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WO-2026092387-A1 - PHARMACEUTICAL COMBINATION CONTAINING ANTI-IGF-1R AND ANTI-CD40L ANTIBODIES, AND USE THEREOF AND METHOD FOR USING SAME

WO2026092387A1WO 2026092387 A1WO2026092387 A1WO 2026092387A1WO-2026092387-A1

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.

Inventors

  • LU, SHUJIE
  • LI, YIMING
  • QIAN, LEI

Assignees

  • 信达生物制药(苏州)有限公司

Dates

Publication Date
20260507
Application Date
20251027
Priority Date
20241028

Claims (20)

  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. According to claim 1, the drug combination 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 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. Alternatively, the anti-CD40L antibody or its antigen-binding fragment may comprise 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 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.
  3. According to the drug combination of claim 1 or 2, 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 encoded by the amino acid sequence shown in SEQ ID NO:4 or the nucleic acid sequence shown in SEQ ID NO:51, 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. The amino acid sequence may be composed of or comprised of the amino acid sequence shown; or it may contain a light chain variable region (VL) wherein the light chain variable region comprises or 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 comprises or 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 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) Containing 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 drug 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 drug 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 drug 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 drug 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. According to any one of claims 1-12, the drug combination 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 drug 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) Containing 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 is composed 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 drug 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 consists of the amino acid sequence shown in SEQ ID NO:47, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO:48.
  18. The drug combination according to any one of claims 1-17, wherein the anti-IGF1R antibody is a humanized antibody or a chimeric antibody.
  19. The drug 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.
  20. The drug combination according to any one of claims 1-19, wherein the anti-IGF1R antibody is Teprotumumab or Veligrotug.

Description

Drug combinations containing anti-IGF-1R and anti-CD40L antibodies, their uses and methods of administration Cross-reference of related applications 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 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 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 D M, Fortin E. Thyroid eye disease: what is new to know? Curr Opin Ophthalmol. 2018; 29(6):528-534.]. 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. 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. 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. 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. 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. Therefore, there remains a need in this field to develop drugs and therapies for further treatment of thyroid eye diseases and to improve symptoms. Invention Overview 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 thyro