoglobulin heavy chain can vary, but the human IgG heavy chain Fc region is typically defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification or by recombinant manipulation of the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include a population of antibodies in which all K447 residues have been removed, a population of antibodies in which the K447 residues have not been removed, and a population of antibodies having a mixture of antibodies with the K447 residues removed and antibodies with the K447 residues not removed. Native-sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0075] A "native sequence Fc region" includes an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions, as well as naturally-occurring variants thereof.

[0076] A "variant Fc region" contains an amino acid sequence that is different from that of the native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to the native sequence Fc region or the Fc region of the parent polypeptide, for example, about 1 to about 10 amino acid substitutions in the native sequence Fc region or in the Fc region of the parent polypeptide, and preferably about 1 to about 5 amino acid substitutions. The variant Fc region is herein considered to have at least about 80% homology with the native sequence Fc region and / or the Fc region of the parent polypeptide, and most preferably at least about 90% homology with it, more preferably at least about 95% homology with it.

[0077] As used herein, a "chimeric antibody" refers to an antibody (immunoglobulin) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, but the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, in addition to fragments of such antibodies, provided that the antibody exhibits the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies for the purposes herein include PRIMATIZED™ antibodies in which the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing a cynomolgus with the antigen of interest. As used herein, a "humanized antibody" is a subset of "chimeric antibodies".

[0078] A "humanized" form of a non-human (e.g., mouse) antibody is a chimeric antibody that contains minimal sequences derived from non-human immunoglobulins. In some embodiments, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's HVRs have been replaced with residues from the HVRs of a non-human species (donor antibody), such as a mouse, rat, rabbit, or non-human primate, that have the desired specificity, affinity, and / or capacity. In some cases, the FR residues of the human immunoglobulin are replaced with the corresponding non-human residues. Additionally, a humanized antibody may contain residues not found in either the recipient antibody or the donor antibody. These modifications can be added to further improve antibody properties such as binding affinity. Generally, a humanized antibody has at least one, and typically two, variable domains in which all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin sequence and all or substantially all of the FR regions correspond to those of the human immunoglobulin sequence, but the FR regions may contain one or more individual FR residue substitutions that improve antibody properties such as binding affinity, isomerization, immunogenicity, etc., and will typically contain substantially all of the variable domains. The number of these amino acid substitutions in the FRs is typically six or fewer in the H chain and three or fewer in the L chain. A humanized antibody will also typically contain at least a portion of the immunoglobulin constant region (Fc), typically that of a human immunoglobulin, if desired. For further details, see, for example, Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).For example, see also Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0079] "Human antibody" refers to an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and / or an antibody produced using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) are also available for the preparation of human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal whose endogenous locus has been inactivated but which has been modified to produce such antibodies in response to an antigen challenge, e.g., immunized xenomice. (See, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE (TM) technology). See also Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006) for human antibodies produced by human B cell hybridoma technology.)

[0080] "Acceptor human framework", as used herein, is a framework that includes the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain existing amino acid sequence variations. In some embodiments, the number of existing amino acid variations is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When existing amino acid variations are present in VH, these preferred variations occur exclusively at positions 71H, 73H, and 78H, in three, two, or one of these positions, respectively. For example, the amino acid residues at these positions can be 71A, 73T, and / or 78A. In some embodiments, the VL acceptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

[0081] The "human consensus framework" is a framework that represents the amino acid residues that are most frequently present when selecting human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from subgroups of variable domain sequences. Generally, the subgroups of sequences are subgroups such as those in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). As an example, for VL, the subgroups can be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al., supra. In addition, for VH, the subgroups can be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0082] "Amino acid modification" at a specified position refers to substitution or deletion of the specified residue, or insertion of at least one amino acid residue adjacent to the specified residue. An insertion "adjacent" to the specified residue means an insertion within 1 to 2 residues thereof. The insertion can be on the N-terminal side or the C-terminal side of the specified residue. Preferred amino acid modifications herein are substitutions.

[0083] "Identity", as used herein, indicates that at any particular position in the aligned sequences, the amino acid residues are identical between the sequences. "Similarity", as used herein, indicates that at any particular position in the aligned sequences, the amino acid residues are of a similar type between the sequences. For example, leucine can be substituted with isoleucine or valine. Other amino acids that are likely to be frequently substituted with each other include, but are not limited to, the following: - phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains); - Lysine, arginine, and histidine (amino acids with basic side chains); - Aspartic acid and glutamic acid (amino acids with acidic side chains); - Asparagine and glutamine (amino acids with amide side chains); and - Cysteine and methionine (amino acids with sulfur-containing side chains).

[0084] The degree of identity and similarity can be easily calculated. (See, for example, Computational Molecular Biology, Lesk, A.M., ed., Oxford University Press, New York, 1988; Biocomputing. Informatics and Genome Projects, Smith, D.W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991)

[0085] As used herein, "interaction" between IGF-1R and a second protein includes, but is not limited to, protein-protein interaction, physical interaction, chemical interaction, binding, covalent bond, and ionic bond. As used herein, an antibody "inhibits the interaction" between two proteins if the antibody disrupts, reduces, or completely abolishes the interaction between the two proteins. An antibody of the present disclosure, or a fragment thereof, "inhibits the interaction" between two proteins if the antibody or the fragment thereof binds to one of the two proteins.

[0086] As used herein, "percent amino acid sequence identity (%)" and "homology" with respect to a peptide, polypeptide or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent sequence identity, and where any conservative substitutions are not considered part of the sequence identity. Alignments for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill in the art, using publicly available computer software such as, for example, BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art for achieving maximum alignment over the full length of the sequences being compared. The term "prevent" is recognized in the art and, when used with respect to a condition such as thyroid eye disease (TED) related symptoms, is with respect to a patient who has not received treatment.

[0087] "Causing to recover" refers to the act of returning to a normal or healthy state. Recovery may be partial (e.g., where the subject returns to a state that is less than normal or healthy), or it may be complete (e.g., where the subject returns to a state that is the same as or nearly the same as the normal or healthy state). An example of a normal or healthy state is the vision of a patient prior to thyroid eye disease (TED).

[0088] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction, such as an attraction or binding between a target and an antibody, that is a factor in determining the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically or preferentially binds to a target or epitope binds to this target or epitope with greater affinity, binding strength, more readily, and / or for a longer period of time than it binds to other targets, or other epitopes of the target. It is understood that, for example, an antibody (or portion) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. An antibody that specifically binds to a target binds with at least about 10 3 M -1 or 10 4 M -1 and, sometimes, about 10 5 M -1 or 10 6 M -1 In other cases, about 10 6 M -1 or 10 7 M -1 about 10 8 M -1 to 10 9 M -1 or about 10 10 M -1 to 10 11 M -1It may have an association constant equal to or higher than that. Various immunoassay formats can be used to select antibodies that specifically immunoreact with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies that specifically immunoreact with a protein. For an explanation of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0089] As used herein, the term "subject" refers to a living mammal and can be used interchangeably with the term "patient". Examples of mammals include any member of the class Mammalia: humans, non-human primates such as chimpanzees, as well as other apes and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; laboratory animals such as rabbits, dogs and cats; and experimental animals including rodents such as rats, mice and guinea pigs, but are not limited thereto. This term does not indicate a particular age or gender.

[0090] The term "therapeutically effective amount" of a compound with respect to a method of treating a subject refers to the amount of the compound in a preparation that, when administered as part of a desired dosage regimen (to a mammal, preferably a human), alleviates symptoms, improves a condition, or delays the onset of a medical condition, according to clinically acceptable criteria for the disorder or condition to be treated or for aesthetic purposes, e.g., at a reasonable benefit-to-risk ratio applicable to any medical treatment. The therapeutically effective amount herein can vary depending on factors such as the patient's disease state, age, gender and weight, as well as the ability of the antibody to elicit the desired response in an individual.

[0091] As used herein, the term "treating" or "treatment" includes reducing, preventing, or reversing the symptoms, clinical signs, or underlying pathology of a condition in order to stabilize or improve the condition of a subject, or to reduce the likelihood that the condition of the subject will deteriorate to the same extent as if the subject had not received treatment. "Improving vision" refers to an act of enhancing the ability or state that can be seen relative to before treatment, including improving the acuity, sensitivity, and / or range of the visual field. antibody

[0092] In certain embodiments, pharmaceutical compositions comprising anti-IGF-1R antibodies are provided herein. Also provided herein are anti-IGF-1R antibodies having a heavy chain that includes a charged amino acid at its C-terminus.

[0093] The insulin-like growth factor 1 receptor, called IGF-1R (also known as IGF1R or IGF-IR), is a receptor with tyrosine kinase activity that has 70% homology with the insulin receptor IR. IGF-1R is a glycoprotein with a molecular weight of approximately 320 kDa. It is a heterotetrameric receptor in which each of the halves linked by disulfide bridges is composed of an extracellular α-subunit and a transmembrane β-subunit. IGF-1R binds to IGF1 and IGF2 with very high affinity (Kd #1 nM), but at the same time can bind to insulin with an affinity 1 / 100 to 1 / 1000 that of IGF-1R. Conversely, IR binds to insulin with very high affinity, while IGF binds to the insulin receptor with only 1 / 100 the affinity of insulin. The tyrosine kinase domain of IGF-1R and the tyrosine kinase domain of IR have very high sequence homology, but regions of lower homology are involved in the cysteine-rich region located on the α-subunit and the C-terminal portion of the β-subunit, respectively. The differences in the sequences observed in the α-subunit are located in the ligand-binding zone and are thus at the origin of the relative affinities of IGF-1R and IR for IGF and insulin, respectively. The differences in the C-terminal portion of the β-subunit result in differences in the signaling pathways of the two receptors; IGF-1R mediates mitogenic, differentiating and anti-apoptotic effects, while activation of IR is mainly associated with effects at the metabolic pathway level.

[0094] Cytoplasmic tyrosine kinase proteins are activated by the binding of a ligand to the extracellular domain of the receptor. Also, activation of the kinase is accompanied by the stimulation of different intracellular substrates including IRS-1, IRS-2, Shc and Grb 10. The two major substrates of IGF-1R are IRS and Shc, which mediate most of the growth and differentiation effects associated with the attachment of IGF to this receptor by the activation of a very large number of downstream effectors. Therefore, substrate availability determines the ultimate biological effects associated with the activation of IGF-1R. When IRS-1 is dominant, cells tend to proliferate and transform. When Shc is dominant, cells tend to differentiate. The pathway mainly involved in the protective effect against apoptosis seems to be the phosphatidyl-inositol 3-kinase (PI 3-kinase) pathway.

[0095] In certain embodiments, such antibodies exhibit a high ability to be internalized after IGF-1R binding. As used herein, an "internalized" or "internalizing" antibody is an antibody that, when bound to IGF-1R on mammalian cells, is taken up by the cell (which means it "enters" the cell). Certain anti-IGF-1R antibodies provided herein are disclosed in U.S. Patent No. 10,202,458, which is hereby incorporated by reference herein for the antibodies, antibody sequences and related compositions that it discloses.

[0096] In certain embodiments, the anti-IGF-1R antibody is rontumumab or an anti-IGF-1R antibody derived from rontumumab (e.g., sharing at least one CDR, e.g., CDRH3, with rontumumab).

[0097] In certain embodiments, the anti-IGF-1R antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6, as shown in the table below.

Table 32

[0098] In some embodiments, the anti-IGF-1R antibody is

Chemical formula

[0099] In some embodiments, the anti-IGF-1R antibody is

Chemical formula

[0100] In some embodiments, the anti-IGF-1R antibody is

Chemical formula

[0101] In some embodiments, the antibody includes a heavy chain that further contains a charged amino acid (e.g., a C-terminal arginine, histidine, lysine, aspartic acid, or glutamic acid) at its C-terminus. In some embodiments, the charged amino acid is a positively charged amino acid (e.g., arginine, histidine, or lysine). In some embodiments, the charged amino acid is a negatively charged amino acid (e.g., aspartic acid or glutamic acid).

[0102] In some embodiments, the anti-IGF-1R antibody

Chemical formula

[0103] In some embodiments, the anti-IGF-1R antibody

Chemical formula

[0104] In some embodiments, the anti-IGF-1R antibody

Chemical formula

[0105] In some embodiments, the anti-IGF-1R antibody [Chem.] comprises a heavy chain comprising the amino acid sequence of

[0106] In some embodiments, the anti-IGF-1R antibody [Chem.] [Chem.] comprises a heavy chain comprising the amino acid sequence of

[0107] In some embodiments, the anti-IGF-1R antibody [Chem.] comprises a light chain comprising the amino acid sequence of. In some embodiments, the light chain comprises a sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In certain embodiments, the light chain comprises a sequence that is identical to SEQ ID NO: 10 apart from 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid substitutions, additions and / or deletions. In certain embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the amino acid substitutions, additions and / or deletions occur outside the heavy chain CDR domains.

[0108] Full-length antibodies can be prepared by using recombinant DNA manipulation techniques. Such engineered versions include, for example, those created from natural antibody variable regions by insertions, deletions, or changes within or to the amino acid sequence of the natural antibody. Specific examples of this type include engineered variable region domains containing at least one CDR from one antibody and, optionally, one or more framework amino acids, and the remainder of the variable region domain from a second antibody. DNA encoding an antibody can be prepared by deleting all but the desired portions of the DNA encoding the full-length antibody. DNA encoding a chimeric antibody can be prepared by recombining DNA encoding a human constant region substantially or exclusively and DNA encoding a variable region substantially or exclusively derived from the sequence of a non-human mammalian variable region. DNA encoding a humanized antibody can be prepared by recombining DNA encoding the constant and variable regions other than the complementarity determining regions (CDRs) substantially or exclusively derived from the corresponding human antibody regions and DNA encoding CDRs substantially or exclusively derived from a non-human mammalian source.

[0109] Suitable sources of DNA molecules encoding antibodies include cells that express full-length antibodies, such as hybridomas. For example, antibodies can be isolated from host cells that express expression vectors encoding the heavy and / or light chains of the antibody.

[0110] Antibody fragments, including but not limited to Fab fragments, and / or antibody derivatives can also be prepared by using recombinant DNA manipulation techniques, including manipulation and re-expression of DNA encoding antibody variable and constant regions. Standard molecular biology techniques can be used to further modify, add, or delete amino acids or domains as desired. Any changes to the variable or constant regions are also encompassed by the terms "variable" and "constant" regions as used herein. In some cases, C H C such that translation of one domain stops at an interchain cysteineH PCR is used to generate antibody fragments by introducing a stop codon immediately after the codon encoding the inter-chain cysteine of 1. Methods for designing suitable PCR primers are well known in the art, and the sequence of the antibody C H 1 domain is readily available. In some embodiments, the stop codon can be introduced using site-directed mutagenesis techniques.

[0111] The antibodies of the present disclosure can be derived from any antibody isotype ( "class"), including, for example, IgG, IgM, IgA, IgD, and IgE, and its subclasses, including, for example, IgG1, IgG2, IgG3, and IgG4. In certain preferred embodiments, the heavy and light chains of the antibody are from IgG. The heavy and / or light chains of the antibody may be from murine IgG or human IgG. In certain other preferred embodiments, the heavy and / or light chains of the antibody are from human IgG1. In still other preferred embodiments, the heavy and / or light chains of the antibody are from human IgG4.

[0112] The antibodies of the present disclosure can be monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, human antibodies, chimeric antibodies, multispecific antibodies, antibody fragments thereof, or derivatives thereof. In some embodiments, the antibody is a humanized antibody.

[0113] The antibodies of the present disclosure can also be antibody fragments, such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, or single-chain antibody molecules. In some embodiments, the antibody fragment is a Fab fragment.

[0114] In some embodiments, the antibody can be a human monoclonal antibody prepared, expressed, produced or isolated by recombinant means, e.g., (a) an antibody isolated from an animal (e.g., a mouse) in which the human immunoglobulin gene or a hybridoma prepared therefrom is transgenic or translchromosomal (further described below), (b) an antibody isolated from a host cell transformed to express the antibody, e.g., a transfectoma, (c) an antibody isolated from a recombinant, combinatorial human antibody library, and (d) an antibody prepared, expressed, produced or isolated by any other means involving splicing of the human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline and / or non-germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subject to in vitro mutagenesis (or, if an animal in which the human Ig sequence is transgenic is used, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions are derived from and related to human germline V H and V L sequences, but are sequences that may not naturally occur in the human antibody germline repertoire in vivo.

[0115] In some embodiments, the antibody can be a humanized and / or chimeric monoclonal antibody produced by immunizing a rodent (e.g., a mouse, rat, hamster and guinea pig) with either (1) native IGF-1R obtained from enzymatic digestion of IGF-1R purified from human plasma or serum, or (2) a recombinant IGF-1R or a fragment derived therefrom expressed by either a eukaryotic cell line or a prokaryotic cell line. Other animals, such as non-human primates, transgenic mice expressing human immunoglobulins, and severe combined immunodeficiency (SCID) mice transplanted with human B lymphocytes can be used for immunization.

[0116] Polyclonal and monoclonal antibodies are naturally produced as immunoglobulin (Ig) molecules in response to pathogens by the immune system. The predominant form at a concentration of 8 mg / ml in human serum, the ~150 kDa IgG1 molecule, is composed of two identical ~50 kDa heavy chains and two identical ~25 kDa light chains.

[0117] Hybridomas can be generated by conventional procedures involving fusing B lymphocytes from immunized animals with myeloma cells. Additionally, antibodies can be generated by screening recombinant single-chain Fv or Fab libraries from human B lymphocytes in a phage display system. The specificity of MAbs against human IGF-1R can be tested by enzyme-linked immunosorbent assay (ELISA), Western blotting, or other immunochemical techniques. Nucleic Acids, Vectors, and Host Cells

[0118] Antibodies suitable for use in the methods of the present disclosure can be produced using recombinant methods and compositions, such as those described in U.S. Patent No. 4,816,567. In some embodiments, an isolated nucleic acid having a nucleotide sequence encoding any of the antibodies of the present disclosure is provided. Such nucleic acids can encode the amino acid sequence containing the V L / C L of the antibody, and / or the amino acid sequence containing the V H / C H 1 of the antibody. In some embodiments, one or more vectors (e.g., expression vectors) containing such nucleic acids are provided. Host cells containing such nucleic acids can also be provided. The host cells contain (1) a vector containing a nucleic acid encoding the amino acid sequence containing the V L / C L of the antibody and the amino acid sequence containing the V H / C H 1 of the antibody, or (2) a first vector containing a nucleic acid encoding the amino acid sequence containing the V L / C L of the antibody, and the V H / C H It may contain a second vector containing a nucleic acid encoding an amino acid sequence containing 1 (for example, transfected therewith). In some embodiments, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (for example, Y0, NS0, Sp20 cells). In some embodiments, the host cell is a bacterium such as E. coli.

[0119] A method for producing an anti-IGF-1R antibody is disclosed herein. The method includes culturing a host cell of the present disclosure containing a nucleic acid encoding an anti-IGF-1R antibody under conditions suitable for the expression of the antibody. In some embodiments, the antibody is then recovered from the host cell (or host cell culture medium).

[0120] For the recombinant production of the humanized anti-IGF-1R antibody of the present disclosure, a nucleic acid encoding the antibody is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acids can be easily isolated and sequenced using conventional procedures (for example, by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody).

[0121] Suitable vectors containing nucleic acid sequences encoding any of the antibodies of the present disclosure or fragments thereof, polypeptides (including antibodies) described herein, include, but are not limited to, cloning vectors and expression vectors. Suitable cloning vectors can be constructed according to standard techniques or selected from a number of cloning vectors available in the art. The cloning vector selected may vary depending on the host cell intended to be used, but useful cloning vectors generally have the ability to self-replicate, may have a single target for a particular restriction endonuclease, and / or may carry a gene for a marker that can be used in selecting clones containing the vector. Suitable examples include plasmids and bacterial viruses, such as pUC18, pUC19, Bluescript (e.g., pBS SK+ ) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors, such as pSA3 and pAT28. These and other cloning vectors are available from commercial vendors such as BioRad, Stratagene, and Invitrogen.

[0122] A vector containing the nucleic acid of interest can be introduced into a host cell by any of a number of suitable means, including electroporation; transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran or other substances; particle bombardment; lipofection; and infection (e.g., if the vector is an infectious agent such as vaccinia virus). The choice of the introduced vector or polynucleotide will often depend on the characteristics of the host cell. In some embodiments, the vector contains a nucleic acid containing one or more amino acid sequences encoding the anti-IGF-1R antibody of the present disclosure.

[0123] Host cells suitable for the cloning or expression of antibody encoding vectors include prokaryotic or eukaryotic cells. For example, the anti-IGF-1R antibodies of the present disclosure can be produced in bacteria, particularly when glycosylation and Fc effector functions are not required. For the expression of antibody fragments and polypeptides in bacteria (e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523, which describe the expression of antibody fragments in E. coli; and Charlton, Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254). In other embodiments, the antibodies of the present disclosure can be produced in eukaryotic cells, such as Chinese hamster ovary (CHO) cells or lymphocyte-derived cells (e.g., Y0, NS0, Sp20 cells) (e.g., U.S. Patent Application No. 14 / 269,950, U.S. Pat. No. 8,981,071, Eur J Biochem. 1991 Jan 1;195(1):235-42). After expression, the antibody can be isolated from the bacterial cell paste in the soluble fraction and further purified. Pharmaceutical Compositions and Administration

[0124] The present disclosure generally relates to pharmaceutical compositions comprising the anti-IGF-1R antibodies disclosed herein. As used herein, the expression "pharmaceutical composition" (also referred to as "pharmaceutical formulation") means a combination of at least one active ingredient (e.g., the anti-IGF-1R antibodies disclosed herein) and at least one inactive ingredient, which is suitable for therapeutic administration to humans or non-human animals when combined with the active ingredient and / or one or more additional inactive ingredients.

[0125] In certain embodiments, provided herein is a pharmaceutical composition comprising (a) at least 75 mg / ml of an anti-IGF-1R antibody; (b) 20-30 mM histidine; and (c) 4%-6% D-sorbitol, and having a pH of 5.5-6.5.

[0126] In certain embodiments, the pharmaceutical composition comprises at least 75 mg / ml of an anti-IGF-1R antibody. In some embodiments, the pharmaceutical composition comprises at least 100 mg / ml, at least 125 mg / ml, at least 150 mg / ml, at least 175 mg / ml, at least 200 mg / ml, or at least 250 mg / ml of an anti-IGF-1R antibody. In certain embodiments, the pharmaceutical composition comprises 75 mg / ml to 300 mg / ml, 100 mg / ml to 300 mg / ml, or 125 mg / ml to 250 mg / ml of an anti-IGF-1R antibody. In some embodiments, the pharmaceutical composition comprises about 125 mg / ml, about 150 mg / ml, about 175 mg / ml, about 200 mg / ml, or about 250 mg / ml of an anti-IGF-1R antibody.

[0127] In some embodiments, the pharmaceutical composition comprises 20 to 30 mM histidine. In certain embodiments, the pharmaceutical composition comprises about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM or about 30 mM histidine.

[0128] In some embodiments, the pharmaceutical composition comprises 4% to 6% D-sorbitol. In certain embodiments, the pharmaceutical composition comprises about 4%, 5% or 6% D-sorbitol.

[0129] In some embodiments, the pharmaceutical composition has a pH of 5.5 to 6.5. In certain embodiments, the pharmaceutical composition has a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5.

[0130] In some embodiments, the pharmaceutical composition does not contain polysorbate 80. In some embodiments, the pharmaceutical composition contains a small amount of polysorbate 80 (e.g., less than 0.05%). In certain embodiments, the pharmaceutical composition contains 0.05% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.02% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.01% or less of polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.005% or less of polysorbate 80. In certain embodiments, the pharmaceutical composition further contains 0.002% - 0.05% of polysorbate 80. In some embodiments, the pharmaceutical composition contains about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045% or about 0.05% of polysorbate 80.

[0131] In some embodiments, the pharmaceutical composition does not contain poloxamer 188. In some embodiments, the pharmaceutical composition contains a small amount of poloxamer 188 (e.g., less than 0.1%) as a surfactant. In certain embodiments, the pharmaceutical composition contains 0.1% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.05% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.02% or less of poloxamer 188. In some embodiments, the pharmaceutical composition contains 0.01% or less of poloxamer 188. In some embodiments, the pharmaceutical composition further contains 0.01% - 0.1% of poloxamer 188. In certain embodiments, the pharmaceutical composition contains about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09% or about 0.1% of poloxamer 188.

[0132] In certain embodiments, the pharmaceutical compositions provided herein exhibit a high level of stability. As used herein with respect to a pharmaceutical composition, the term "stable" means that the antibody in the pharmaceutical composition retains an acceptable degree of structure and / or function and / or biological activity after storage for a defined period. A composition may be stable if, after storage for a defined period, the antibody contained therein retains, even if not 100% of its structure and / or function and / or biological activity. Under certain circumstances, retention of about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98% or about 99% of the structure and / or function and / or biological activity of the antibody after storage for a defined period may be considered "stable".

[0133] Stability can be measured, inter alia, by determining the percentage of native antibody remaining in the composition after storage at a given temperature for a defined period. The percentage of native antibody can be determined, inter alia, by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). “Acceptable degree of stability,” when this phrase is used herein, means that at least 90% of the antibody in monomeric form can be detected in the composition after storage at a given temperature for a defined period. In certain embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the antibody in monomeric form can be detected in the composition after storage at a given temperature for a defined period. The defined period after which stability is measured can be at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or a period exceeding that. When evaluating stability, the temperature at which the pharmaceutical composition can be stored can be any temperature from about -80°C to about 45°C, for example, storage at about -30°C, about -20°C, about 0°C, about 5°C, about 25°C or about 45°C. For example, a pharmaceutical composition can be considered stable if more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC after storage at 5°C for 3 months. A pharmaceutical composition can also be considered stable if more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC after storage at 5°C for 6 months. A pharmaceutical composition can also be considered stable if more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC after storage at 5°C for 9 months. A pharmaceutical composition can also be considered stable if more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC after storage at 25°C for 3 months.The pharmaceutical composition may also be considered stable if, after storage at 25°C for 6 months, more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC. The pharmaceutical composition may also be considered stable if, after storage at 25°C for 9 months, more than about 90%, 95%, 96% or 97% of the monomeric antibody is detected by SE-HPLC.

[0134] To evaluate the stability of the pharmaceutical compositions disclosed herein, other methods can be used, such as differential scanning calorimetry (DSC) to determine temperature stability, controlled agitation to determine mechanical stability, and absorbance at about 350 nm or about 405 nm to determine solution turbidity. For example, the pharmaceutical compositions disclosed herein, after storage at about 5°C to about 25°C for 6 months or more months, the OD of the composition 405 of the composition at t = 0 405 If the change from is less than about 0.05 (e.g., 0.04, 0.03, 0.02, 0.01, or less), it may be considered stable.

[0135] Stability can also be evaluated by measuring the biological activity of the antibody and / or its binding affinity for its target. For example, the compositions disclosed herein, after storage for a defined period (e.g., 1 to 12 months) at, for example, 5°C, 25°C, 45°C, etc., the anti-IGF-1R antibody contained in the composition binds to IGF-1R with an affinity of at least 50%, 60%, 70%, 80%, 90%, 95%, or higher than the binding affinity of the antibody before said storage, it may be considered stable. Additional methods for evaluating the stability of the antibody in the composition are demonstrated in the examples presented below.

[0136] In certain embodiments, after 12 weeks at -20°C and 2 - 8°C, the pharmaceutical compositions provided herein continue to exhibit very good stability in terms of low aggregation, as confirmed by both visual evaluation and SEC-HPLC. Data from SEC-HPLC do not demonstrate a perceptible increase in high molecular weight species (HMWS) from T0 to T12w in equivalent runs at both temperatures. CEX-HPLC analysis demonstrates that the compositions exhibit good chemical stability after 12 weeks at -20°C and 2 - 8°C. From the CEX-HPLC data, slightly higher values of the major species % are observed for samples maintained at 2 - 8°C. This indicates that the freeze-thaw cycles experienced by samples at -20°C do not affect aggregation but are detrimental to the chemical stability of the molecules. The improved chemical stability is obtained from formulation 3a which contains sorbitol as an isotonicity modifier and no PS80 is added (seen in Example 1 at both 2 - 8°C and -20°C).

[0137] DLS measurements demonstrate that the particle size Z D remains virtually unchanged after 12 weeks at both temperatures. The PDI values tend to increase with time, but all compositions remain monodisperse after 12 weeks.

[0138] In some embodiments, the pharmaceutical composition is stable for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks. In some embodiments, the pharmaceutical composition is stable at temperatures from -20°C to 8°C.

[0139] In the case of a fluid form, the pharmaceutical composition provided herein may exhibit low to medium levels of viscosity in certain embodiments. "Viscosity", as used herein, can be "kinematic viscosity" or "absolute viscosity". "Kinematic viscosity" is a measure of the resistive flow of a fluid under the influence of gravity. When two fluids of equal volume are placed in the same capillary viscometer and allowed to flow by gravity, the viscous fluid takes longer to flow through the capillary than the less viscous fluid. For example, if one fluid takes 200 seconds to complete its flow and another fluid takes 400 seconds, the second fluid is twice as viscous as the first fluid on the dynamic viscosity scale. "Absolute viscosity", sometimes called dynamic or simple viscosity, is the product of kinematic viscosity and fluid density (absolute viscosity = kinematic viscosity × density). The magnitude of kinematic viscosity is L 2 / T, where L is length and T is time. Generally, kinematic viscosity is expressed in centistokes (cSt). The International System of Units (SI) unit of kinematic viscosity is mm 2 / s, which is 1 cSt. Absolute viscosity is expressed in units of centipoise (cP). The SI unit of absolute viscosity is millipascal - second (mPa·s), and in this case, 1 cP = 1 mPa·s.

[0140] As used herein, a low level of viscosity shall refer to an absolute viscosity of less than about 20 centipoise (cP) with respect to the pharmaceutical compositions disclosed herein. For example, the pharmaceutical compositions disclosed herein, when measured using standard viscosity measurement techniques, shall be considered to have "low viscosity" if the composition exhibits an absolute viscosity of about 19 cP, about 18 cP, about 17 cP, about 16 cP, about 15 cP, about 14 cP, about 13 cP, about 12 cP, about 11 cP, about 10 cP, about 9 cP, about 8 cP, about 7 cP, about 6 cP, about 5 cP, about 4 cP, or less at 21°C. As used herein, a medium level of viscosity shall refer to an absolute viscosity between about 30 cP and about 20 cP at 21°C with respect to the pharmaceutical compositions disclosed herein. For example, the pharmaceutical compositions disclosed herein, when measured using standard viscosity measurement techniques, shall be considered to have "medium viscosity" if the composition exhibits an absolute viscosity of about 30 cP, about 29 cP, about 28 cP, about 27 cP, about 26 cP, about 25 cP, about 24 cP, about 23 cP, about 22 cP, about 21 cP, or about 20 cP at 21°C.

[0141] In some embodiments, the weight osmolality of the pharmaceutical composition is within a physiological weight osmolality range of 250 to 400 mOsm / kg. In some embodiments, the viscosity of the pharmaceutical composition is 30 cP or less at 21°C. In some embodiments, the viscosity of the pharmaceutical composition is 15 cP or less at 21°C. In some embodiments, the viscosity of the pharmaceutical composition is about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 21 cP, about 22 cP, about 23 cP, about 24 cP, about 25 cP, about 26 cP, about 27 cP, about 28 cP, about 29 cP, or about 30 cP at 21°C. Syringe

[0142] In certain embodiments, the present disclosure relates to a syringe comprising a pharmaceutical composition disclosed herein. In some embodiments, the syringe comprises a delivery volume of 2 ml or less. In some embodiments, the syringe comprises a needle sized 24G (e.g., 25G, 27G) or less. In some embodiments, the syringe is an automated reusable fixed-dose pen. In some embodiments, the syringe is an automated reusable variable-dose pen. In some embodiments, the syringe is an automated disposable fixed-dose self-injector.

[0143] In some embodiments, the pharmaceutical compositions provided herein can be contained within any container suitable for storage of drugs and other therapeutic compositions. For example, the pharmaceutical composition can be contained within a sealed, sterile plastic or glass container having a defined volume, such as a vial, ampule, syringe, cartridge, or bottle. For example, different types of vials, including transparent and opaque (e.g., amber) glass or plastic vials, can be used to contain the compositions provided herein. Similarly, any type of syringe can be used to contain and / or administer the pharmaceutical compositions disclosed herein.

[0144] The pharmaceutical compositions provided herein can be contained within a "normal tungsten" syringe or a "low tungsten" syringe. As will be understood by those skilled in the art, the process of making a glass syringe generally involves the use of a high temperature tungsten rod, which serves to make holes in the glass, thereby creating holes through which liquid can be withdrawn and discharged from the syringe. This process results in the deposition of trace amounts of tungsten on the inner surface of the syringe. Subsequent washing and other processing steps can be used to reduce the amount of tungsten in the syringe. As used herein, the term "normal tungsten" means that the syringe contains more than 500 parts per billion (ppb) of tungsten. The term "low tungsten" means that the syringe contains less than 500 ppb of tungsten. For example, a low tungsten syringe can contain less than or equal to about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 ppb of tungsten.

[0145] The pharmaceutical compositions provided herein can be contained within a plastic syringe. For the past decade, the use of filled plastic syringes for pharmaceutical proteins and peptide pharmaceuticals has been approved. For example, the pharmaceutical composition can be contained within a Daikyo Crystal Zenith (CZ) syringe (Daikyo Seiko, Ltd., Tokyo).

[0146] The rubber plunger used in a syringe and the rubber stopper used to close the opening of a vial can be coated to prevent contamination of the medical contents of the syringe or vial and / or to maintain their stability. Thus, the pharmaceutical compositions provided herein can, according to certain embodiments, be contained within a syringe containing a coated plunger or within a vial sealed by a coated rubber stopper. For example, the plunger or stopper can be coated with a fluorocarbon thin film. Examples of coated stoppers and / or plungers suitable for use with vials and syringes containing the pharmaceutical compositions disclosed herein are described, for example, in U.S. Patent Nos. 4,997,423; 5,908,686; 6,286,699; 6,645,635; and 7,226,554, the contents of these reference patent documents being hereby incorporated by reference in their entirety. Certain exemplary coated rubber stoppers and plungers that can be used in the methods disclosed herein are commercially available under the trade name "FluroTec®" and are available from West Pharmaceutical Services, Inc. (Lionville, Pa.).

[0147] In certain embodiments, the pharmaceutical composition can be administered to a patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, suborbital, intravitreal, intraocular, subconjunctival, retrobulbar, periocular and / or intrathecal injection). A very large number of reusable pens and / or self-injector delivery devices can be used to subcutaneously deliver the pharmaceutical compositions disclosed herein. By way of example only, and without limitation, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pens and / or self-injector delivery devices applicable to subcutaneous delivery of the pharmaceutical compositions disclosed herein include, by way of example only and without limitation, SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and HUMIRA™ Pen (Abbott Labs, Abbott Park, Ill.).

[0148] The use of West SelfDose and SmartDose injection systems for delivering the pharmaceutical compositions disclosed herein is also encompassed herein. The use of microinfusers for delivering the pharmaceutical compositions disclosed herein is also encompassed herein. As used herein, the term "microinfuser" means a subcutaneous delivery device designed to slowly administer a large volume (e.g., up to about 2.5 mL or more) of a therapeutic composition over an extended period of time (e.g., about 10, 15, 20, 25, 30 minutes or longer fractions). See, e.g., U.S. Patent Nos. 6,629,949; 6,659,982, and Meehan et al., J. Controlled Release 46:107-116 (1996). Methods of treatment

[0149] In certain embodiments, the disclosure relates to a method of preventing, reducing the risk of developing, or treating a disease or disorder associated with IGF-1R, the method comprising administering a pharmaceutical composition and / or an anti-IGF-1R antibody disclosed herein. The disclosure also generally relates to a method of preventing, reducing the risk of developing, or treating IGF-1R-related diseases and disorders, the method comprising administering an anti-IGF-1R antibody disclosed herein. The disclosure also generally relates to a method of preventing, reducing the risk of developing, or treating IGF-1R-related diseases and disorders, the method comprising administering a pharmaceutical composition using a syringe disclosed herein. In some embodiments, the disease or disorder is thyroid eye disease (TED).

[0150] In some embodiments, the disease or disorder is stroke, acromegaly, diabetic nephropathy (diabetic kidney disease), idiopathic pulmonary fibrosis, interstitial lung disease, obesity, type 2 diabetes, juvenile idiopathic arthritis (JIA), diffuse cutaneous systemic sclerosis, Sjogren's syndrome with calcinosis and vasculitis, cachexia and sarcopenia, diabetic macular edema, atherosclerosis, peripheral arterial disease (PAD), myocardial infarction and stroke, diabetic foot and skin lesions, rheumatoid arthritis, neurofibromatosis type 1, neurofibromatosis type 2, polycystic kidney disease, multiple hepatic cysts, polycystic ovary syndrome, Alzheimer's disease, cognitive decline, dementia, depressive and anxiety states, asthma, aging, thyroid ophthalmopathy, idiopathic orbital inflammation, human type 2 lipodystrophy and related cardiomyopathy, autosomal dominant polycystic kidney disease (ADPKD), NASH, Graves' disease, and / or Hashimoto's thyroiditis.

[0151] In some embodiments, the disease or disorder is thyroid eye disease (TED). Thyroid eye disease (TED), also known as Graves ophthalmopathy or orbitopathy (GO), thyrotoxic exophthalmos, thyroid-associated ophthalmopathy, and by several other terms, is an orbital disease associated with thyroid dysfunction. TED is divided into two types. Active TED, which typically lasts from 1 to 3 years, is characterized by a continuous autoimmune / inflammatory reaction in the orbital soft tissues. Active TED causes the expansion and remodeling of the orbital soft tissues. The autoimmune / inflammatory reaction of active TED resolves spontaneously, and the condition progresses to inactive TED. Inactive TAO is a term used to describe the long-term / permanent sequelae of active TED. The cause of TED is unknown. TED is typically associated with Graves hyperthyroidism but can also occur as part of other autoimmune pathologies that affect the thyroid and cause lesions in the orbit and peripheral tissues, rarely, lesions in the pretibial skin (pretibial myxedema) or fingers (thyroid acropachy). TED is an autoimmune orbital disease in which the orbital and periorbital soft tissues are primarily secondarily affected the eye and vision. In TED, the eyes are pushed forward (protrude) from their sockets as a result of inflammation and expansion of the orbital soft tissues, primarily the extraocular muscles and fat, a phenomenon known as proptosis or exophthalmos. Most cases of TED do not result in vision loss, but this condition can cause exposure keratopathy, which threatens vision, troublesome diplopia (double vision), and compressive thyroid optic neuropathy. TED can precede, occur simultaneously with, or follow the systemic complications of hypothyroidism. The ocular manifestations of TED include upper eyelid retraction, eyelid lag, swelling, erythema, conjunctivitis, and globe expansion (proptosis or exophthalmos), chemosis, periorbital edema, and alterations in eye movements with significant functional, social, and aesthetic consequences. Many of the signs and symptoms of TED, including proptosis and eye congestion, result from the expansion of the orbital adipose tissue and the periorbital muscles. The adipose tissue volume increases, in part, due to de novo adipocyte generation (adipogenesis) within the orbital fat.Accumulation of hydrophilic glycosaminoglycans, mainly hyaluronic acid, in orbital adipose tissue and perimuscular connective tissue between extraocular muscle fibers further enlarges the adipose compartment and increases the extraocular muscle mass. Hyaluronic acid is produced by fibroblasts present in orbital fat and extraocular muscles, and its synthesis in vitro is stimulated by several cytokines and growth factors including IL-1 beta, interferon-gamma, platelet-derived growth factor, thyroid-stimulating hormone (TSH) and insulin-like growth factor I (IGF-I).

[0152] Antibodies that activate the insulin-like growth factor I receptor (IGF-IR) have also been detected in active TED and are involved in active TED. Without being bound by any theory, TSHR and IGF-IR are thought to form a physical and functional complex in orbital fibroblasts, and blockade of IGF-IR appears to attenuate both IGF-1-dependent and TSH-dependent signaling. Blockade of IGF-IR using antibody antagonists has been suggested to reduce both TSHR-dependent and IGF-I-dependent signaling and thus to be able to interfere with the pathogenic activity of autoantibodies that act as agonists to either receptor.

[0153] IGF-IR is a widely expressed heterotetrameric protein involved in the regulation of proliferation and metabolic functions of many cell types. It is a tyrosine kinase receptor containing two subunits. IGF-IR alpha contains the ligand-binding domain, while IGF-IR beta is involved in signaling and contains tyrosine phosphorylation sites.

[0154] Thyroid eye disease (TED) is a debilitating autoimmune disorder that occurs in patients with Graves' disease in which inflammation of the muscles and adipose tissue behind the eyes leads to proptosis, diplopia, redness, pain, and swelling, and ultimately, in severe cases, blindness. The basis of the mechanism of TED involves a complex interaction between thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) signaling autoantibody-mediated stimulation in orbital fibroblasts that causes orbital tissue inflammation and expansion. Current treatments include corticosteroids and teprotumumab, as well as surgical intervention to prevent vision loss. Ronigutamab is a high-affinity (K D <50 pM) monoclonal antibody directed against IGF-1R that induces rapid and efficient receptor internalization. Ronigutamab is under development as a potential treatment for TED. To support the clinical development of ronigutamab, a multicolor flow cytometry assay has been developed to monitor the binding of ronigutamab to IGF-1R on the surface of human peripheral blood mononuclear cells (PBMCs).

[0155] Ronigutamab is a humanized monoclonal antibody against IGF-1R. Ronigutamab has high affinity and specificity for IGF-1R. Specifically, ronigutamab has picomolar affinity for IGF-1R. In certain preferred embodiments, ronigutamab has a k D of approximately 30 pM for the binding epitope of IGF-1R. When ronigutamab binds to IGF-1R, it induces receptor internalization, as a result of which the signal from IGF-1R is blocked, and the therapeutic effect of ronigutamab can thus occur. IGF-1R internalization can occur within minutes after administration of a pharmaceutical composition containing ronigutamab. In certain preferred embodiments, the therapeutic effective serum concentration of ronigutamab can be reached approximately 1 hour after administration of a pharmaceutical composition containing ronigutamab.

[0156] Lonigutamab has unique and beneficial pharmacological properties. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 70%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 80%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 85%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 90%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 95%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 97%. In certain preferred embodiments, administration of a pharmaceutical composition comprising lonigutamab induces IGF-1R internalization that is greater than about 99%.

[0157] In certain embodiments of the compositions and methods provided herein, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is administered subcutaneously. In certain embodiments, the pharmaceutical composition is formulated for intramuscular administration. In certain embodiments, the pharmaceutical composition is administered intramuscularly. In some embodiments, the pharmaceutical composition is formulated for infraorbital, intravitreal, intraocular, subconjunctival, retrobulbar, periocular and / or intrathecal administration. In certain embodiments, the pharmaceutical composition is administered by infraorbital, intravitreal, intraocular, subconjunctival, retrobulbar, periocular and / or intrathecal injection.

[0158] In certain embodiments, the pharmaceutical composition is administered with a delivery volume of 3 ml, 2.5 ml, 2 ml, 1.5 ml or 1 ml or less. In some embodiments, the pharmaceutical composition is administered with a delivery volume of 2 ml or less.

[0159] In certain embodiments, the pharmaceutical composition is administered with a needle sized 24G, 25G or 27G or less. In some embodiments, the pharmaceutical composition is administered with a 24G needle, 25G needle or 27G needle.

[0160] In certain embodiments, the pharmaceutical composition is administered at a radiation output of 14N, 13N, 12N, 11N, 10N, 9N, 8N, 7N, or 6N or less. In some embodiments, the pharmaceutical composition is administered at a radiation output of 12N or less. In certain embodiments, the pharmaceutical composition is administered at a radiation output of about 4N, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N, or about 12N.

[0161] In some embodiments, the method reduces the severity of thyroid eye disease (TED). In some embodiments, the method reduces proptosis in the eyes of a subject having thyroid eye disease (TED). In some embodiments, the proptosis is reduced by at least 2 mm. In some embodiments, the proptosis is reduced by at least 3 mm. In some embodiments, the proptosis is reduced by at least 4 mm.

[0162] In some embodiments, the method reduces the clinical activity score (CAS) of thyroid eye disease (TED). In some embodiments, the clinical activity score (CAS) is reduced by at least 2 points. In some embodiments, the clinical activity score (CAS) is reduced to one (1). In some embodiments, the clinical activity score (CAS) of the subject is reduced to zero (0). In some embodiments, the method improves the quality of life of the subject. In some embodiments, the quality of life is measured by the quality of life in Graves' ophthalmopathy (GO-QoL) assessment. In some embodiments, the quality of life is measured by the visual function or its appearance subscale. In some embodiments, the quality of life is measured by the European Group on Graves' Orbitopathy (EUGOGO) guidelines. In some embodiments, the method reduces the severity of diplopia. 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.

[0163] In certain embodiments, the present invention provides a method of administering a pharmaceutical composition comprising raniglutamab. Such pharmaceutical compositions can be administered to patients suffering from thyroid eye disease (TED). In certain embodiments, the pharmaceutical compositions of the present invention can be administered intravenously. The method of the present invention provides for intravenous infusion of a pharmaceutical composition comprising raniglutamab at up to about 3.0 mg / kg. In certain embodiments, the method of the present invention provides for administration as an intravenous infusion of a pharmaceutical composition comprising about 0.1, 0.3, 1.0 or 3.0 mg / kg of raniglutamab. The present invention further provides that the intravenous infusion can be carried out over a period of from about 15 minutes to about 120 minutes. In certain preferred embodiments, the intravenous infusion is carried out for about 60 minutes.

[0164] In certain embodiments, the present invention provides for administration of a pharmaceutical composition comprising raniglutamab by subcutaneous injection. In certain embodiments, the method of the present invention provides for subcutaneous administration of up to about 250 mg of raniglutamab. In certain embodiments, the pharmaceutical composition for subcutaneous administration comprises about 20 mg, 40 mg, 125 mg or 250 mg of raniglutamab. The pharmaceutical composition for subcutaneous administration can have a volume of from about 0.5 mL to about 3 mL. In a preferred embodiment, the volume administered is up to about 2 mL. Advantageously, subcutaneous administration is carried out within the tolerance volume, so that the pharmaceutical composition can be administered in an outpatient setting or the pharmaceutical composition of the present invention can be self-administered by the patient. This leads to a convenient and efficient method for the administration of a pharmaceutical composition comprising raniglutamab. In particular, subcutaneous administration of the pharmaceutical composition is beneficial compared to intravenous administration due to the ease of administration of the pharmaceutical composition.

[0165] In certain embodiments of the present invention, administration of a pharmaceutical composition comprising lonigutamab results in a maximal IGF-1R receptor occupancy by an anti-IGF-1R antibody. This maximal occupancy of IGF-1R can be achieved at any time after administration of the pharmaceutical composition comprising lonigutamab. In certain embodiments, this is achieved at about 12 hours after administration of the pharmaceutical composition comprising lonigutamab. The pharmaceutical composition to be administered may comprise from about 100 mg to about 300 mg of lonigutamab. In preferred embodiments, the pharmaceutical composition may comprise about 125 mg or about 250 mg of lonigutamab. Notably, the maximal IGF-1R receptor occupancy can be maintained for up to several months after a single administration. In a preferred embodiment, the IGF-1R receptor occupancy is maintained for at least about 4 weeks after a single administration of the pharmaceutical composition comprising lonigutamab. The maximal receptor occupancy level can be maintained after a single subcutaneous injection or intravenous infusion of the pharmaceutical composition comprising lonigutamab.

[0166] Teprotumumab, an antibody previously known for IGF-1R occupancy, was maintained at a concentration of 200 μg / mL to have improved efficacy. Lonigutamab is approximately 75-fold more potent compared to teprotumumab, and the equivalent serum concentration required to maintain the therapeutic activity of lonigutamab is predicted to be approximately 3 μg / mL. In certain aspects, the serum concentration required for maximal IGF-1R internalization is an approximately 3 μg / mL lonigutamab concentration. Thus, the therapeutically effective serum concentration of lonigutamab is at least about 1 μg / mL. In certain preferred embodiments, the therapeutically effective serum concentration of lonigutamab is at least about 3 μg / mL. Importantly, the pharmaceutical composition of the present invention provides a therapeutically effective serum concentration of lonigutamab to a patient.

[0167] In certain aspects of the present invention, a pharmaceutical composition comprising lonigutamab administered to a patient is safe and well tolerated. Furthermore, there are few adverse events associated with the pharmaceutical composition of the present invention.

[0168] In certain embodiments, the present invention provides a method for treating thyroid eye disease (TED), the method comprising the step of subcutaneously administering a pharmaceutical composition comprising from about 10 mg to about 500 mg of rontigumab. In certain embodiments, the pharmaceutical composition comprises about 20 mg of rontigumab. In certain embodiments, the pharmaceutical composition comprises about 40 mg of rontigumab. In certain embodiments, the pharmaceutical composition comprises about 125 mg of rontigumab. In certain embodiments, the pharmaceutical composition comprises about 250 mg of rontigumab.

[0169] In certain embodiments, the pharmaceutical composition comprising rontigumab is administered once a week. In certain embodiments, the pharmaceutical composition comprising rontigumab is administered twice a week. In certain embodiments, the pharmaceutical composition comprising rontigumab is administered three times a week. In certain embodiments, the pharmaceutical composition comprising rontigumab is administered every other day, i.e., once every two days. In certain preferred embodiments, the pharmaceutical composition comprising rontigumab is administered once every two (2) weeks. In certain preferred embodiments, the pharmaceutical composition comprising rontigumab is administered once every three (3) weeks. In certain preferred embodiments, the pharmaceutical composition comprising rontigumab is administered once every four (4) weeks. In certain embodiments, the pharmaceutical composition comprising rontigumab is administered once every five (5) weeks. In certain embodiments, the pharmaceutical composition comprising rontigumab is administered once every six (6) weeks.

[0170] In certain preferred embodiments, the pharmaceutical composition comprising rontigumab is administered on day 1 and day 14. In other preferred embodiments, the pharmaceutical composition comprising rontigumab is administered on day 1 and day 21. In other preferred embodiments, the pharmaceutical composition comprising rontigumab is administered on day 1 and day 28.

Example

[0171] (Example 1) Pre-formulation development of anti-human IGF-1R mAb A pharmaceutical formulation for a high-dose anti-IGF-1R antibody at 125 mg / mL, which has a higher concentration of the active ingredient (API) than the drug substance at 20 mg / mL, was prepared. The composition of the excipients remained the same for both the 20 mg / mL formulation and the 125 mg / mL formulation.

[0172] The anti-IGF-1R antibody is formulated in an isotonic, sterile solution and manufactured at two concentrations, 20 mg / mL and 125 mg / mL, to enable delivery by IV and SC administration. The composition of the pharmaceutical is the same as that of the drug substance in both product formulations. The pharmaceutical is provided in single-dose, depyrogenated type 1 glass vials.

[0173] The process 1 drug substance was manufactured at 20 mg / mL in a formulation buffer at pH 6.0 containing 25 mM histidine and 6% sucrose. No process development was conducted for the manufacture of the 20 mg / mL batch. The process consists of sterile filtration through two filters attached in series and a filling and finishing step.

[0174] For the production of the 125 mg / mL pharmaceutical product (DP), manufacturing process development was conducted to optimize the critical parameters of the ultrafiltration process used to concentrate the antibody to a 125 mg / mL concentration prior to the sterile filtration and filling and finishing steps through two filters in series. During process development, industrial batches with a product concentration of 125 mg / mL were manufactured.

[0175] L-Histidine is used at a concentration of 25 mM as a pH buffer in the pharmaceutical formulation. Sucrose is a stabilizer and also a weight osmolarity regulator (tonicity agent). It can protect the active ingredient from degradation and maintain the weight osmolarity of the pharmaceutical. Hydrochloric acid is used as a pH adjuster. Water is used as a solvent.

[0176] The data obtained so far have demonstrated that the above excipients in the formulation were able to efficiently maintain the stability of the pharmaceutical and did not have a negative impact on the quality characteristics of the pharmaceutical. Formulation Development

[0177] In the initial formulation development phase, several buffer formulations (25 mM glutamate, 25 mM acetate, 25 mM histidine, and 25 mM phosphate) were tested in combination with NaCl (150 mM), sucrose (9%), and polysorbate 80 (0.02%) over a pH range (4.5 - 7.5). Fourteen (14) formulations were prepared and further studied. The following tests were conducted during the pre-formulation development phase: visual appearance, protein content, CE-SES (reduced and non-reduced), SEC-HPLC, CEX-HPLC, and DLS.

[0178] Preliminary screening studies were conducted to select the formulation conditions for a humanized anti-IGF-1R antibody that would allow for good stability based on defined analytical criteria.

[0179] The purpose of the screening was to make a limited selection of four (4) formulations. The effects of the following four factors were studied in the preliminary screening studies: (i) nature of the buffer: 25 mM histidine or 25 mM phosphate; (ii) pH: pH 6 - pH 7; (iii) NaCl concentration: 0 - 150 mM, and (iv) polysorbate 80 concentration: 0 - 0.1% v / v.

[0180] Two experimental designs (one for each buffer) were established such that response surfaces could be modeled for each design. The center points were analyzed in triplicate to estimate experimental variability. Two different experimental designs were constructed with two different buffers as follows (cubic composite matrix with center points in triplicate): 25 mM Histidine Buffer Experimental Design (see Table 1) 25 mM Phosphate Buffer Experimental Design (see Table 2) Table 1. 25 mM Histidine Buffer Experimental Design

Table 1

[0181] Table 2. 25 mM Phosphate Buffer Experimental Design

Table 2

[0182] The implemented experimental designs were run using dedicated software applications (Nemrod and MODDE) for performing statistical analysis of the data to verify the validity and relevance of the generated models. These tools make it possible to see the effect of the test factors on the response studied by drawing the response surface and calculating the optimal conditions according to defined criteria.

[0183] For each of the plans, the response studied was (i) the melting temperature T at °C at T0 m1 and T m2 values (DSF analysis); (ii) the increase in the rate of acidic variants after 10 days of stress at 40 °C (CIEX analysis) and (iii) the rate of multimers after 10 days of stress at 40 °C (SEC analysis).

[0184] The analysis of the histidine plan showed that pH has a significant effect on all three responses: high pH (pH 7) causes an increase in T m , the multimer rate and the rate of acidic variants. The presence of NaCl causes an increase in T m and the multimer rate, but does not tend to produce many acidic variants. Finally, polysorbate 80 has little effect on the three responses; nevertheless, its presence will tend to act favorably on the appearance of multimers at the percentages tested. The response surfaces are shown below (Figures 1 - 4).

[0185] To minimize the multimer rate, it was preferable to employ a pH of 6 - 6.5 and < 100 mM of salt. The addition of polysorbate 80 at the percentages tested is not desirable since the presence of the surfactant increases the multimer rate.

[0186] To limit the appearance of acidic variants, it is also necessary in this case to employ a rather low pH (6 - 6.5); the presence of NaCl is advantageous to stabilize this criterion. However, the presence of polysorbate 80 has no significant effect.

[0187] High T m For it to act favorably on the value, pH 7 is preferred and polysorbate 80 at the percentages tested was not desirable.

[0188] For the 15 phosphate formulations, the measured T m values are almost constant: T m1 is between 67.0 - 68.3 °C and T m2 is different only between 84 - 85 °C. The variation of the tested factors does not affect these two criteria. Therefore, it is not appropriate to analyze the response surfaces for these two responses.

[0189] The analysis of the histidine plan shows that there is a significant effect on pH: a high pH (pH 7) increases not only the acidic variants but also the multimer rate. Similar to histidine, the presence of NaCl tends to increase the multimer rate but limits the appearance of acidic variants. Finally, polysorbate 80 has no significant effect on the responses studied. The response surfaces are illustrated in Figures 5 and 6.

[0190] To minimize the monomer rate, it was preferred to employ a pH of 6 - 6.5. The addition of polysorbate 80 at the percentages tested was not desirable because the presence of the surfactant increases the multimer rate. The salt has no significant effect.

[0191] To limit the appearance of acidic variants, it was also necessary in this case to employ a rather low pH (6 - 6.5). Similar to histidine, the presence of NaCl is advantageous to stabilize this criterion. However, the presence of polysorbate 80 has no significant effect.

[0192] The effect of the phosphate buffer factor was very close to that of the observed histidine factor (pH 6 - 6.5, in the absence of polysorbate 80). However, it is important to note that the levels of multimerization rate and the appearance of acidic variants were higher in histidine than in phosphate. The minimum and maximum values obtained for 15 histidine and 15 phosphate formulations are shown in Table 3. Table 3. Minimum and maximum values obtained for 15 histidine and 15 phosphate formulations [Table 3]

[0193] An inclusive overview was created using dedicated software applications (Nemrod and MODDE).

[0194] Conclusions of the screening study: (1) It is preferable to formulate the antibody in histidine rather than in phosphate to limit the appearance of multimers and acidic variants; (2) For histidine, the most favorable pH zone is between pH 6 and pH 6.5; (3) The presence of polysorbate 80 at the tested percentages is not desirable; this surfactant is not favorable for stability (based on the criteria studied); (4) In the case of histidine, the presence of NaCl in the formulation is desirable. However, a low concentration (maximum 100 mM) should act favorably.

[0195] After performing screening studies, other factors were considered. Monitoring the stability of previously produced antibody lots indicates the emergence of a high degree of opalescence (for some lots, > standard IV). This opalescence did not correlate with the evolution of the physicochemical characteristics of the antibody (neither degradation nor aggregation was observed), but it appeared to be correlated with the antibody concentration. To limit opalescence, it seems preferable to reduce the antibody concentration to 10 g / L or even 5 g / L, but preformulation studies were conducted at the worst-case scenario of 20 g / L. The results obtained for the selected formulation (P001) are shown in Table 4. Table 4. Opalescence results for Lot P001

Table 4

[0196] For each of the four formulations, opalescence was not observed at T0, but the level increased significantly at the time of storage at +4°C for 1 month.

[0197] Lot P001 did not comply, but these results provide insights into the appropriateness of these formulation choices for the next lot. Therefore, additional tests were conducted under stress conditions. Five other formulations using citrate or histidine buffer with or without NaCl were evaluated for 15 days under stress at 40°C. The presence of NaCl and antibody concentration appear to increase the opalescence phenomenon. The single formulation stands out in terms of low opalescence levels: histidine buffer at pH 6. Three citrate formulations with a pH below 6 had strong opalescence. Analytical monitoring of these five stressed formulations showed that a histidine buffer at pH 6 with 5 g / L protein exhibited the least affected charge variant profile and SEC. A formulation of histidine, pH 6, 30 mM NaCl with 6% sucrose demonstrated low opalescence. The SEC profile was also still acceptable after stress. Sucrose was added to generate a diversity of formulations to test for the next P lot. Based on all the results obtained and considerations,

[0198] the final four formulations as presented in Table 5 were selected. The selected formulation at pH 6.0 with 25 mM histidine and 6% sucrose was judged to be the highest performing formulation for initial clinical development. Table 5. Final Selection of Four Formulations for Lot P003

Table 5

[0199] Additional formulation development studies were conducted to enable a high-concentration solution of the anti-IGF-1R antibody. A formulation at pH 6.0 containing 25 mM histidine and 5% D-sorbitol was selected for future DS manufacturing.

[0200] Four lead formulations at 125 mg / mL were developed and appropriate tests were conducted. Histidine was used in drug formulation at a concentration of 25 mM as a pH buffer as previously established. Sucrose and D-sorbitol were selected as weight osmolarity regulators (isotonic agents). Polysorbate 80 (PS80) was included as a surfactant in two of the four selected formulations. The compositions of the selected formulations are presented in Table 6, while the test plan is included in Table 7. Table 6. Selected Compositions for Formulations at 125 mg / mL

Table 6

[0201] Table 7. Test Plan for Further Development of High-Dose Formulations

Table 7

[0202] Data resulting from formulation development are summarized below.

[0203] After a 12-week period, the samples stored at -20°C and 2 - 8°C were taken out and visually evaluated. All the formulations remained clear, without opalescence, and were pale amber. A very small number of visible particles were present in some of the samples at -20°C and 2 - 8°C. The SEC-HPLC results obtained after 12 weeks at -20°C are shown in Table 8. All the formulations did not show a detectable increase in aggregation, and the values of high molecular weight substances (HMWS) were equivalent to the first test at T0. The SEC-HPLC results obtained after storage at 2 - 8°C for 12 weeks are shown in Table 9. There was no clear difference in stability among the formulations at this temperature, and only a slight increase in HMWS was observed, with the difference being approximately 0.25%. After 2 weeks at 25°C, all the formulations showed only a slight decrease in monomer%, with the decrease being about 0.3%, and there was no observable difference in stability among the formulations at this temperature and time point (Table 10). After 2 weeks at 40°C, all the formulations had a small decrease of about 1.1% in monomer%, which indicates very good stability, and there was no observable difference in stability among the four formulations (Table 11). After 2 weeks at 50°C, all the formulations had a more significant decrease in monomer%, with an overall decrease of about 5.3%. Only a very slight decrease in stability was observed for Formulations 1b and 3b containing PS80 (Table 12). There was no obvious difference between the formulations sucrose and sorbitol. Table 8. Temperature Stability: -20°C SEC-HPLC Results

Table 8-1

Table 8-2

[0204] Table 9. Temperature Stability: 2 - 8°C SEC-HPLC Results

Table 9-1

Table 9-2

[0205] Table 10. Temperature stability: SEC-HPLC results at 25°C [Table 10]

[0206] Table 11. Temperature stability: SEC-HPLC results at 40°C [Table 11]

[0207] Table 12. Temperature stability: SEC-HPLC results at 50°C [Table 12-1] [Table 12-2]

[0208] CEX-HPLC analysis indicated that the formulation showed good chemical stability after 12 weeks at -20°C (Table 13) and 2-8°C (Table 14). From the CEX-HPLC data, slightly higher values of the major species % were observed for the samples stored at 2-8°C. This indicated that the freeze-thaw cycles experienced by the samples at -20°C did not affect aggregation but were more significant for the chemical stability of the molecules. Table 13. Temperature stability: CEX-HPLC results at -20°C [Table 13-1] [Table 13-2]

[0209] Table 14. Temperature stability: CEX-HPLC results at 2-8°C [Table 14-1] [Table 14-2]

[0210] The DLS measurement demonstrated that the particle size Z D was virtually unchanged after 12 weeks at both temperatures. The PDI values showed a tendency to increase with time, but all formulations remained monodisperse after 12 weeks (Figures 7 and 8). Conclusion:

[0211] The results obtained led to the conclusion that formulation 3a, which contains 25 mM histidine without PS80 and sorbitol as an isotonicity regulator, provides slightly better stability than the other formulations. The formulation containing 25 mM histidine and sucrose demonstrated a similar profile to the formulation with sorbitol. Therefore, the drug substance formulated at pH 6.0 in 25 mM histidine, 6% sucrose, which was originally selected at 20 mg / mL, was considered safe and acceptable for the manufacture of the clinical product at 125 mg / mL. Establishment of the manufacturing process for the high-dose antibody pharmaceutical (125 mg / mL)

[0212] The pharmaceutical manufacturing process for the low-dose pharmaceutical for the Phase 1 clinical trial shown in Figure 9. The antibody drug substance (20 mg / mL) is thawed at 2 - 8°C. The formulation is then sterile filtered, filled into vials, and sealed.

[0213] Prior to the manufacture of the high-dose pharmaceutical, a tangential flow filtration (TFF) step is performed to concentrate the drug substance to 125 mg / mL. TFF, also known as a cross-flow filtration system, is a rapid and efficient method used to concentrate a solution by removing fluid while retaining solute molecules. This process is carried out by selecting a filter or membrane with a pore size significantly smaller than the solute molecules to allow retention of the solute molecules. Pall's Minimate EVO system, which has a pump, pressure gauge, hold-up screw clamp, reservoir, and tube connections, is used for this process.

[0214] A small-scale concentration process using bulk drug substance from GMP batches, discussed below, was developed.

[0215] A PES membrane with a molecular weight cut-off (MWCO) of 30 kDa was used to concentrate the pharmaceutical solution from 20 mg / mL to a target concentration of 125 mg / mL. The TFF process flow diagram is presented in Figure 10.

[0216] The process of concentrating the pharmaceutical solution started with the preparation of a formulation buffer containing histidine and sucrose. The TFF membrane was pre-conditioned with the formulation buffer before the addition of the sample. Pre-conditioning was used to remove air bubbles and equilibrate the system.

[0217] After buffer pre-conditioning, the thawed drug substance solution (20 mg / mL) was added using a peristaltic pump at a flow rate of approximately 40 mL / min and mixed. The drug substance solution was concentrated to a final volume of 18 - 20 mL in the container. After collecting the retentate, the system was flushed with the formulation buffer, which was then added to the concentrated product intermediate. The concentrated product intermediate was filtered through a 0.4 μm pre-filter, followed by two 0.22 μm PVDF filters. The filtered solution was aliquoted into 2R class 1 glass vials and stoppered. The process parameters and components of this industrial batch used for manufacturing were representative of those proposed for the manufacture of the 125 mg / mL clinical batch. The industrial batch was tested using the same method as that used for the release of the clinical DP batch, and it was set as a representative batch for safety to generate safety data before the manufacture of the GMP batch. Compatibility at Use

[0218] The antibody pharmaceutical (DP) is supplied as a solution for subcutaneous injection (SC) and intravenous infusion (IV). The antibody is diluted with saline for administration by IV infusion, but no dilution is required for SC administration. The compatibility at use study demonstrated good stability of the pharmaceutical diluted to 2.1 mg / mL and 0.07 mg / mL in saline under the following various holding conditions and infusion rates: · Ambient temperature, up to 24 h, high infusion rate of 100 mL / h · Ambient temperature, maximum 24 h, low injection rate at 50 mL / h · Refrigerated condition, 24 h, followed by holding at ambient temperature for an additional 24 h, high injection rate at 100 mL / h · Refrigerated condition, 24 h, followed by holding at ambient temperature for an additional 24 h, low injection rate at 50 mL / h

[0219] The compatibility study during use confirmed that the pharmaceutical product did not adhere to the bag and / or tubing, and there was no aggregation and / or material loss during the filtration phase. The infusion set used in the compatibility study during use was representative of the infusion set proposed for the clinical study. Therefore, the antibody is compatible with the selected infusion system. The compatibility study during use encompasses the proposed infusion parameters as defined in the pharmacy manual and supports the accurate administration of the antibody pharmaceutical product in the clinic.

[0220] A transparent ethylene vinyl acetate (EVA) infusion bag (100 mL) equipped with three connection points (supplier ICU Medical P / N SN2010BP), and a Pump / gravity Clearlink set with in-line BCV, a vented chamber equipped with a 15 micrometer filter, ClickLuer, SafePrime, line label (supplier Baxter International Inc, P / N BXISMMC96901L) were used in this study. The drug substance, batch T102 formulated with histidine and sucrose formulation, was tested. T102 DS was qualified as a reference standard substance.

[0221] Two dilution solutions at concentrations of 2.1 mg / mL and 0.07 mg / mL in saline solution were tested. The total volume after dilution was greater than 100 mL to enable charging the bulk solution into two infusion bags for each storage condition. T0 samples were taken out and analyzed in duplicate for both concentrations under each storage condition.

[0222] For the compatibility study, a fill volume of 50 mL, which is 50% of the maximum volume of the infusion bag, was selected to mimic the worst-case scenario with a large surface area contact. The lowest concentration in the bag was considered the worst-case scenario due to the higher surface-to-protein exposure ratio. The infusion bags were stored at room temperature and at 2 - 8°C. After the planned storage, the infusion bags were retrieved, connected to the remainder of the infusion set, and the solution was passed through the infusion line / filter at infusion rates of 100 mL / 1 hour (“high speed”) and 50 mL / 1 hour (“low speed”). After the injection process was completed, the samples were analyzed. Two samples were taken for each infusion rate. A representative diagram is provided in Figure 11 to show the “high speed” and “low speed” ports with the other infusion devices connected as described above.

[0223] For the infusion bags held at room temperature, the samples were analyzed after 2 hours (time point (T) = 2h), 4 hours (T = 4h), and 24 hours (T = 24h).

[0224] For the infusion bags held at 2 - 8°C: The bags were held at 2 - 8°C for 24h. At the end of the storage period, the infusion bags were removed from the refrigerator and equilibrated to ambient temperature for 2h. Samples were taken at the end of the 2h equilibration period (T = 2h) for analysis, after an additional 2 hours (T = 4h), and 24 hours after removal from the refrigerator (T = 24h). For all samples, the test items included appearance, protein content by A 280 including protein content by A, SEC-HPLC, and CEX-HPLC. The method was carried out and the reliability of the results was ensured by system suitability.

[0225] The results of appearance and protein content in the in-use compatibility study are presented in Tables 15 - 22. The trends for monomer content by SEC-HPLC and main form content by CEX-HPLC are shown in Figures 12 - 15. All four quality characteristics of the diluted antibody pharmaceutical showed excellent stability throughout storage in the infusion bags at both ambient and refrigerated temperatures, as well as after passing through the infusion line and filter at high and low infusion rates. Table 15. Results of the usability study at room temperature, 2.1 mg / mL in saline, and an infusion rate of 100 mL / hour

Table 15

[0226] Table 16. Results of the usability study at room temperature, 0.07 mg / mL in saline, and an infusion rate of 100 mL / hour

Table 16-1

Table 16-2

[0227] Table 17. Results of the usability study at room temperature, 2.1 mg / mL in saline, and an infusion rate of 50 mL / hour

Table 17

[0228] Table 18. Results of the usability study at room temperature, 0.07 mg / mL in saline, and an infusion rate of 50 mL / hour

Table 18

[0229] Table 19. Results of the usability study at 2 - 8°C, 2.1 mg / mL in saline, and an infusion rate of 100 mL / hour

Table 19-1

Table 19-2

[0230] Table 20. Results of the usability study at 2 - 8°C, 0.07 mg / mL in saline, and an infusion rate of 100 mL / hour

Table 20

[0231] Table 21. Results of the usability study at 2 - 8°C, 2.1 mg / mL in saline, and an infusion rate of 50 mL / hour

Table 21 - 1

Table 21 - 2

[0232] Table 22. Results of the usability study at 2 - 8°C, 0.07 mg / mL in saline, and an infusion rate of 50 mL / hour

Table 22

[0233] (Example 2) High - concentration formulation development and injectability study Investigate the high - concentration behavior of the antibody in the potent buffer selected from the previous stage. · Buffer 3a: 25 mM L - histidine, 5% w / v D - sorbitol, pH 6.0. · Concentrate VB421 to 150, 175, and 200 mg / mL (although the stability at 125 mg / mL is understood, it will also be tested).

[0234] Evaluate the stability at these concentrations by visual appearance, SEC, and DLS. Measure the viscosity and conduct an injectability assessment to ensure that the injection output is not too high.

[0235] Buffer exchange: The sample was loaded into a Sartorius VivaSpin® 20 (20 mL volume, 30 kDa MWCO, PES membrane) (DS details: 20 mg / mL, F50085, Hz208F2-4, G101D). Five cycles of buffer exchange were performed.

[0236] Concentration: The sample was concentrated to 125, 150, 175, and 200 mg / mL. The concentration was confirmed by measuring protein A280.

[0237] Observation: Similar to the above, there were no problems encountered during concentration, and there was no visible formation of microfibers / particles or clogging of the filter membrane.

[0238] Appearance method The vial was gently vortexed and examined under an off-white light source (10 W LED, 2000 - 3750 lux). The vial was observed with both black and white backgrounds.

[0239] At high concentrations, the only visual effect noticed was a slightly darker amber color than that observed at 125 mg / mL. There was no opalescence or visible aggregation in all samples.

[0240] SEC-HPLC method The sample was analyzed at 1 mg / mL (diluted with the mobile phase). The injection volume was 10 μL. The buffer was 150 mM sodium phosphate, pH 6.9. Run: uniform concentration, 0.35 mL / min, 15 min. Column temperature: ambient temperature. Column: Agilent AdvanceBio SEC column (p / n 1580-5301). HPLC system: Dionex Ultimate-3000 UHPLC system. Detection wavelength: 280 nm. The sample was injected in duplicate - the average result is reported.

[0241] There was a very slight increase (0.2%) in the amount of HMWS during the concentration of DS from 20 mg / mL. There was no further increase in HMWS between 125 - 200 mg / mL, and the same was true for the monomer %. LMWS was approximately 1.5% at all concentrations.

[0242] Zetasizer method: System: Zetasizer Ultra. Cell: ZEN2112, Low Volume Quartz Batch Cuvette. Measurement temperature: 25 °C. Equilibration time: 120 seconds. Data processing: General purpose. Detection angle: Backscatter. Attenuation: Automatic. Measurement process: Automatic. No pause after sub-run. No optical filter. Pause between runs: 0 seconds. 1 × replicate experiment; 5 × measurements per replicate experiment. Sample preparation: Centrifugation and filtration through a 0.22 μm filter. Sample volume approximately 50 μL for proper sample analysis.

[0243] There was a non-significant increase in the z-average (Z D ) at higher concentrations. The PDI also increased at higher concentrations but still remained < 0.2, indicating a high level of monodispersity. It is interesting to note that the lowest Z D and PDI values were seen at 150 mg / mL.

[0244] Viscosity measurement Viscosity was measured with a RheoSense m-VROC viscometer. Measurements were recorded at 21 °C. The speed sweep was performed by varying the shear rate between 10 - 90% of the chip range for injectionability assessment. The viscosity at 150 mg / mL was slightly lower than that at 125 mg / mL, which is consistent with the DLS results showing a similar trend.

[0245] Injectionability assessment Many high-concentration therapeutic agents exhibit non-Newtonian (shear-thinning) behavior - meaning the viscosity is reduced at high shear rates. During injection with a 27G needle, the shear rate > 100000 s at an injection rate of 0.1 mL / s -1can be reached. If the injectability is solely evaluated from the low shear rate viscosity measurement, there is a possibility that an injection output exceeding the prediction may be calculated. This may lead to the potential formulation of interest being excluded from further consideration based on an incorrect injectability assessment.

[0246] The injection output for a non-Newtonian fluid can be calculated as follows: [Number] (where F v = injection output (N), l n = length of the needle (m), σ w = shear stress at the needle wall calculated by plotting shear stress and shear rate (Pa). R p = inner diameter of the syringe (m). R n = inner diameter of the needle (m)).

[0247] When the force (F v - unit N) is calculated, this can be used as a rough guide as to how easily the fluid can be injected. Recent research (Robinson et al., Adv. Healthcare. Mater., 2020, 9, 1901521) has suggested the following: F v < 12 N, minimal effort is required for injection. F v = 12 - 38 N, effort is required. F v = 38 - 64 N, significant effort is required. F v > 64 N, injection is impossible.

[0248] This method solely estimates the contribution of viscosity to the injection output of the fluid in the syringe. Frictional forces are not considered. Frictional forces are diverse and depend on the materials of the syringe piston and barrel. The lubricating effect of the barrel and piston from the drug in the syringe is not incorporated into this calculation. In addition, the resistance of the injection fluid to the SC tissue is not considered.

[0249] 300 to 100,000 s -1 When the shear rate was changed to -1 , a viscosity drop of about 1 cP occurred. There was a proportional relationship between the shear rate and the shear stress.

[0250] At 125 mg / mL, the viscosity was relatively low (9.5 - 8.5 cP). The injection forces were calculated for various needle / syringe combinations. The preferred combinations are underlined in Table 23 and provide injection forces well within the desired range (<12 N). The "26s" needle has approximately the same outer diameter as a normal 26G needle but has a smaller inner diameter and thicker wall to improve durability, which results in a significantly higher injection force for this variant.

[0251] Table 23. Results of injectability assessment at 125 mg / ml.

Table 23

[0252] 300 to 100,000 s -1 When the shear rate was changed to -1 , a viscosity drop of about 1 cP occurred. The viscosity appeared to be lower at 150 mg / mL. There was a proportional relationship between the shear rate and the shear stress. Non - Newtonian behavior was observed at higher shear rates at 150 mg / mL. Similar to the 125 mg / mL sample, the only syringe / needle combination that presented potential injectability issues was the combination with the 26s needle.

[0253] Table 24. Results of injectability assessment at 150 mg / ml.

Table 24 - 1

Table 24 - 2

[0254] 250 to 100,000 s -1When the shear rate was changed, a viscosity drop of about 2.5 cP occurred. There was a proportional relationship between the shear rate and the shear stress. At 175 mg / mL, non-Newtonian behavior was observed at higher shear rates. Also in this case, the only sample indicating potential problems was the one using a 26 s needle.

[0255] Table 25. Results of injectability evaluation at 175 mg / ml.

Table 25-1

Table 25-2

[0256] 250 to 100000 s -1 When the shear rate was changed, a viscosity drop of about 2.5 cP occurred. There was a proportional relationship between the shear rate and the shear stress. At 200 mg / mL, non-Newtonian behavior was observed at higher shear rates. Also in this case, the only sample indicating potential problems was the one using a 26 s needle.

[0257] Table 26. Results of injectability evaluation at 200 mg / ml.

Table 26

[0258] The higher the concentration, the more significant non-Newtonian behavior was observed. The antibody seemed to be injectable under most of the conditions tested. At 200 mg / mL, the ejection force for a speed of 200 mm 3 / s was <10 N. The preferred combination of a 3 mL syringe and a 26G needle resulted in calculated ejection forces of 2.5 - 4.7 N, and all of these calculated ejection forces were lower than the suggested value of 12 N, which is the value at which effort is required to inject the fluid.

[0259] The antibody was concentrated to 200 mg / mL without any loss of visual appearance, and remained opalescent and free of visible aggregates throughout the concentration step. SEC and DLS did not vary significantly between 125 and 200 mg / mL. Viscosity increased, particularly at 175 and 200 mg / mL, but still remained within the range of 14 - 16 cP. The injectability of the antibody showed an output force of <5 N at all concentrations, suggesting that little effort is required to inject this composition.

[0260] (Example 3) Deamidation and oxidation analysis Deamidation and oxidation analysis was performed on the samples in Table 27.

[0261] Table 27. Samples for deamidation and oxidation analysis. [Table 27]

[0262] Table 28. Details of the formulation samples. [Table 28]

[0263] Sample preparation: buffer exchange into Tris-HCl pH8, digestion using Immobilized Trypsin (Smart Digest, Thermo Scientific), reduction with DTT.

[0264] RP-ESI-MSe analysis: System: Waters Nano Aquity UPLC equipped in series with Xevo G2S QTOF; injection volume: 2 μL (1 μg of IgG); separation: RP on a Waters Acquity UPLC BEH300 C18 1.7 μm 2.1×100 mm column. Buffer A: 0.1% FA in water, Buffer B: 0.1% FA in acetonitrile; elution with a linear gradient from 3% to 50% B; mass spectrometry: positive ion mode, MSe scan 250 - 2000 m / z.

[0265] UNIFI (trademark) and PTM identification criteria used for further manual investigation: accurate mass within 20 ppm for intact peptides, fragment ion patterns for confirmation of identity, distinct resolved isotope patterns.

[0266] Deamidation was identified exclusively by HC. Between N and Q, deamidation was identified only at N, and the majority of the ions of the fragments containing either N or Q were found to be non-deamidated. A second deamidation (2x) was not seen for any of the deamidated peptides in either HC or LC.

[0267] Table 29. List of antibody fragments and their deamidation.

Table 29-1

Table 29-2

[0268] Deamidation is identified exclusively by HC. Between N and Q, deamidation is identified only at N, and the majority of the ions of the fragments containing either N or Q are found to be non-deamidated. At HC: T35, the N residue of the peptide (2x) was found to be deamidated (showing the second amidation as 2x).

[0269] Oxidation was identified at both M and W residues of the fragment ions, but the majority of the fragment ions containing M and W residues were found to be non-oxidized. At HC: T24, two W residues of the peptide chain were found to be oxidized (showing the second oxidation as 2x). At LC: T1, 1x oxidation was also observed.

[0270] Table 30. List of antibody fragments and their oxidation.

Table 30-1

Table 30-2

[0271] Oxidation was identified on both the M and W residues of the fragment ions. At HC:T24, two W residues of the peptide chain were found to be oxidized (the second oxidation is shown as 2x). No oxidation was observed by LC.

[0272] PTM of the VAIO-1799 sample analyzed using deamidation for Q and N and oxidation at M and W. Peptides were digested by reverse-phase LC-MS and identified by accurate mass and fragment sequence tags. Deamidation was identified at N, while oxidation was identified at both M and W. Increased deamidation observed in 1a and 3a compared to 1b and 3b, respectively. Increased oxidation observed in 1b compared to 1a (especially for HC-88-124). Similarly, increased oxidation observed in 3a compared to 3b. (Example 4) Safety, Tolerability, and Pharmacokinetics

[0273] A Phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics (PD) of single ascending doses (SAD) of intravenous (IV) or subcutaneous (SC) ronigutamab in healthy participants. The study conducted was a single-site, randomized, double-blind, placebo-controlled, sequential single ascending dose (SAD) study. The study included eight (8) cohorts of healthy volunteers, which were divided into the following two groups: four (4) cohorts receiving intravenous administration of ronigutamab and four (4) cohorts receiving subcutaneous administration of ronigutamab.

[0274] Specifically, cohorts 1-4 received intravenous administration of 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, or 3.0 mg / kg of ronigutamab or matching placebo over a 60-minute period. Cohorts 5-8 received fixed-dose subcutaneous injections of 20 mg, 40 mg, 125 mg, or 250 mg doses of ronigutamab or matching placebo in a volume of 2 mL or less.

[0275] The participants in the study were healthy according to the study protocol. Specifically, at the time of registration for the study, the participants were between 18 and 55 years of age and had a body mass index (BMI) in the range of 18 to 32 kg / m 2 .

[0276] During the study process, routine laboratory tests, audiological, pharmacokinetic and pharmacodynamic evaluations were performed at predetermined time points in each of the cohorts involved in the study. In addition, the safety and tolerability of the administered drugs were evaluated throughout the study process by assessing adverse events and monitored for 99 days.

[0277] Pharmacokinetic data were obtained using electrochemiluminescence immunoassay with demonstrated efficacy. Receptor occupancy was evaluated using a qualified flow cytometry assay.

[0278] The study involved the enrollment of sixty-three (63) participants. Of these participants, forty-seven (47) received rontigumab and sixteen (16) received placebo. In this study, four (4) participants were unable to be followed up or discontinued for other reasons. This loss of participants was not considered to have an impact on the primary analysis.

[0279] The baseline characteristics and demographics of the participants are provided in Table 31 below. Table 31: Baseline Characteristics:

Table 31-1

Table 31-2

[0280] The data in Table 31 are provided as n (%) or mean (range). There were no significant differences across treatment groups for any of the characteristics.

[0281] Preliminary data for safety and tolerability assessment, obtained by tracking treatment-emergent adverse events (TEAEs), are presented in Figure 16.

[0282] The data demonstrate that no serious adverse events (SAEs) occurred. All adverse events were mild and moderate in severity, and dose-related safety events occurred. Overall, particularly notable adverse events related to the target (AESIs) that were carefully monitored included type I allergic reactions / anaphylaxis, hyperglycemia, infusion-related reactions, diarrhea / inflammatory bowel disease exacerbation, hearing impairment, and muscle spasms. During the study, one (1.6%) AESI of "possible" or "probable" relationship to rontigumab was observed in one (1) participant in the 20 mg SC cohort, with gastrointestinal disorders (abdominal pain, abdominal distension, and increased frequency of defecation). (The participant reported more than one TEAE).

[0283] One participant had an infusion-related reaction, and three (3) had "possible" or "probable" injection site reactions related to rontigumab. All reactions were mild and self-limiting and resolved within a few hours without medical intervention.

[0284] Pharmacokinetic evaluation: The mean serum rontigumab concentration-time profiles after intravenous (IV) administration are presented in Figure 17. The mean serum rontigumab concentration-time profiles after subcutaneous (SC) administration are presented in Figure 18.

[0285] In the data provided in Figures 17 and 18, samples below the limit of quantification (0.1 μg / mL) were plotted as 0 μg / mL at 3.0 mg / kg, and n does not include one participant who had the study prematurely terminated due to the development as described above. The shaded portions in Figures 17 and 18 represent serum concentrations of rontigumab that exceed IGF-1R internalization saturation.

[0286] As is apparent from the data provided in FIGS. 17 and 18, the mean serum concentration of lonigutamab increased in a supra-proportional manner over the tested dose range. Further, FIGS. 17 and 18 also provide evidence of target-mediated drug disposition (TMDD) following IV and / or SC administration of lonigutamab. TMDD describes a non-linear pharmacokinetic (PK) phenomenon caused by the high-affinity binding of a compound to its pharmacological target. When lonigutamab binds to IGF-1R, the resulting complex is degraded. At low concentrations, lonigutamab binds efficiently to IGF-1R and is degraded, so the serum concentration of lonigutamab rapidly decreases, and hence there is a rapid decrease in the measured serum concentration of lonigutamab. On the other hand, at high concentrations, the target IGF-1R is saturated with lonigutamab and the serum concentration of lonigutamab decreases slowly. This slow decrease in the serum concentration of lonigutamab indicates that lonigutamab is available to bind to newly generated IGF-1R. In addition to the pharmacology of lonigutamab, this data provides additional evidence of IGF-1R internalization.

[0287] This data demonstrates that the TMDD threshold (above which IGF-1R internalization is saturated) appears to be approximately 3 μg / mL for lonigutamab. Compared to IV administration, SC administration of lonigutamab overcomes TMDD and maintains pharmacologically significant concentrations of lonigutamab.

[0288] Pharmacodynamic evaluation: FIG. 19 provides the mean lonigutamab receptor occupancy on peripheral blood mononuclear cells over time after intravenous administration. FIG. 20 provides the mean lonigutamab receptor occupancy on peripheral blood mononuclear cells over time after subcutaneous administration. The shaded portions in FIGS. 19 and 20 demonstrate the optimal IGF-1R internalization portion after administration of the pharmaceutical composition containing lonigutamab.

[0289] As indicated by the data provided in Figures 19 and 20, the maximum IGF-1R occupancy was observed by the first time point (12 hours) in all cohorts. The duration of receptor saturation increased with increasing doses of lonigutamab. 1.0 mg / kg and 3.0 mg / kg (administered as intravenous infusions) as well as 125 mg and 250 mg (administered as subcutaneous injections) were maintained at maximum levels of receptor occupancy for at least a 4-week period. As noted above, in the 3.0 mg / kg cohort, n does not include one (1) participant who had the study terminated early. The shaded portions in Figures 19 and 20 indicate receptor saturation. (Example 5) Repeated dose study of subcutaneous administration:

[0290] In the planned study, 36 participants with thyroid eye disease (TED) will be enrolled in a multi-site, double-masked, placebo-controlled, randomized, repeated dose escalating (MAD) clinical trial to evaluate lonigutamab against placebo. This study will involve up to three (3) cohorts, with each cohort receiving three (3) different treatment arms.

[0291] The proposed eligibility criteria for participation in this study are provided below: Eligible age for participation in the study: 18 years to 65 years (adult, elderly) Eligible gender for participation in the study: all

[0292] Criteria Key inclusion criteria: · Male or female, ≥18 years and ≤65 years. · Proptosis defined as ≥3 mm above normal values in the study eye. · Clinical Activity Score (CAS) ≥4 (using a 7-item scale) for the most severely affected eye. · Onset of active TED symptoms within 24 months prior to baseline · Agreement to use highly effective contraception as defined in the protocol is mandatory

[0293] Key exclusion criteria: ·Inflammatory bowel disease or irritable bowel syndrome proven by biopsy or clinically suspected. ·Clinically significant lesions related to hearing ·Corneal decompensation that does not respond to medical management. ·Previous orbital irradiation (regardless of reason) or any previous surgical treatment for TED. ·Subjects with diabetes or hemoglobin A1c > 6.0%. ·Any steroid use (intravenous [IV] or oral) at a cumulative dose equivalent to > 3 g of methylprednisolone for the treatment of TED ·Previous steroid use (IV or oral), particularly for the treatment of TED, not exceeding a total dose of 1 g over 8 weeks prior to screening. ·Previous use of teprotumumab or any other IGF-1 receptor (IGF-1R) inhibitor. ·Any previous treatment with biological agents (e.g., rituximab and tocilizumab) for the treatment of TED.

[0294] Cohort 1 will receive a single subcutaneous injection of 20 mg of lonigutamab or placebo on Days 1 and 21.

[0295] Cohort 2 will receive a single subcutaneous injection of 125 mg of lonigutamab or placebo on Days 1 and 21.

[0296] Cohort 3 will receive a single subcutaneous injection of 250 mg of lonigutamab or placebo on Days 1 and 21.

[0297] The primary evaluation items to be measured during the study will include the incidence and characterization of adverse events (TEAEs) occurring under non-severe treatment between Days 1 and 113. The evaluation items to be measured will also include the incidence and characterization of severe TEAEs between Days 1 and 113.

[0298] The secondary evaluation items to be measured will include the following: 1. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Area under the concentration-time curve from zero time to infinity (AUCO-inf) 2. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Observed maximum concentration (Cmax) 3. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Time at which Cmax was observed (Tmax) 4. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Area under the concentration-time curve from zero time to the last quantifiable concentration (AUC0-last) 5. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Elimination half-life (T1 / 2 el) 6. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Elimination rate constant (Kel) 7. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Total body clearance (CL / F) 8. PK profile of Ronigutamab [Time frame: Day 1 to Day 113] Volume of distribution (Vz / F) 9. Percentage of subjects who develop anti-drug antibodies (ADA) after administration of multiple doses of Ronigutamab [Time frame: Day 1 to Day 113] Pharmacokinetic and pharmacodynamic data Incorporation by reference

[0299] Throughout this disclosure, reference is made to other documents, such as patents, patent applications, patent publications, periodicals, books, papers, web content, public databases, and they are cited. All such documents are hereby incorporated by reference in their entirety for all purposes. Equivalents

[0300] In addition to what has been shown and described in this specification, various modifications of the invention and many further embodiments thereof will become apparent to those skilled in the art from the entire contents of this document, including references to scientific and patent documents cited herein. The subject matter herein encompasses important information, exemplification, and guidance that can be adapted for the practice of the invention in its various embodiments and their equivalents.

Claims

1. (a) At least 75 mg / ml of anti-IGF-1R antibody comprising CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6; (b) with 20-30 mM histidine; (c) 4% to 6% D-sorbitol and A pharmaceutical composition containing, The pH is between 5.5 and 6.

5. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the antibody comprises a heavy chain variable domain containing the amino acid sequence of SEQ ID NO:

7.

3. The pharmaceutical composition according to claim 1, wherein the antibody comprises a light chain variable domain containing the amino acid sequence of SEQ ID NO:

8.

4. The pharmaceutical composition according to claim 1, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO:

13.

5. The pharmaceutical composition according to claim 1, wherein the antibody comprises a light chain having the amino acid sequence of SEQ ID NO:

10.

6. The pharmaceutical composition according to claim 1, wherein the antibody comprises a human IgG1 heavy chain constant domain and a human kappa light chain constant domain.

7. The pharmaceutical composition according to claim 1, wherein the antibody is ronigtamab.

8. The pharmaceutical composition according to claim 1, comprising at least 100 mg / ml, at least 125 mg / ml, at least 150 mg / ml, at least 175 mg / ml, at least 200 mg / ml, or at least 250 mg / ml of the anti-IGF-1R antibody.

9. The pharmaceutical composition according to claim 1, comprising the anti-IGF-1R antibody in a concentration of 75 mg / ml to 300 mg / ml, 100 mg / ml to 300 mg / ml, or 125 mg / ml to 250 mg / ml.

10. The pharmaceutical composition according to claim 1, comprising approximately 125 mg / ml, approximately 150 mg / ml, approximately 175 mg / ml, approximately 200 mg / ml, or approximately 250 mg / ml of the anti-IGF-1R antibody.

11. The pharmaceutical composition according to claim 1, comprising approximately 20 mM, approximately 21 mM, approximately 22 mM, approximately 23 mM, approximately 24 mM, approximately 25 mM, approximately 26 mM, approximately 27 mM, approximately 28 mM, approximately 29 mM, or approximately 30 mM histidine.

12. The pharmaceutical composition according to claim 1, comprising approximately 4%, 5%, or 6% D-sorbitol.

13. The pharmaceutical composition according to claim 1, having a pH of approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, or approximately 6.

5.

14. The pharmaceutical composition according to claim 1, wherein the weight osmolality of the pharmaceutical composition is within the physiological weight osmolality range of 250 to 400 mOsm / kg.

15. The pharmaceutical composition according to claim 1, wherein the viscosity of the pharmaceutical composition is 30 cP or less at 21°C.

16. The pharmaceutical composition according to claim 15, wherein the viscosity of the pharmaceutical composition is 15 cP or less at 21°C.

17. The pharmaceutical composition according to claim 15, wherein the viscosity of the pharmaceutical composition is about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 21 cP, about 22 cP, about 23 cP, about 24 cP, about 25 cP, about 26 cP, about 27 cP, about 28 cP, about 29 cP, or about 30 cP at 21°C.

18. The pharmaceutical composition according to claim 1, which is stable for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, or at least 16 weeks.

19. The pharmaceutical composition according to claim 18, which is stable at temperatures from -70°C to 40°C.

20. A pharmaceutical composition according to any one of claims 1 to 19 for treating thyroid eye disease (TED).

21. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is administered subcutaneously.

22. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is administered intramuscularly.

23. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is administered in a delivery volume of 2 ml or less.

24. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is administered by a needle of size 24G or smaller.

25. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is administered at an injection force of 12 N or less.

26. The pharmaceutical composition according to claim 25, characterized in that the pharmaceutical composition is administered at an injection force of about 4N, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N, or about 12N.

27. ​​The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition reduces the severity of thyroid eye disease (TED).

28. The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition reduces exophthalmos in the eye of a subject having thyroid eye disease (TED).

29. The pharmaceutical composition according to claim 28, wherein exophthalmos is reduced by at least 2 mm.

30. The pharmaceutical composition according to claim 28, wherein exophthalmos is reduced by at least 3 mm.

31. The pharmaceutical composition according to claim 28, wherein exophthalmos is reduced by at least 4 mm.

32. The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition reduces the clinical activity score (CAS) of thyroid eye disease (TED).

33. The pharmaceutical composition according to claim 32, wherein the clinical activity score (CAS) is reduced by at least 2 points.

34. The pharmaceutical composition according to claim 32, wherein the clinical activity score (CAS) is reduced to (1).

35. The pharmaceutical composition according to claim 32, wherein the clinical activity score (CAS) of the subject is reduced to zero (0).

36. The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition improves the quality of life of the subject.

37. The pharmaceutical composition according to claim 36, wherein the quality of life is measured by a quality of life (GO-QoL) assessment for Graves' ophthalmopathy.

38. The pharmaceutical composition according to claim 36, wherein the quality of life is measured by a subscale of visual function or its appearance.

39. The pharmaceutical composition according to claim 36, wherein the quality of life is measured according to the European Group on Graves' orbitophthalmia (EUGOGO) guidelines.

40. The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition reduces the severity of diplopia.

41. The pharmaceutical composition according to claim 40, wherein the diplopia is a persistent diplopia.

42. The pharmaceutical composition according to claim 40, wherein the diplopia is non-permanent.

43. The pharmaceutical composition according to claim 40, wherein the diplopia is intermittent.

44. A syringe comprising the pharmaceutical composition according to any one of claims 1 to 19.

45. The syringe according to claim 44, comprising a delivery volume of 2 ml or less.

46. The syringe according to claim 44, comprising a needle of size 24G or less.

47. The syringe according to claim 44, which is an automatic, reusable, fixed-dose pen.

48. The syringe according to claim 44, which is an automatic, reusable, variable-dose pen.

49. The syringe according to claim 44, which is an automatic, disposable, fixed-dose auto-injector.

50. A syringe according to claim 44 for treating thyroid eye disease (TED), characterized in that the pharmaceutical composition is administered using the syringe.

51. The syringe according to claim 50, characterized in that the pharmaceutical composition is administered subcutaneously.

52. The syringe according to claim 50, characterized in that the pharmaceutical composition is administered intramuscularly.

53. The syringe according to claim 50, characterized in that the pharmaceutical composition is administered with an injection force of 12 N or less.

54. The syringe according to claim 53, characterized in that the pharmaceutical composition is administered at an injection force of about 4N, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, about 11N, or about 12N.

55. (a) a heavy chain comprising CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, and a charged amino acid at its c-terminus; and (b) A light chain comprising CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6 An anti-IGF-1R antibody containing [specific component].

56. The anti-IGF-1R antibody according to claim 55, wherein the heavy chain comprises a variable domain containing the amino acid sequence of SEQ ID NO:

7.

57. The anti-IGF-1R antibody according to claim 55, wherein the light chain comprises a variable domain having the amino acid sequence of SEQ ID NO:

8.

58. The anti-IGF-1R antibody according to claim 55, wherein the charged amino acid is a positively charged amino acid.

59. The anti-IGF-1R antibody according to claim 58, wherein the positively charged amino acid is lysine, histidine, or arginine.

60. The anti-IGF-1R antibody according to claim 59, wherein the positively charged amino acid is lysine.

61. The anti-IGF-1R antibody according to claim 58, wherein the heavy chain comprises the sequence of SEQ ID NO:

11.

62. The anti-IGF-1R antibody according to claim 58, wherein the heavy chain comprises the sequence of SEQ ID NO:

12.

63. The anti-IGF-1R antibody according to claim 58, wherein the heavy chain comprises the sequence of SEQ ID NO:

13.

64. The anti-IGF-1R antibody according to claim 55, wherein the charged amino acid is an overcharged amino acid.

65. The anti-IGF-1R antibody according to claim 64, wherein the positively charged amino acid is aspartic acid or glutamic acid.

66. The anti-IGF-1R antibody according to claim 64, wherein the heavy chain comprises the sequence of SEQ ID NO:

14.

67. The anti-IGF-1R antibody according to claim 64, wherein the heavy chain comprises the sequence of SEQ ID NO:

15.

68. A pharmaceutical composition comprising the antibody described in any one of claims 55 to 67.

69. The pharmaceutical composition according to claim 68 for use in the treatment of thyroid eye disease (TED).

70. The pharmaceutical composition for use according to claim 69, wherein the pharmaceutical composition is administered subcutaneously.

71. The pharmaceutical composition for use according to claim 69, wherein the pharmaceutical composition is administered intramuscularly.

72. A pharmaceutical composition for a method of treating thyroid eye disease (TED), comprising ronigtamab, characterized in that the pharmaceutical composition is administered by injection.

73. The pharmaceutical composition according to claim 72, wherein the injection is intravenous infusion.

74. The pharmaceutical composition according to claim 72, characterized in that the injection is administered subcutaneously.

75. The pharmaceutical composition according to claim 73, characterized in that the pharmaceutical composition is administered by intravenous infusion at a dose of ronigtamab of about 0.1 mg / kg.

76. The pharmaceutical composition according to claim 73, characterized in that the pharmaceutical composition is administered by intravenous infusion at a dose of ronigtamab of about 0.3 mg / kg.

77. The pharmaceutical composition according to claim 73, characterized in that the pharmaceutical composition is administered by intravenous infusion at a dose of ronigtamab of about 1.0 mg / kg.

78. The pharmaceutical composition according to claim 73, characterized in that the pharmaceutical composition is administered by intravenous infusion at a dose of ronigtamab of about 3.0 mg / kg.

79. The pharmaceutical composition according to claim 74, characterized in that the pharmaceutical composition is administered by subcutaneous injection at a dose of 20 mg of ronigtamab.

80. The pharmaceutical composition according to claim 74, characterized in that the pharmaceutical composition is administered by subcutaneous injection at a dose of 40 mg of ronigtamab.

81. The pharmaceutical composition according to claim 74, characterized in that the pharmaceutical composition is administered by subcutaneous injection at a dose of 125 mg of ronigtamab.

82. The pharmaceutical composition according to claim 74, characterized in that the pharmaceutical composition is administered by subcutaneous injection at a dose of 250 mg of ronigtamab.

83. The pharmaceutical composition according to claim 72, wherein the administration of the pharmaceutical composition results in a serum concentration of about 3 μg / mL or higher.

84. The pharmaceutical composition according to claim 73, wherein intravenous administration is performed for a maximum of approximately 60 minutes.

85. The pharmaceutical composition according to claim 72, wherein the administration of the pharmaceutical composition causes little to no harmful effects.

86. The pharmaceutical composition according to claim 72, wherein the administration of the pharmaceutical composition achieves an IGF-1R occupancy rate of 95% or higher.

87. The pharmaceutical composition according to claim 86, wherein an IGF-1R occupancy rate of 95% or higher can be achieved one hour after administration of the pharmaceutical composition.

88. The pharmaceutical composition according to claim 86, wherein an IGF-1R occupancy rate of 90% or higher is maintained for at least 28 days after administration of the pharmaceutical composition.

89. A pharmaceutical composition for the treatment of thyroid eye disease (TED), comprising about 10 mg to about 300 mg of ronigtamab, characterized in that the pharmaceutical composition is administered subcutaneously.

90. The pharmaceutical composition according to claim 89, wherein the pharmaceutical composition comprises about 20 mg of ronigtamab.

91. The pharmaceutical composition according to claim 89, wherein the pharmaceutical composition comprises about 125 mg of ronigtamab.

92. The pharmaceutical composition according to claim 89, wherein the pharmaceutical composition comprises about 250 mg of ronigtamab.

93. The pharmaceutical composition according to claim 89, characterized in that the pharmaceutical composition is administered once a week.

94. The pharmaceutical composition according to claim 89, characterized in that the pharmaceutical composition is administered once every two weeks.

95. The pharmaceutical composition according to claim 89, characterized in that the pharmaceutical composition is administered once every three weeks.

96. The pharmaceutical composition according to claim 89, characterized in that the pharmaceutical composition is administered once every four (four) weeks.

97. The pharmaceutical composition according to claim 90, characterized in that the pharmaceutical composition is administered on day 1 and day 21.

98. The pharmaceutical composition according to claim 91, characterized in that the pharmaceutical composition is administered on day 1 and day 21.

99. The pharmaceutical composition according to claim 92, characterized in that the pharmaceutical composition is administered on day 1 and day 21.

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