Pharmaceutical combination containing Anti-IGF-1r and Anti-CD40l antibodies, and use thereof and method for using same

Abstract

The present invention relates to a pharmaceutical combination containing anti-IGF-1R and anti-CD40L antibodies, and the use thereof and a method for using same. The present invention belongs to the pharmaceutical field. Specifically, the present invention relates to a pharmaceutical combination containing anti-IGF-1R and anti-CD40L antibodies for treating diseases associated with CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway, such as thyroid eye disease. The present invention further relates to the use and a method for treating diseases associated with CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway, such as thyroid eye disease, by using the pharmaceutical combination.

Description

Drug combinations containing anti-IGF-1R and anti-CD40L antibodies, their uses and methods of administration

[0001] Cross-references to related applications

[0002] This application is based on and claims priority to Chinese patent applications No. 202411514004.1, filed on October 28, 2024, and No. 202411529138.0, filed on October 30, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of medicine. Specifically, this invention relates to a pharmaceutical combination comprising an anti-IGF-1R antibody or its antigen-binding fragment and an anti-CD40L antibody or its antigen-binding fragment for the treatment of thyroid eye diseases. This invention also relates to the use and methods of treating thyroid eye diseases using said pharmaceutical combination. Background Technology

[0004] Thyroid eye disease (TED), also known as thyroid-associated ophthalmopathy (TAO) or Graves' ophthalmopathy (GO), is an orbital disease closely related to thyroid disease. It is an autoimmune disease affecting ocular tissues, usually associated with Graves' disease (GD). Approximately 25-50% of GD patients develop TED, but it can also be seen in other thyroid diseases, and even in people with normal thyroid function [Li Z, Cestari DM, Fortin E. Thyroid eye disease: what is new to know? Curr Opin Ophthalmol. 2018; 29(6):528-534.].

[0005] The estimated annual incidence of TED is 16 per 100,000 (women) and 2.9 per 100,000 (men). Based on disease severity, it can be classified as mild, moderate, and severe. While TAO appears to affect women more frequently, severe cases are more common in men. Patients aged 30–50 years are most commonly affected, with severe cases more frequently occurring in those over 50. The pathogenesis of TED is not fully understood, but multiple studies have shown that orbital fibroblasts (OFs) present in the interstitial space of muscle fibers and orbital fibrous connective tissue are key factors contributing to orbital soft tissue enlargement in TAO.

[0006] The natural course of pterygium dermatitis (TED) is divided into active and inactive phases. The most common symptoms are dry eye, a gritty feeling in the eye, photophobia, tearing, diplopia, and a feeling of pressure behind the eye. Typical signs include upper eyelid retraction, eyelid edema, periorbital and conjunctival edema, and exophthalmos. TED is usually mild to moderate, with approximately 3–5% of patients experiencing severe TED, characterized by intense pain, vision-threatening corneal ulcers, or compressive optic neuropathy. Besides potentially affecting vision, TED has an extremely serious impact on a patient's appearance, social functioning, and quality of life.

[0007] The European Graves Orbital Disease Collaboration guidelines and the Chinese guidelines for the management of thyroid eye disease have listed the anti-IGF-1R antibody teprotumumab as a second-line treatment for moderate to severe active thyroid eye disease (TED). The joint consensus of the American Thyroid Association and the European Thyroid Association recommends it as the first-line treatment for TED with significant exophthalmos or diplopia. While the IGF-1R monoclonal antibody teprotumumab has shown positive clinical responses, there is still room for improvement in efficacy indicators such as exophthalmos response rate and degree of improvement, diplopia response, and safety.

[0008] CD40 ligand (CD40L), also known as CD154, gp39, TNF-associated activating protein (TRAP), 5c8 antigen, or T-BAM, is a 39 kDa type II transmembrane protein. CD40L belongs to the tumor necrosis factor (TNF) superfamily and exists on the cell membrane as a homotrimer. It is primarily expressed on activated T cells, but is also present on other types of immune and non-immune cells, such as epithelial cells, monocytes, dendritic cells, fibroblasts, smooth muscle cells, endothelial cells, and platelets. The CD40L / CD40 signaling pathway mediates various immune and inflammatory responses and plays a crucial role in normal immune responses. Existing research indicates that the CD40L / CD40 signaling pathway not only mediates signal transduction between various lymphocytes but also participates in interactions between non-immune cells. Therefore, the CD40L / CD40 signaling pathway plays an important pathogenic role in a variety of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative diseases, graft-versus-host disease, tumors, and atherosclerosis.

[0009] CD40L antibodies have been developed for thyroid eye diseases or tumors such as solid tumors, but there is still room for further improvement in their therapeutic effects.

[0010] Therefore, there remains a need in this field to develop drugs and therapies for further treatment of thyroid eye diseases and to improve symptoms.

[0011] Invention Overview

[0012] The present invention aims to provide drug combinations that can effectively treat diseases related to the CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, to provide patients with more treatment options and meet clinical needs.

[0013] The inventors have surprisingly discovered that the drug combination of the present invention, by combining anti-IGF-1R antibody or its antigen-binding fragment and anti-CD40L antibody or its antigen-binding fragment, can further enhance the therapeutic effect of thyroid eye disease on the existing basis, and is expected to further inhibit the activation of orbital fibroblasts in thyroid eye disease, thereby additionally inhibiting the progression of thyroid eye disease, and is expected to be applied to patients with thyroid eye disease in both active and inactive phases.

[0014] Diseases that can be treated with the drug combination of the present invention also include other diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as solid tumors.

[0015] In a first aspect, the present invention provides a pharmaceutical combination comprising:

[0016] (i) a first active ingredient, wherein the first active ingredient is an anti-CD40L antibody or an antigen-binding fragment thereof; and

[0017] (ii) A second active ingredient, wherein the second active ingredient is an anti-IGF-1R antibody or an antigen-binding fragment thereof.

[0018] In a second aspect, the invention provides a kit or kit containing the drug combination of the invention, preferably in the form of drug dosage units. This allows dosage units to be provided according to a dosing regimen or drug administration interval.

[0019] In one embodiment, the kit or kit of the present invention comprises, within the same package:

[0020] - A pharmaceutical composition containing a first active ingredient, an antiCD40L antibody or an antigen-binding fragment thereof, for example, contained in a first container;

[0021] - A pharmaceutical composition containing a second active ingredient, an anti-IGF-1R antibody or an antigen-binding fragment thereof, for example, contained in a second container;

[0022] And optionally, instructions for use, which describe the administration methods of the two pharmaceutical compositions.

[0023] In a preferred embodiment, the kit or set of medications is contained within the same package:

[0024] - A pharmaceutical composition containing an antiCD40L antibody or its antigen-binding fragment as the first active ingredient as the sole active ingredient, for example, contained in a first container;

[0025] - A pharmaceutical composition containing an anti-IGF-1R antibody or its antigen-binding fragment as a second active ingredient as the sole active ingredient, for example, contained in a second container;

[0026] And optionally, instructions for use, which describe the administration methods of the two pharmaceutical compositions.

[0027] In some embodiments, the pharmaceutical composition optionally contains pharmaceutically acceptable excipients.

[0028] In a third aspect, the present invention provides a method for treating diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, comprising administering an anti-CD40L antibody or an antigen-binding fragment thereof, or administering a combination of drugs of the present invention, or a kit or package containing said combination of drugs; or comprising administering in combination an anti-CD40L antibody or an antigen-binding fragment thereof, and an IGF-1R antibody or an antigen-binding fragment thereof.

[0029] In a fourth aspect, the invention provides the use of an anti-CD40L antibody or its antigen-binding fragment thereof for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors, optionally in combination with an anti-IGF-1R antibody or its antigen-binding fragment. In some embodiments, the invention provides the use of an anti-CD40L antibody or its antigen-binding fragment thereof for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors. In some embodiments, the invention provides the use of an anti-CD40L antibody or its antigen-binding fragment thereof for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors, in combination with an anti-IGF-1R antibody or its antigen-binding fragment. The present invention also provides the use of an anti-IGF1R antibody or its antigen-binding fragment thereof for co-administration with an anti-CD40L antibody or its antigen-binding fragment for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0030] In a fifth aspect, the present invention provides the use of an anti-CD40L antibody or its antigen-binding fragment in the preparation of a medicament for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors, optionally, the medicament being administered in combination with an anti-IGF-1R antibody or its antigen-binding fragment. In some embodiments, the present invention provides the use of an anti-CD40L antibody or its antigen-binding fragment in the preparation of a medicament for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors. In some embodiments, the present invention provides the use of an anti-CD40L antibody or its antigen-binding fragment in the preparation of a medicament for treatment, in combination with an anti-IGF-1R antibody or its antigen-binding fragment, of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors. The present invention also provides the use of an anti-IGF1R antibody or its antigen-binding fragment in the preparation of a medicament for use in combination with an anti-CD40L antibody or its antigen-binding fragment to treat diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0031] In a sixth aspect, the present invention provides an anti-CD40L antibody or an antigen-binding fragment thereof for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors, optionally administered in combination with an anti-IGF-1R antibody or an antigen-binding fragment thereof. In some embodiments, the present invention provides an anti-CD40L antibody or an antigen-binding fragment thereof for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors. In some embodiments, the present invention provides an anti-CD40L antibody or an antigen-binding fragment thereof for use in combination with an anti-IGF-1R antibody or an antigen-binding fragment thereof for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid eye disease or solid tumors. The present invention also provides an anti-IGF1R antibody or its antigen-binding fragment thereof for use in combination with an anti-CD40L antibody or its antigen-binding fragment for the treatment of diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0032] In a seventh aspect, the present invention provides the use of the pharmaceutical combination of the present invention, or a kit or kit containing the pharmaceutical combination, for treating diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0033] In an eighth aspect, the present invention provides a pharmaceutical combination of the present invention, or a kit or package containing the pharmaceutical combination, for treating diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0034] In a ninth aspect, the invention provides the use of the pharmaceutical combination of the invention in the preparation of a cassette or pharmaceutical product for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

[0035] In some embodiments of the above-described aspects of the present invention, the anti-CD40L antibody or its antigen-binding fragment is used for injection, such as intramuscular injection or intravenous infusion. In some embodiments of the above-described aspects of the present invention, the anti-IGF-1R antibody or its antigen-binding fragment is used for injection, such as intramuscular injection or intravenous infusion. In some embodiments of the above-described aspects of the present invention, both the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF-1R antibody or its antigen-binding fragment are used for injection, such as intramuscular injection or intravenous infusion, or both are used for intravenous infusion.

[0036] In some embodiments of the above-described aspects of the invention, the pharmaceutical combination comprises an anti-CD40L antibody or its antigen-binding fragment and an anti-IGF-1R antibody or its antigen-binding fragment as the only active ingredients.

[0037] In some embodiments of the foregoing aspects of the present invention, the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF-1R antibody or its antigen-binding fragment are administered simultaneously in a single pharmaceutical composition or simultaneously or separately (e.g., sequentially) in separate pharmaceutical compositions. In some embodiments of the foregoing aspects of the present invention, the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF-1R antibody or its antigen-binding fragment are administered simultaneously or separately, for example, sequentially, to a patient.

[0038] In some embodiments of the above-described aspects of the present invention, the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF-1R antibody or its antigen-binding fragment are respectively administered in an effective amount, such as a therapeutically effective amount. Attached Figure Description

[0039] Figures 1A, 1B, and 1C show the combined activity of IGF-1 and CD40L in promoting the proliferation of orbital fibroblasts in patients with thyroid eye, and the inhibitory activity of anti-CD40L antibody, anti-IGF1R antibody, or a combination thereof on the proliferation of orbital fibroblasts in patients with thyroid eye.

[0040] Figures 2A, 2B, 2C, and 2D show the combined activity of IGF-1 and CD40L in promoting hyaluronic acid (HA) secretion from orbital fibroblasts in patients with thyroid eye, and the activity of anti-CD40L antibody, anti-IGF1R antibody, or a combination thereof in inhibiting HA secretion from orbital fibroblasts in patients with thyroid eye.

[0041] Invention Details

[0042] The anti-CD40L antibody or its antigen-binding fragment applicable to various aspects of the present invention can be any anti-CD40L antibody or its antigen-binding fragment.

[0043] In some embodiments, the anti-CD40L antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, or respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively. The amino acid sequence composition shown in NO:9, for example, the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM or combinations thereof such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are determined according to the Kabat scheme.

[0044] In some specific embodiments, the anti-CD40L antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, and HCDR3 are those contained in VH as shown in SEQ ID NO:4, and LCDR1, LCDR2, and LCDR3 are those contained in SEQ ID NO:4. The VL shown in NO:10 contains LCDR1, LCDR2, and LCDR3, wherein the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM, or combinations thereof, such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are determined according to the Kabat scheme.

[0045] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:4 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence encoded by the nucleic acid sequence shown in SEQ ID NO:51, or is composed of said amino acid sequence, or comprises an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, or is composed of said amino acid sequence; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with ... The amino acid sequence shown in NO:10 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence encoded by the nucleic acid sequence shown in SEQ ID NO:52, or is composed of said amino acid sequence, or contains or is composed of said amino acid sequence.

[0046] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence, or is composed of the amino acid sequence, and the light chain variable region comprises an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:10 or the nucleic acid sequence shown in SEQ ID NO:52, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence, or is composed of the amino acid sequence.

[0047] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51 or is composed of the amino acid sequence shown in SEQ ID NO:10 or is composed of the amino acid sequence shown in SEQ ID NO:52.

[0048] In some embodiments, the anti-CD40L antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, or respectively composed of the amino acid sequences shown in SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26. The amino acid sequence composition shown in NO:26, for example, the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM or combinations thereof such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are determined according to the Kabat scheme.

[0049] In some specific embodiments, the anti-CD40L antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, and HCDR3 are those contained in VH as shown in SEQ ID NO:19, and LCDR1, LCDR2, and LCDR3 are those contained in SEQ ID NO:19. The VL shown in NO:20 includes LCDR1, LCDR2, and LCDR3, wherein the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM, or combinations thereof, such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are determined according to the Kabat scheme.

[0050] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:19, or comprises or consists of the amino acid sequence shown in SEQ ID NO:19; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:20, or comprises or consists of the amino acid sequence shown in SEQ ID NO:20.

[0051] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:19 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:20 and an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0052] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:19, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:20.

[0053] In some embodiments of the present invention, the anti-CD40L antibody or antigen-binding fragment thereof suitable for use in the present invention is the anti-CD40L antibody or antigen-binding fragment thereof disclosed in WO2017011544A1, such as the INX-021 antibody or antigen-binding fragment thereof. In some embodiments, the anti-CD40L antibody or antigen-binding fragment thereof suitable for use in the present invention comprises 1, 2, 3, 4, 5, or 6 CDRs of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody disclosed in WO2017011544A1, such as the INX-021 antibody. In some embodiments, the anti-CD40L antibody or antigen-binding fragment thereof suitable for use in the present invention comprises 1, 2, or 3 heavy chain variable region CDRs, namely HCDR1, HCDR2, and HCDR3, of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody disclosed in WO2017011544A1, such as the INX-021 antibody. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises one, two, or three light chain variable regions (CDRs), namely LCDR1, LCDR2, and LCDR3, of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises three heavy chain variable regions (CDRs) and three light chain variable regions (CDRs) of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain variable region or a light chain variable region of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises the heavy chain variable region and light chain variable region of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises either the heavy chain or light chain of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises the heavy chain and light chain of a known antibody that specifically binds to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1.In some embodiments, the anti-CD40L antibody or its antigen-binding fragment suitable for use in this invention comprises two heavy chains and two light chains of known antibodies that specifically bind to CD40L, such as the anti-CD40L antibody INX-021 disclosed in WO2017011544A1. WO2017011544A1 is incorporated herein by reference in its entirety.

[0054] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention further comprises an Fc region, for example, wherein the Fc region is or is derived from human IgG Fc, for example, is or is derived from human IgG1 Fc, is or is derived from human IgG2 Fc, is or is derived from human IgG3 Fc or is derived from human IgG4 Fc; preferably, the Fc region comprises a mutation that reduces or eliminates effector function, and / or eliminates the binding affinity to FcγR while retaining the binding affinity to FcRn, preferably, the mutation is an L234A / L235A and / or P329 deletion mutation, for example, an L234A / L235A and P329 deletion mutation. In some embodiments of the present invention, the Fc region

[0055] (i) Contains or is composed of the amino acid sequence shown in SEQ ID NO: 13 or 14;

[0056] (ii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:13; or

[0057] (iii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:14, and contains L234A / L235A and P329 deletion mutations.

[0058] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention further comprises a heavy chain constant region, which is or is derived from a constant region of (human) IgG1, IgG2, IgG3, or IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the Fc and CH1 regions described herein. In some embodiments, the CH1 region comprises or is composed of the amino acid sequence shown in SEQ ID NO:15 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

[0059] In some embodiments, the heavy chain constant region suitable for the anti-CD40L antibody or its antigen-binding fragment of the present invention

[0060] (i) Contains or is composed of the amino acid sequence shown in SEQ ID NO:5 or 16;

[0061] (ii) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:16; or

[0062] (iii) Contains an amino acid sequence that has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:5, and has L234A / L235A and P329 deletion mutations.

[0063] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention further comprises a light chain constant region, said light chain constant region being or derived from the light chain constant region of (human) lambda or Kappa. Preferably, said light chain constant region comprises or consists of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO: 11; or comprises or consists of the amino acid sequence shown in SEQ ID NO: 11.

[0064] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain, wherein the heavy chain...

[0065] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:6; or

[0066] (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:6; or

[0067] It contains a light chain, wherein the light chain

[0068] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO: 12; or

[0069] (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:12.

[0070] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:6; and the light chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:12.

[0071] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:6, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:12.

[0072] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment applicable to the present invention comprises two heavy chains and two light chains, wherein the heavy chains comprise or consist of the amino acid sequence shown in SEQ ID NO:6, and the light chains comprise or consist of the amino acid sequence shown in SEQ ID NO:12.

[0073] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain, wherein the heavy chain...

[0074] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:27; or

[0075] (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:27; or

[0076] It contains a light chain, wherein the light chain

[0077] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:28; or

[0078] (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:28.

[0079] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:27; and the light chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:28.

[0080] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:27, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:28.

[0081] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment applicable to the present invention comprises two heavy chains and two light chains, wherein the heavy chains comprise or consist of the amino acid sequence shown in SEQ ID NO:27, and the light chains comprise or consist of the amino acid sequence shown in SEQ ID NO:28.

[0082] In some embodiments of the present invention, the anti-CD40L antibody suitable for use in the present invention is a monoclonal antibody. In some embodiments of the present invention, the anti-CD40L antibody suitable for use in the present invention is a humanized antibody or a chimeric antibody. In some embodiments of the present invention, the anti-CD40L antibody suitable for use in the present invention is a full-length antibody. In some embodiments of the present invention, the antigen-binding fragment of the anti-CD40L antibody suitable for use in the present invention is an antibody fragment selected from the following: Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibody), linear antibody, single-chain antibody (e.g., scFv); single-domain antibody (sdAb) such as VHH, bivalent antibody or fragment thereof, or camelid antibody or diabody antibody. In some embodiments of the present invention, the anti-CD40L antibody suitable for use in the present invention also encompasses multispecific antibodies, such as bispecific antibodies.

[0083] In some embodiments of the present invention, the anti-CD40L antibody or its antigen-binding fragment is recombinantly expressed in host cells such as mammalian cells like HEK 293 cells or CHO cells.

[0084] In some embodiments, the anti-CD40L antibody suitable for use in this invention is the anti-CD40L antibody disclosed in PCT application number PCT / CN2024 / 1090122, or its antigen-binding fragment, which is incorporated herein by reference in its entirety as if its entire contents were set forth herein. Preferably, the CD40L antibody is the anti-CD40L antibody Hz33B9C5 disclosed in PCT application number PCT / CN2024 / 1090122, which consists of two heavy chain sequences shown in SEQ ID NO:6 and two light chain sequences shown in SEQ ID NO:12.

[0085] The anti-IGF1R antibody or its antigen-binding fragment applicable to various aspects of the present invention can be any anti-IGF1R antibody or its antigen-binding fragment.

[0086] In some embodiments of the present invention, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention is an anti-IGF1R antibody or antigen-binding fragment thereof disclosed in CN100453645C, such as a Teprotumumab antibody or antigen-binding fragment thereof. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention comprises 1, 2, 3, 4, 5, or 6 CDRs of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention comprises 1, 2, or 3 heavy chain variable region CDRs of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C, namely HCDR1, HCDR2, and HCDR3. In some embodiments, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention comprises one, two, or three light chain variable region CDRs, namely LCDR1, LCDR2, and LCDR3, of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention comprises three heavy chain variable region CDRs and three light chain variable region CDRs of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain variable region or a light chain variable region of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises a heavy chain variable region and a light chain variable region of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises either the heavy chain or light chain of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises both the heavy chain and light chain of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C.In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in this invention comprises two heavy chains and two light chains of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Teprotumumab disclosed in CN100453645C. CN100453645C is incorporated herein by reference in its entirety.

[0087] In some embodiments, the anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36, or respectively composed of the amino acid sequences shown in SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36. The amino acid sequence composition shown in NO:36, for example, the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM or combinations thereof such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are determined according to the Kabat scheme.

[0088] In some specific embodiments, the anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, and HCDR3 are those contained in VH as shown in SEQ ID NO:29, and LCDR1, LCDR2, and LCDR3 are those contained in SEQ ID NO:29. The VL shown in NO:30 contains LCDR1, LCDR2, and LCDR3, wherein the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM, or combinations thereof, such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are determined according to the Kabat scheme.

[0089] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:29, or comprises or consists of the amino acid sequence shown in SEQ ID NO:29; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:30, or comprises or consists of the amino acid sequence shown in SEQ ID NO:30.

[0090] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:29 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:30 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0091] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:29, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:30.

[0092] In some embodiments of the present invention, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention is an anti-IGF1R antibody or antigen-binding fragment thereof disclosed in US7538195B2, such as Veligrotug antibody or antigen-binding fragment thereof. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention comprises known IGF1R-specific antibodies, such as the 1, 2, 3, 4, 5, or 6 CDRs of the anti-IGF1R antibody such as Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in the present invention comprises known IGF1R-specific antibodies, such as the 1, 2, or 3 heavy chain variable region CDRs of the anti-IGF1R antibody such as Veligrotug disclosed in US7538195B2, namely HCDR1, HCDR2, and HCDR3. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises one, two, or three light chain variable region CDRs, namely LCDR1, LCDR2, and LCDR3, of known IGF1R-specific antibodies such as the anti-IGF1R antibody Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises three heavy chain variable region CDRs and three light chain variable region CDRs of known IGF1R-specific antibodies such as Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises a heavy chain variable region or a light chain variable region of a known IGF1R-specific antibody such as Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises a heavy chain variable region and a light chain variable region of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises either the heavy chain or light chain of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Veligrotug disclosed in US7538195B2. In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for the present invention comprises both the heavy chain and light chain of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Veligrotug disclosed in US7538195B2.In some embodiments, the anti-IGF1R antibody or antigen-binding fragment thereof suitable for use in this invention comprises two heavy chains and two light chains of a known antibody that specifically binds to IGF1R, such as the anti-IGF1R antibody Veligrotug disclosed in US7538195B2. US7538195B2 is incorporated herein by reference in its entirety.

[0093] In some embodiments, the anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), a third heavy chain complementarity-determining region (HCDR3), a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, or respectively composed of the amino acid sequences shown in SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, respectively. The amino acid sequence composition shown in NO:46, for example, the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM or combinations thereof such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 are determined according to the Kabat scheme.

[0094] In some specific embodiments, the anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, and HCDR3 are those contained in VH as shown in SEQ ID NO:39, and LCDR1, LCDR2, and LCDR3 are those contained in SEQ ID NO:39. The VL shown in NO:40 includes LCDR1, LCDR2, and LCDR3, wherein the CDR is determined by any CDR assignment scheme, such as Kabat, Chothia, IMGT, AbM, or combinations thereof, such as the Kabat and Chothia combination. For example, HCDR1 is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are determined according to the Kabat scheme.

[0095] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:39, or comprises or consists of the amino acid sequence shown in SEQ ID NO:39; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:40, or comprises or consists of the amino acid sequence shown in SEQ ID NO:40.

[0096] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:39 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:40 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it, or is composed of said amino acid sequence.

[0097] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:39, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:40.

[0098] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention further comprises an Fc region, for example, wherein the Fc region is or is derived from human IgG Fc, for example, is or is derived from human IgG1 Fc, is or is derived from human IgG2 Fc, is or is derived from human IgG3 Fc or is derived from human IgG4 Fc; preferably, the Fc region comprises a mutation that reduces or eliminates effector function, and / or eliminates the binding affinity to FcγR while retaining the binding affinity to FcRn, preferably, the mutation is an L234A / L235A and / or P329 deletion mutation, for example, an L234A / L235A and P329 deletion mutation. In some embodiments of the present invention, the Fc region

[0099] (i) Contains or consists of the amino acid sequence shown in SEQ ID NO:13 or 14;

[0100] (ii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:13; or

[0101] (iii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:14, and contains L234A / L235A and P329 deletion mutations.

[0102] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention further comprises a heavy chain constant region, which is or is derived from a constant region of (human) IgG1, IgG2, IgG3, or IgG4. In some embodiments, the heavy chain constant region comprises or is composed of the Fc and CH1 regions described herein. In some embodiments, the CH1 region comprises or is composed of the amino acid sequence shown in SEQ ID NO:15 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it.

[0103] In some embodiments, the heavy chain constant region is suitable for the anti-IGF1R antibody or its antigen-binding fragment of the present invention.

[0104] (i) Contains or is composed of the amino acid sequence shown in SEQ ID NO:5 or 16;

[0105] (ii) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:16; or

[0106] (iii) Contains an amino acid sequence that has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:5, and has L234A / L235A and P329 deletion mutations.

[0107] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention further comprises a light chain constant region, said light chain constant region being or derived from the light chain constant region of (human) lambda or Kappa. Preferably, said light chain constant region comprises or consists of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO: 11; or comprises or consists of the amino acid sequence shown in SEQ ID NO: 11.

[0108] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain, wherein the heavy chain...

[0109] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:37; or

[0110] (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:37; or

[0111] It contains a light chain, wherein the light chain

[0112] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:38; or

[0113] (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:38.

[0114] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use with the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:37; and the light chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:38. In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use with the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:37, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:38. In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises two heavy chains and two light chains, wherein the heavy chains comprise or consist of the amino acid sequence shown in SEQ ID NO:37, and the light chains comprise or consist of the amino acid sequence shown in SEQ ID NO:38.

[0115] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for the present invention comprises a heavy chain, wherein the heavy chain...

[0116] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:47; or

[0117] (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:47; or

[0118] It contains a light chain, wherein the light chain

[0119] (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:48; or

[0120] (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:48.

[0121] In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:47; and the light chain comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:48. In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment suitable for use in the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:47, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:48. In some embodiments of the present invention, the anti-IGF1R antibody or its antigen-binding fragment applicable to the present invention comprises two heavy chains and two light chains, wherein the heavy chains comprise or consist of the amino acid sequence shown in SEQ ID NO:47, and the light chains comprise or consist of the amino acid sequence shown in SEQ ID NO:48.

[0122] In some embodiments of the present invention, the anti-IGF1R antibody suitable for use in the present invention is a monoclonal antibody. In some embodiments of the present invention, the anti-IGF1R antibody suitable for use in the present invention is a humanized antibody or a chimeric antibody. In some embodiments of the present invention, the anti-IGF1R antibody suitable for use in the present invention is a full-length antibody. In some embodiments of the present invention, the antigen-binding fragment of the anti-IGF1R antibody suitable for use in the present invention is an antibody fragment selected from the following: Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibody), linear antibody, single-chain antibody (e.g., scFv); single-domain antibody (sdAb) such as VHH, bivalent antibody or fragment thereof, or camelid antibody or diabody antibody. In some embodiments of the present invention, the anti-IGF1R antibody suitable for use in the present invention also encompasses multispecific antibodies, such as bispecific antibodies.

[0123] In some embodiments of the present invention, the anti-IGF1R antibody is recombinantly expressed in host cells such as mammalian cells such as HEK 293 cells or CHO cells.

[0124] In various aspects of the present invention, such as the methods, uses, pharmaceutical combinations, or kits or flasks comprising the present invention, for the treatment of diseases or conditions related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway. In some embodiments, a patient suffering from a disease or condition related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway may have one or more of the following characteristics:

[0125] (i) Compared to healthy individuals, individuals with CD40L / CD40-mediated overactive immune systems;

[0126] (ii) Abnormal activation of CD40L / CD40-mediated signaling pathways compared to healthy individuals;

[0127] (iii) Compared to healthy individuals, there is abnormal activation of the IGF1 / IGF1R-mediated signaling pathway;

[0128] (iv) Compared to healthy individuals, they produce or deposit excessive amounts of anti-autoantibodies;

[0129] (v) Compared to healthy individuals, there is abnormal activation of the CD40L / CD40-mediated signaling pathway and excessive production and deposition of anti-autoantibodies;

[0130] (vi) The cells in patients with the disease or condition (e.g., activated T cells or other types of immune or non-immune cells, such as epithelial cells, monocytes, dendritic cells, fibroblasts, smooth muscle cells, endothelial cells and platelets) have increased expression of CD40L or CD40, for example, compared to the corresponding cells in healthy individuals.

[0131] (vii) The cells of patients with the disease or condition, such as tumor cells, have increased IGF1R expression on their surface, for example, compared to the corresponding cells of healthy individuals;

[0132] (viii) It responds to the inhibition of the CD40L / CD40-mediated signaling pathway;

[0133] (ix) It responds to the inhibition of IGF1 / IGF1R-mediated signaling pathways.

[0134] In some embodiments, the diseases or conditions associated with the CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway used in this invention are selected from thyroid eye diseases or solid tumors (e.g., solid malignant tumors). In some embodiments, the diseases or conditions associated with the CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway used in this invention are thyroid eye diseases.

[0135] In various aspects of the invention, such as the methods, uses, pharmaceutical combinations, or kits or pharmacies comprising the invention, the anti-CD40L antibody or its antigen-binding fragment, or the anti-IGF1R antibody or its antigen-binding fragment, is used for parenteral administration, such as injection or intravenous infusion. In some embodiments, the anti-CD40L antibody or its antigen-binding fragment, and the anti-IGF1R antibody or its antigen-binding fragment, in the pharmaceutical combinations or kits or pharmacies comprising the invention are used for intravenous infusion.

[0136] In various aspects of the invention, the anti-CD40L antibody or its antigen-binding fragment and / or the anti-IGF1R antibody or its antigen-binding fragment may be formulated, individually or together, into a pharmaceutical composition, such as any suitable dosage form, for example, suitable for intravenous infusion. In some embodiments, the pharmaceutical composition comprises pharmaceutically acceptable excipients.

[0137] In various aspects of the invention, the first and second active ingredients are administered simultaneously or separately. In various aspects of the invention, the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF1R antibody or its antigen-binding fragment are administered in combination in the same or different pharmaceutical compositions, for example, simultaneously or separately.

[0138] In various aspects of the present invention, the pharmaceutical combination may contain other suitable active ingredients in addition to the anti-CD40L antibody or its antigen-binding fragment, and the IGF1R antibody or its antigen-binding fragment, provided that such other suitable active ingredients do not impair the beneficial effects of the anti-CD40L antibody or its antigen-binding fragment, and the IGF1R antibody or its antigen-binding fragment. Preferably, the pharmaceutical combination described above contains the anti-CD40L antibody or its antigen-binding fragment, and the IGF1R antibody or its antigen-binding fragment as the sole active ingredients.

[0139] The drug combinations of the present invention have effective therapeutic effects on diseases or conditions related to the CD40L / CD40 signaling pathway and / or IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, and even show additive, enhancing or synergistic therapeutic effects, with acceptable safety.

[0140] definition

[0141] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this invention, the following terms are defined below.

[0142] Unless otherwise specified, terms used in the singular may also include the plural, and vice versa, where appropriate.

[0143] The term "drug combination" or "drug combination product" refers to non-fixed or fixed combinations, including but not limited to cassettes and pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients (e.g., (i) an anti-CD40L antibody or its antigen-binding fragment, and (ii) an anti-IGF1R antibody or its antigen-binding fragment) are administered to a patient simultaneously, without a specific time limit, or sequentially at the same or different time intervals, in separate entities, wherein such administration to the patient provides a preventive or therapeutically effective level of two or more active agents. In some embodiments, the anti-CD40L antibody or its fragment and the anti-IGF1R antibody or its antigen-binding fragment used in the drug combination are administered at levels not exceeding those achieved when used alone. The term "fixed combination" means that two or more active agents are administered to a patient simultaneously in the form of a single entity. Preferably, the dosage and / or time interval of the two or more active agents are selected so that the combined use of the components produces an effect greater than that achieved by using any one component alone in treating a disease or condition. The components may be formulated in different pharmaceutical compositions or formulations. The components may each be in separate formulations, which may be the same or different.

[0144] In addition to the first active ingredient, anti-CD40L antibody or its antigen-binding fragment, and the second active ingredient, anti-IGF1R antibody or its antigen-binding fragment, the pharmaceutical composition of the present invention may also contain additional active ingredients, provided that such additional active ingredients do not affect the aforementioned beneficial effects of the first and second active ingredients. Similarly, the additional active ingredients may be in the same pharmaceutical composition as the first and / or second active ingredients or in separate pharmaceutical compositions. The various active ingredients in the pharmaceutical composition of the present invention may have the same or different dosage forms and may be administered via the same or different routes of administration.

[0145] The dosing regimen and dosage of the active ingredient in the drug combination of this invention are selected based on a variety of factors, including patient type, species, age, weight, sex, and overall health status; the disease to be treated and its severity; and the route of administration. Physicians, clinicians, or veterinarians with general technical skills can easily determine the required effective amount.

[0146] The terms "combination therapy," "combination administration," or "combined administration" refer to the administration of two or more therapeutic agents or modes of treatment to treat the disease described herein. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule containing active ingredients in a fixed proportion. Alternatively, such administration includes the co-administration of individual active ingredients in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration includes the sequential administration of each type of therapeutic agent at substantially the same time or at different times. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or symptom described herein.

[0147] As used herein, the term "pharmaceutically acceptable" means that the substance, composition, dosage form, etc., described below, does not have excessive toxicity, irritation, allergic reactions, or other unwanted properties in mammals, especially humans, and has a reasonable benefit / risk ratio when applied to animals or humans.

[0148] As used herein, the term "pharmaceutical composition" refers to a composition comprising an active ingredient and optionally one or more pharmaceutically acceptable excipients, such as a single pharmaceutical formulation. Such pharmaceutical formulations can be used for various routes of administration, such as oral administration, parenteral administration, and topical administration.

[0149] As used herein, the term "parenteral" or "internal administration" includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions. The pharmaceutical compositions of the present invention are preferably administered via parenteral administration.

[0150] The term "pharmaceutically acceptable excipient" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to an individual. Examples of pharmaceutically acceptable excipients include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

[0151] The term "pharmacy kit" refers to a package containing one or more individual pharmaceutical compositions, wherein at least one pharmaceutical composition contains an effective amount of an anti-CD40L antibody or its antigen-binding fragment, and another pharmaceutical composition contains an effective amount of an anti-IGF1R antibody or its antigen-binding fragment, and a packaging insert containing instructions for the use of the anti-CD40L antibody or its antigen-binding fragment and the anti-IGF1R antibody or its antigen-binding fragment for the prevention or treatment of a disease. The pharmacy kit may also contain other therapeutic agents with the same or different activities. It is understood that when a pharmacy kit contains multiple individual pharmaceutical compositions, each pharmaceutical composition may contain different doses and / or be administered via different routes.

[0152] As used herein, the term "treatment" refers to the administration of the pharmaceutical combination of the present invention to an individual in need to achieve beneficial effects, including but not limited to reducing or lessening the severity of at least one symptom or condition, slowing or halting its progression, or curing said condition, such as inhibiting the proliferation of orbital fibroblasts in patients with thyroid eye disease, inhibiting the secretion of HA by orbital fibroblasts, and improving the quality of life of patients with thyroid eye disease.

[0153] The terms "patient" and "subject" are used interchangeably to refer to animals. Preferably, the patient or subject is a mammal, such as a primate (e.g., human, monkey, orangutan), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. More preferably, the patient or subject is a human.

[0154] The term "effective dose" refers to the amount of a substance that effectively achieves the desired therapeutic or preventative effect at the required dosage and for the required duration. It can be determined by the physician or veterinary practitioner involved and will vary depending on factors such as the compound, the disease state being treated, the severity of the disease, the individual's age and relevant health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0155] All numerical ranges herein should be understood as disclosing every numerical value and subset thereof within that range, regardless of whether they are specifically disclosed otherwise. For example, reference to any numerical range should be considered as reference to every numerical value within that range, such as every integer within that range. This invention relates to all values ​​falling into these ranges, all smaller ranges, and upper or lower limits of numerical ranges.

[0156] The term “about” when used in conjunction with a numeric value means a range of numeric values ​​that have a lower limit of 5%, 4%, 3%, 2%, or 1% smaller than the specified numeric value and an upper limit of 5%, 4%, 3%, 2%, or 1% larger than the specified numeric value.

[0157] When the term “and / or” is used to connect two or more options, it should be understood to mean any one of the options or any two or more of the options.

[0158] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover situations consisting of the mentioned elements, integers, or steps. For example, when referring to an antibody variable region “comprising” a specific sequence, it is also intended to cover the antibody variable region consisting of that specific sequence.

[0159] The term "CD40L" refers to a ligand expressed on activated T cells. Other names for it are also known in the art, such as CD154, CD40 ligand (CD40L), CD40 anti-receptor (CD40CR), gp39, T-BAM, T-cell activation molecule, TRAF, TNF-associated activating protein (TRAP), and tumor necrosis factor ligand superfamily member 5 (TNFSF5). These terms are used interchangeably throughout the application. In some embodiments, the amino acid sequence of human CD40L is shown in Uniport P29965. In some embodiments, CD40L comprises the sequence shown in SEQ ID NO:17.

[0160] As used herein, the terms “anti-CD40L antibody,” “anti-CD40L,” “CD40L antibody,” or “antibody that binds to CD40L” refer to antibodies that are capable of binding with sufficient affinity to (human or cynomolgus monkey) CD40L or fragments thereof such that the antibody can be used as a diagnostic and / or therapeutic agent targeting (human or cynomolgus monkey) CD40L.

[0161] The term "insulin-like growth factor 1 receptor (IGF1R)" as used herein refers to a cell membrane-based receptor tyrosine kinase belonging to the insulin receptor subfamily. IGF1R can be activated by insulin-like growth factors (IGF1 or IGF2), leading to phosphorylation of its own tyrosine kinase domain and initiating intracellular signal transduction, regulating cell growth and differentiation, as well as various life activities in higher organisms such as growth, development, and aging. The molecular structure of IGF1R consists of a heterodimer (α2β2) formed by two subunits, α and β, linked by disulfide bonds. The α subunit is located outside the cell membrane and has a cysteine-rich region that can specifically bind to IGF-1; while the transmembrane β subunit contains a tyrosine kinase catalytic subunit that can catalyze the phosphorylation of its own phosphorylation site, inducing intracellular signal transduction. In some embodiments, the amino acid sequence of human IGF1R is shown in Uniprot P08069.

[0162] As used herein, the terms “anti-IGF1R antibody,” “anti-IGF1R,” “IGF1R antibody,” or “antibody that binds to IGF1R” refer to antibodies that are capable of binding with sufficient affinity to (human or cynomolgus monkey) IGF1R or fragments thereof such that the antibody can be used as a diagnostic and / or therapeutic agent targeting (human or cynomolgus monkey) IGF1R.

[0163] In this article, the term “antibody” is used in the broadest sense to refer to a protein that contains an antigen-binding site, encompassing natural and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies, full-length antibodies, multispecific antibodies, or bispecific antibodies.

[0164] The terms “full-length antibody,” “complete antibody,” and “intact antibody” are used interchangeably herein to refer to glycoproteins comprising at least two heavy chains (H) and two light chains (L) linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region. The light chain constant region consists of one domain: CL. The VH and VL regions can be further subdivided into hypervariable regions (complementarity-determining regions (CDRs) interspersed with more conserved regions (framework regions (FRs)). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant regions do not directly participate in antibody-antigen binding but exhibit various effector functions.

[0165] "Antibody fragment" refers to a molecule distinct from the intact antibody that contains a portion of the intact antibody and binds to the antigen bound by the intact antibody. The term "antigen-binding fragment" as used herein refers to a molecule distinct from the intact antibody that contains a portion of the intact antibody and binds to the antigen bound by the intact antibody.

[0166] The term "antigen-binding fragment" in antibody refers to a molecule distinct from a full-length antibody. It comprises a portion of the full-length antibody but can bind to the antigen of the full-length antibody or compete with the full-length antibody (i.e., the full-length antibody from which the antigen-binding fragment originates) for antigen binding. Antigen-binding fragments can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibody), linear antibodies, single-chain antibodies (e.g., scFv); single-domain antibodies (sdAb) such as VHH, bivalent antibodies or fragments thereof, or camelid antibodies or diabody antibodies. For example, the Fab fragment can be obtained by digesting a full-length antibody with papain. Furthermore, digestion of a complete antibody with pepsin below the disulfide bonds in the hinge region produces F(ab')2, a dimer of Fab' and a divalent antibody fragment. F(ab')2 can be reduced under neutral conditions by breaking the disulfide bonds in the hinge region, thereby converting the F(ab')2 dimer into Fab' monomers. The Fv fragment consists of the VL and VH domains of the antibody single arm. The two domains, VL and VH, of the Fv fragment can be encoded by independent genes, but they can also be generated as a single protein chain by using a recombinant approach and connecting the two domains with a synthetic linker peptide. In this single protein chain, the VL and VH regions pair to form a single-chain Fv (scFv).

[0167] The complementarity-determining region (CDR) or CDR is a region within the antibody variable domain that is highly variable in sequence and forms a structurally defined loop ("hypervariant loop") and / or contains antigen contact residues ("antigen contact sites"). The CDR is primarily responsible for binding to antigen epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus. CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while those located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of many known antibody CDR assignment schemes, including, for example: Chothia (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)) based on antibody three-dimensional structure and CDR loop topology; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., USDapartment of Health and Human Services, National Institutes of Health (1987)) based on antibody sequence variability; AbM (University of Bath); Contact (University College London); and the International ImMunoGeneTics. The database (IMGT) (on the World Wide Web at imgt.cines.fr / ) and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0168] Unless otherwise stated, in this invention, the term "CDR" or "CDR sequence" encompasses a CDR sequence determined in any of the foregoing methods or combinations thereof. A CDR may also be determined based on having the same Kabat numbering position as a reference CDR sequence (e.g., any of the exemplary CDRs of this invention). Unless otherwise stated, in this invention, when referring to the position of residues in the antibody variable region (including heavy chain variable region residues and light chain variable region residues), it means the numbering position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0169] In some embodiments, the CDR of the heavy chain variable region of the antibody in this invention is determined according to Kabat or Chothia, or a combination of Kabat and Chothia. In some embodiments, the CDR of the light chain variable region of the antibody in this invention is determined according to Kabat.

[0170] In some embodiments, the CDR1 of the antibody heavy chain variable region in this invention is determined according to the Kabat and Chothia combination scheme (hereinafter referred to as "Kabat and Chothia combination", corresponding to H26-H32 in the Kabat numbering system), and the CDR2, CDR3 of the heavy chain variable region, and the LCDR1, LCDR2 and LCDR3 of the light chain variable region are determined according to the Kabat scheme.

[0171] A "humanized antibody" is an antibody that retains the antigen-specific reactivity of a non-human antibody (such as a mouse monoclonal antibody) while exhibiting low immunogenicity when administered to humans as a therapeutic agent. This can be achieved, for example, by retaining the non-human antigen-binding site and replacing the remaining portion of the antibody with its corresponding human portion (e.g., replacing the non-binding portions of the constant region and variable region with the corresponding portions of the human antibody).

[0172] The term "Fc domain" or "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of its constant region. This term includes native sequence Fc regions and variant Fc regions. A native immunoglobulin "Fc domain" contains two or three constant domains: a CH2 domain, a CH3 domain, and optionally a CH4 domain. For example, in native antibodies, an immunoglobulin Fc domain contains the second and third constant domains (CH2 and CH3 domains) of two heavy chains derived from IgG, IgA, and IgD antibodies; or it contains the second, third, and fourth constant domains (CH2, CH3, and CH4 domains) of two heavy chains derived from IgM and IgE antibodies. Unless otherwise stated herein, amino acid residues in the Fc region or heavy chain constant region are numbered according to the EU numbering system (also known as the EU index) described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991, NIH Publication 91-3242. However, the C-terminal lysine (Lys447) in the Fc region may or may not be present. Two Fc regions can dimerize to form a dimer Fc, and two different Fc regions can heterodimerize to form a heterodimeric Fc. In this document, the terms "Fc region," "Fc portion," and "dimeric Fc" do not include the heavy chain variable region VH and light chain variable region VL of immunoglobulins, nor the heavy chain constant region CH1 and light chain constant region CL, but in some cases may include a hinge region or a partial hinge region at the N-terminus of the heavy chain constant region, such as the IgG1 hinge region or a partial IgG1 hinge region, for example, according to EU numbering, the sequence D221 to P230. In one embodiment, the human IgG heavy chain Fc region extends from Asp221 or from Cys226 or from Asp231 to the carboxyl terminus of the heavy chain.

[0173] In some implementations, amino acid substitutions are represented as (original amino acid, amino acid position, mutant amino acid). For example, when the substitution site is located in the C region, "L234A" means that leucine (L) at position 234 of EU is replaced by alanine (A). When referring to combinations of mutations, the mutations in the combination are connected by slashes. "L234A / L235A" indicates that both mutations L234A and L235A are included.

[0174] In some implementations, amino acid deletions are represented by △ + amino acid + mutation site, for example, △P329 represents the deletion of proline at position 329. Amino acid deletions can also be represented by "amino acid + mutation site + deletion", for example, the deletion of proline at position 329 can also be written as "P329 deletion".

[0175] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Any embodiments, technical features, and definitions described herein can be combined in any way to constitute embodiments not directly described in the specification but consistent with the spirit of this invention, and these embodiments are also encompassed within the scope of this invention. Any or all features discussed above and throughout this application can be combined in various embodiments of this invention.

[0176] It should be understood that the present invention is not limited to the specific methods and experimental conditions described in this specification, as these methods and conditions can be varied. Furthermore, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting. Additionally, the terminology used herein is for illustrating specific embodiments only and is not intended to be limiting. Other features, objects, and advantages of the invention will become apparent from this specification and the accompanying drawings, and from the appended claims.

[0177] All publications, patent applications, patents and other references mentioned in this article are incorporated in full by way of citation. Example

[0178] The following examples are provided to help those skilled in the art better understand the present invention and are not intended to limit the scope of the appended claims in any way.

[0179] Example 1. Preparation of antibodies targeting IGF-1R and CD40L

[0180] According to PCT application number PCT / CN2024 / 1090122, an antibody Hz33B9C5 specifically binding to CD40L was obtained, and its functions and activities were tested. This antibody has the heavy chain sequence of SEQ ID NO:6 and the light chain sequence of SEQ ID NO:12. PCT application number PCT / CN2024 / 1090122 is hereby incorporated by reference in its entirety.

[0181] Specifically, the sequence of Hz33B9C5 was cloned into the pcDNA3.1 vector for later use. ExpiCHO cells were harvested, and the cell density was measured to be 8.0–10 x 10⁻⁶ cells / cm². 6 The viability of cells should be between 95-99%, and the cell density should be adjusted to 6.0 x 10⁶ cells / mL. 6Viable cells / mL. Take an appropriate-sized container and add Fectamine (source: Gibco) transfection buffer at 8% of the cell volume. Add the corresponding amount of plasmid at 0.8 μg / mL for cell transfection. Filter the transfection buffer containing DNA plasmid through a 0.22 μm filter to sterilize it into a new clean container. Add FectPro (source: Polyplus) transfection reagent at a ratio of 3.2 μL / mL to the filtered mixture and let it stand for 10 min. Quickly add the complex formed by the transfection reagent and plasmid DNA to the cells, gently shaking the flask while adding. Incubate at 36.5℃ on a shaker with 8% CO2. After 18-22 h of culture, add Enhancer (source: Gibco) at 6 μL / mL of cell volume and Feed (source: Gibco) at 300 μL / mL of cell volume. On day 7, collect the cell supernatant. Purify the protein using affinity chromatography to obtain the final antibody molecule. The purified antibody solution was centrifuged in a 15 ml ultrafiltration centrifuge tube at 4000 rpm for 10 minutes. The protein was then diluted with PBS and centrifuged again at 4000 rpm for 10 minutes. This process was repeated several times, changing the buffer solution each time. The antibodies were pooled after each buffer change, and the antibody concentration was measured. The components of the monoclonal antibody were further qualitatively analyzed using liquid chromatography-mass spectrometry (LC-MS) and size exclusion chromatography (SEC), and quantified using a UV-Vis spectrophotometer.

[0182] According to patent application publication number WO2017011544A1, an antibody INX-021 specifically binding to CD40L was obtained. This antibody has the heavy chain sequence of SEQ ID NO:27 and the light chain sequence of SEQ ID NO:28. Patent application WO2017011544A1 is incorporated herein by reference in its entirety.

[0183] Similar to Hz33B9C5, an antibody specifically binding to IGF-1R, Teprotumumab, was obtained (INN Drug Database PL101, https: / / www.who.int / publications / m / item / inn-pl-101). This antibody has the heavy chain sequence of SEQ ID NO:37 and the light chain sequence of SEQ ID NO:38. Patent application CN100453645C is incorporated herein by reference in its entirety. In this document, Teprotumumab is also referred to as IBI311.

[0184] Similar to Hz33B9C5, an antibody specifically binding to IGF-1R, Veligrotug (INN Drug Database PL128, https: / / www.who.int / publications / m / item / inn-pl-128), was obtained. This antibody has the heavy chain sequence of SEQ ID NO:47 and the light chain sequence of SEQ ID NO:48. US Patent Application 7538195B2 is incorporated herein by reference in its entirety.

[0185] 1.1 Expression and purification of antibodies in ExpiCHO cells:

[0186] The heavy and light chain sequences of Hz33B9C5, INX-021, Teprotumumab, and Veligrotug were cloned into the pcDNA3.1 vector for later use. ExpiCHO cells were harvested, and the cell density was checked to ensure it reached 8.0–10 x 10⁶ viable cells / mL, with viability between 95-99%. The cell density was then adjusted to 6.0 x 10⁶ viable cells / mL. A suitable container was prepared, and Fectamine (from Gibco) transfection buffer was added at 8% of the cell volume. The corresponding amount of plasmid was added at 0.8 μg / mL. The transfection buffer containing the DNA plasmid was filtered through a 0.22 μm filter to sterilize it and transferred to a new clean container. FectPro (from Polyplus) transfection reagent was added to the filtered mixture at a ratio of 3.2 μL / mL, and the mixture was allowed to stand for 10 min. The complex formed by the transfection reagent and plasmid DNA was rapidly added to the cells while gently shaking the flask. Cells were cultured on a shaker at 36.5℃ with 8% CO2. After 18-22 hours of culture, Enhancer (source: Gibco) was added at 6 μL / mL cell volume, and Feed (source: Gibco) was added at 300 μL / mL cell volume. On day 7, the supernatant was collected from the cells. Protein purification was performed using affinity chromatography to obtain the final antibody molecules. The purified antibody solution was centrifuged in a 15 mL ultrafiltration centrifuge tube at 4000 rpm for 10 minutes. The protein was diluted with PBS, and centrifugation was repeated at 4000 rpm for 10 minutes. This process was repeated several times, changing the buffer solution each time. The antibodies were pooled after each buffer change, and the antibody concentration was measured. The components of the monoclonal antibody were further qualitatively analyzed using liquid chromatography-mass spectrometry (LC-MS) and size exclusion chromatography (SEC), and quantified using a UV spectrophotometer.

[0187] Example 2. Experiment on the inhibition of orbital fibroblast proliferation by combining an antibody targeting IGF-1R with an antibody targeting CD40L.

[0188] The inhibitory effect of the antibody combination of the present invention on the proliferation of orbital fibroblasts was detected using CCK8 assay.

[0189] First, prepare orbital fibroblasts isolated from orbital tissue in thyroid eye disease. Digest the cells with trypsin, centrifuge, discard the supernatant, and resuspend the cells in complete culture medium (DMEM / F-12 (1:1) (Gibco, Cat C11330500BT) medium + 10% FBS). Count the cells and adjust the cell density to 2*102. 5 Cells / ml were added to T75 culture flasks and cultured overnight. After 24 hours, IFN-γ (R&D systems, 285-IF-100 / CF) 20 ng / ml was added, and the cells were cultured continuously for 4 days (to induce primary cells to increase CD40 expression). After 4 days, the cells were digested with trypsin, centrifuged, the supernatant was discarded, and the cells were resuspended in serum-free medium (DMEM / F-12 (1:1) (Gibco, Cat C11330500BT) medium), counted, and the cell density was adjusted to 6*104 cells / ml, 100 μl / well, and cultured overnight at 6000 cells / well.

[0190] Next, cells were stimulated and treated with antibodies: After culturing cells overnight for 24 hours, 50 μl / well of antibody was added to prepare the antibody (the antibody was prepared using 10% serum medium + 300 ng / ml IGF-1 + 100 ng / ml CD40L, with an initial antibody concentration of 400 nM and 8-fold serial dilutions; see Table 1 for specific components per well in the figure). Cells were incubated in a CO2 incubator for another 4 days, then 10 μl / well of CCK8 (Dojindo, Cat TQ759) reagent was added and incubated for 4 hours. OD450 and OD620 were measured using a microplate reader, and the OD value fitting curve was analyzed using GraphPad analysis software to calculate IC50.

[0191] Table 1: Group Design (Figures 1A, 1B, and 1C)

[0192] The results (Figures 1A-1C) showed that the combination of IGF-1 and CD40L promoted the proliferation of orbital fibroblasts in patients with thyroid eye disease, while the combination of Teprotumumab and Hz33B9C5 synergistically inhibited the proliferation of orbital fibroblasts in patients with thyroid eye disease, with better effects than the single-drug group. Furthermore, Teprotumumab combined with other CD40L antibodies, or Hz33B9C5 combined with other IGF-1R antibodies, still exhibited synergistic effects.

[0193] Example 3. Experiment on the inhibition of HA secretion by orbital fibroblasts by combining an antibody targeting IGF-1R with an antibody targeting CD40.

[0194] The inhibitory effect of the antibody used in this invention on HA secretion from orbital fibroblasts was detected by ELISA in cell culture supernatant.

[0195] First, prepare orbital fibroblasts. Digest the cells with trypsin, centrifuge, discard the supernatant, and resuspend the cells in complete culture medium (DMEM / F-12 (1:1) (Gibco, Cat C11330500BT) medium + 10% FBS). Count the cells and adjust the cell density to 2*102. 5 Cells / ml were added to T75 culture flasks and cultured overnight. After 24 hours, IFN-γ 20 ng / ml was added, and the cells were cultured continuously for 4 days (to induce primary cells to increase CD40 expression). After 4 days, the cells were digested with trypsin, centrifuged, the supernatant was discarded, and the cells were resuspended in serum-free medium. The cells were counted and the cell density was adjusted to 6*10⁻⁶. 4 cells / ml, 100μl / well, cultured overnight, 6000 cells / well.

[0196] Adding stimulation and antibodies: After 24 hours, add 50 μl / well to prepare antibodies (using 10% serum medium + 100 ng or 300 ng / ml IGF-1 + 100 ng / ml CD40L to prepare antibodies, initial antibody concentration 400 nM, serially diluted 8 times; see Table 2 for specific samples in Figure 2A, and Table 3 for specific samples in Figures 2B-D). Continue incubation in a CO2 cell culture incubator for 3 days, collect the culture supernatant, and detect the HA content in the supernatant (20-fold dilution of supernatant) using a Hyaluronan Quantikine ELISA (USA, R&D SYSTEMS, Cat PDHYALO) according to the reagent instructions. Measure OD450 and OD620 using a microplate reader, analyze the OD value fitting curve using GraphPad analysis software, and calculate IC50.

[0197] Table 2: Group Design (Figure 2A)

[0198] Table 3: Group Design (Figures 2B-2D)

[0199] The results, shown in Figures 2A-2D, indicate that the combination of IGF-1 and CD40L can promote hyaluronic acid (HA) secretion from orbital fibroblasts in patients with thyroid eye disease, while the combination of Teprotumumab and Hz33B9C5 can synergistically inhibit HA secretion from orbital fibroblasts in patients with thyroid eye disease, with better effects than the single-drug group. Furthermore, Teprotumumab combined with other CD40L antibodies, or Hz33B9C5 combined with other IGF-1R antibodies, still exhibits a synergistic effect.

[0200] Sequence List:

Claims

1. A drug combination comprising: (i) a first active ingredient, wherein the first active ingredient is an anti-CD40L antibody or an antigen-binding fragment thereof; and (ii) a second active ingredient, wherein the second active ingredient is an anti-IGF-1R antibody or an antigen-binding fragment thereof.

2. The drug combination according to claim 1, wherein the anti-CD40L antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), and a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, or respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:

9. The amino acid sequence shown in NO:9 may be present; or the anti-CD40L antibody or its antigen-binding fragment may contain a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences shown in SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26 or are composed of the amino acid sequences shown in SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26 respectively.

3. The drug combination according to claim 1 or 2, wherein the anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, or is composed of said amino acid sequence, or comprises an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, or is composed of said amino acid sequence; or comprises a light chain variable region (VL), wherein the light chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:10 or the nucleic acid sequence shown in SEQ ID NO:52, or is composed of said amino acid sequence, or comprises an amino acid sequence encoded by ... The amino acid sequence encoded by the amino acid sequence shown in ID NO:10 or the nucleic acid sequence shown in SEQ ID NO:52, or composed of said amino acid sequence; or The anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:19, or comprises or consists of the amino acid sequence shown in SEQ ID NO:19; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:20, or comprises or consists of the amino acid sequence shown in SEQ ID NO:

20.

4. The drug combination according to any one of claims 1-3, wherein the anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, and the light chain variable region comprises or is composed of an amino acid sequence encoded by the amino acid sequence shown in SEQ ID NO:10 or the nucleic acid sequence shown in SEQ ID NO:52; or The anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:19, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:

20.

5. The drug combination according to any one of claims 1-4, wherein the anti-CD40L antibody or its antigen-binding fragment further comprises an Fc region, for example, wherein the Fc region is or is derived from human IgG Fc, for example, is or is derived from human IgG1 Fc, is or is derived from human IgG2 Fc, is or is derived from human IgG3 Fc, or is derived from human IgG4 Fc; preferably, the Fc region comprises a mutation that reduces or eliminates effector function, and / or eliminates the binding affinity to FcγR while retaining the binding affinity to FcRn, preferably, the mutation is an L234A / L235A and P329 deletion mutation, preferably, the Fc region (i) Contains or is composed of the amino acid sequence shown in SEQ ID NO: 13 or 14; (ii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:13; or (iii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:14, and contains L234A / L235A and P329 deletion mutations.

6. The drug combination according to any one of claims 1-5, wherein the anti-CD40L antibody or its antigen-binding fragment further comprises a heavy chain constant region, said heavy chain constant region being or derived from a constant region of IgG1, IgG2, IgG3 or IgG4, preferably, said heavy chain constant region (i) Contains or is composed of the amino acid sequence shown in SEQ ID NO:5 or 16; (ii) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:16; or (iii) Contains an amino acid sequence that has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:5, and has L234A / L235A and P329 deletion mutations; and / or The anti-CD40L antibody or its antigen-binding fragment further comprises a light chain constant region, which is or is derived from the lambda or Kappa light chain constant region. Preferably, the light chain constant region comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:11; or comprises or is composed of the amino acid sequence shown in SEQ ID NO:

11.

7. The pharmaceutical combination according to any one of claims 1-6, wherein The anti-CD40L antibody or its antigen-binding fragment heavy chain, wherein the heavy chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:6; or (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:6; and / or It contains a light chain, wherein the light chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO: 12; or (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:12; or The anti-CD40L antibody or its antigen-binding fragment heavy chain, wherein the heavy chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:27; or (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:27; and / or It contains a light chain, wherein the light chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:28; or (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:

28.

8. The pharmaceutical combination according to any one of claims 1-7, wherein the anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:6, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:12; or the anti-CD40L antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:27, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:

28.

9. The drug combination according to any one of claims 1-8, wherein the anti-CD40L antibody is a humanized antibody or a chimeric antibody.

10. The pharmaceutical combination according to any one of claims 1-9, wherein the antigen-binding fragment of the anti-CD40L antibody is selected from the following antibody fragments: Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibody), linear antibody, single-chain antibody (e.g., scFv); single-domain antibody (sdAb) such as VHH, bivalent antibody or fragment thereof, or camelid antibody or diabody antibody.

11. The pharmaceutical combination according to any one of claims 1-10, wherein the anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), and a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3), wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36 or are composed of the amino acid sequences shown in SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36; or The anti-IGF1R antibody or its antigen-binding fragment comprises a first heavy chain complementarity-determining region (HCDR1), a second heavy chain complementarity-determining region (HCDR2), and a third heavy chain complementarity-determining region (HCDR3), as well as a first light chain complementarity-determining region (LCDR1), a second light chain complementarity-determining region (LCDR2), and a third light chain complementarity-determining region (LCDR3). HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:46, or are composed of the amino acid sequences shown in SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, and SEQ ID NO:

46.

12. The pharmaceutical combination according to any one of claims 1-11, wherein the anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:29, or comprises or consists of the amino acid sequence shown in SEQ ID NO:29; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises or consists of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:30, or comprises or consists of the amino acid sequence shown in SEQ ID NO:30; or The anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain variable region (VH), wherein the heavy chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:39, or is composed of or comprises the amino acid sequence shown in SEQ ID NO:39; or it comprises a light chain variable region (VL), wherein the light chain variable region comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:40, or is composed of or comprises the amino acid sequence shown in SEQ ID NO:

40.

13. The pharmaceutical combination according to any one of claims 1-12, wherein the anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:29, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:30; or The anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:39, and the light chain variable region comprises or is composed of the amino acid sequence shown in SEQ ID NO:

40.

14. The drug combination according to any one of claims 1-13, wherein the anti-IGF1R antibody or its antigen-binding fragment further comprises an Fc region, for example, wherein the Fc region is or is derived from human IgG Fc, for example, is or is derived from human IgG1 Fc, is or is derived from human IgG2 Fc, is or is derived from human IgG3 Fc, or is derived from human IgG4 Fc; preferably, the Fc region comprises a mutation that reduces or eliminates effector function, and / or eliminates the binding affinity to FcγR while retaining the binding affinity to FcRn, preferably, the mutation is an L234A / L235A and P329 deletion mutation, preferably, the Fc region (i) Contains or consists of the amino acid sequence shown in SEQ ID NO:13 or 14; (ii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:13; or (iii) Contains an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or higher identity with the amino acid sequence shown in SEQ ID NO:14, and contains L234A / L235A and P329 deletion mutations.

15. The pharmaceutical combination according to any one of claims 1-14, wherein the anti-IGF1R antibody or its antigen-binding fragment further comprises a heavy chain constant region, said heavy chain constant region being or derived from a constant region of IgG1, IgG2, IgG3 or IgG4, preferably, said heavy chain constant region (i) Contains or is composed of an amino acid sequence selected from or represented by SEQ ID NO:5 or 16; (ii) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:16; or (iii) Contains an amino acid sequence that has at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:5, and has L234A / L235A and P329 deletion mutations; and / or The anti-IGF1R antibody or its antigen-binding fragment further comprises a light chain constant region, which is or is derived from the lambda or Kappa light chain constant region. Preferably, the light chain constant region comprises or is composed of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:11; or comprises or is composed of the amino acid sequence shown in SEQ ID NO:

11.

16. The pharmaceutical combination according to any one of claims 1-15, wherein The anti-IGF1R antibody or its antigen-binding fragment heavy chain, wherein the heavy chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:37; or (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:37; and / or It contains a light chain, wherein the light chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:38; or (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:38; or The anti-IGF1R antibody or its antigen-binding fragment heavy chain, wherein the heavy chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:47; or (ii) Contains or is composed of the amino acid sequence shown in SEQ ID NO:47; and / or It contains a light chain, wherein the light chain (i) comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence shown in SEQ ID NO:48; or (ii) Contains or consists of the amino acid sequence shown in SEQ ID NO:

48.

17. The pharmaceutical combination according to any one of claims 1-16, wherein the anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:37, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:38; or The anti-IGF1R antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:47, and the light chain comprises or is composed of the amino acid sequence shown in SEQ ID NO:

48.

18. The pharmaceutical combination according to any one of claims 1-17, wherein the anti-IGF1R antibody is a humanized antibody or a chimeric antibody.

19. The pharmaceutical combination according to any one of claims 1-18, wherein the antigen-binding fragment of the anti-IGF1R antibody is selected from the following antibody fragments: Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibody), linear antibody, single-chain antibody (e.g., scFv); single-domain antibody (sdAb) such as VHH, bivalent antibody or fragment thereof, or camelid antibody or diabody antibody.

20. The pharmaceutical combination according to any one of claims 1-19, wherein the anti-IGF1R antibody is Teprotumumab or Veligrotug.

21. The pharmaceutical combination according to any one of claims 1-20, wherein the first active ingredient is for administration by injection, such as intravenous infusion; and / or the second active ingredient is for administration by injection, such as intravenous infusion.

22. The pharmaceutical combination according to any one of claims 1-21, wherein the pharmaceutical combination comprises a first active ingredient and a second active ingredient as the only active ingredient.

23. A kit of medicines or a kit of medicines comprising the combination of medicines according to any one of claims 1-22.

24. The medicine box or medicine kit of claim 23, comprising: - A pharmaceutical composition containing a first active ingredient, for example, contained in a first container; - A pharmaceutical composition containing a second active ingredient, for example, contained in a second container; And optionally, an instruction manual that describes the administration methods of the two pharmaceutical compositions; Optionally, the pharmaceutical composition contains pharmaceutically acceptable excipients.

25. The pharmaceutical combination of any one of claims 1-22 or the kit or kit of claims 23 or 24, for the treatment of diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

26. Use of the pharmaceutical combination of any one of claims 1-22 or the kit or kit of claims 23 or 24 for the treatment of diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

27. Use of the pharmaceutical combination of any one of claims 1-22 in the preparation of a cassette or pharmaceutical product for treating diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

28. A method of treating diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, comprising administering a pharmaceutical combination of any one of claims 1-22 or a kit or package of pharmaceuticals as described in claims 23 or 24, for example, wherein the first active ingredient and the second active ingredient are administered simultaneously in a single pharmaceutical composition or simultaneously or separately in separate pharmaceutical compositions.

29. A method for treating diseases related to the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, comprising the combined administration of an anti-CD40L antibody or an antigen-binding fragment thereof, and an IGF-1R antibody or an antigen-binding fragment thereof, wherein the anti-CD40L antibody or an antigen-binding fragment thereof and the IGF-1R antibody or an antigen-binding fragment thereof are administered simultaneously in a single pharmaceutical composition or simultaneously or separately in separate pharmaceutical compositions.

30. An anti-CD40L antibody or an antigen-binding fragment thereof, for use in combination with an anti-IGF-1R antibody or an antigen-binding fragment thereof for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

31. Use of an anti-CD40L antibody or an antigen-binding fragment thereof for the treatment of diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors, by combination administration with an anti-IGF-1R antibody or an antigen-binding fragment thereof.

32. Use of an anti-CD40L antibody or an antigen-binding fragment thereof in the preparation of a medicament for use in combination with an anti-IGF-1R antibody or an antigen-binding fragment thereof to treat diseases associated with the CD40L / CD40 signaling pathway and / or the IGF1 / IGF1R signaling pathway, such as thyroid ophthalmopathy or solid tumors.

33. The method of claim 29, the anti-CD40L antibody of claim 30 or its antigen-binding fragment thereof, the use of claim 31 or the use of claim 32, wherein the anti-CD40L antibody or its antigen-binding fragment is defined as in any one of claims 2-10, and / or the anti-IGF-1R antibody or its antigen-binding fragment is defined as in any one of claims 11-20.

34. A method of treating thyroid eye disease, comprising administering an anti-CD40L antibody or an antigen-binding fragment thereof, wherein the anti-CD40L antibody or the antigen-binding fragment thereof is defined as in any one of claims 2-10.

35. An anti-CD40L antibody or an antigen-binding fragment thereof for the treatment of thyroid eye disease, wherein the anti-CD40L antibody or the antigen-binding fragment thereof is defined as in any one of claims 2-10.

36. Use of an anti-CD40L antibody or an antigen-binding fragment thereof for the treatment of thyroid eye disease, wherein the anti-CD40L antibody or the antigen-binding fragment thereof is defined as in any one of claims 2-10.

37. Use of an anti-CD40L antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating thyroid eye disease, wherein the anti-CD40L antibody or the antigen-binding fragment thereof is defined as in any one of claims 2-10.

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