Application of anti-IGF-1R antibody or antigen binding part thereof in weight loss

Abstract

The invention belongs to the field of biological medicine, and particularly relates to application of an anti-IGF-1R antibody or an antigen binding part thereof in weight loss. The invention provides an application of an anti-IGF-1R antibody or an antigen binding part thereof in weight loss. The anti-IGF-1R antibody or the antigen-binding portion thereof is reduced in weight by at least one of the following mechanisms: (1) inhibiting or blocking the binding between IGF-1R and IGF-1; (2) the activity of IGF-1R is reduced, weakened or neutralized; (3) inhibiting cell proliferation; (4) inhibiting fat synthesis and / or accumulation of cells; and (5) inhibiting collagen synthesis of cells. The anti-IGF-1R antibody or the antigen binding part thereof can significantly inhibit the generation and accumulation of fat and effectively inhibit the formation of collagen, and has a significant effect in the treatment of obesity and weight loss.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to the application of anti-IGF-1R antibodies or antigen-binding portions thereof in weight loss. Background Art

[0002] Obesity and obesity-related complications, including type 2 diabetes, cardiovascular disease, osteoarthritis, obstructive sleep apnea, and multiple cancers, are one of the leading causes of morbidity and mortality worldwide. Obesity refers to excessive weight, usually with a BMI (body mass index) ≥ 25 kg / m 2 Overweight: BMI ≥ 30 kg / m 2 Overweight. Obesity is associated with excessive accumulation or abnormal distribution of fat in the body, and abnormally distributed adipose tissue secretes different adipose factors, including leptin, resistin, adiponectin, and IL-6. The adipose tissue of obese patients releases adipose factors that selectively affect the function of tissues and organs and systemic metabolism, such as high blood pressure, high blood sugar, high cholesterol, etc.; there may even be mental problems, such as depression and anxiety.

[0003] The basis of obesity management is lifestyle intervention (eating habits, physical exercise). Studies have shown that intensive lifestyle intervention can reduce body weight by an average of 7-10% within 52 weeks. More and more researchers have come to realize that obesity is caused by central appetite disorders, and failure to maintain a healthy lifestyle for a long time can easily lead to weight rebound. Therefore, clinical practice guidelines recommend the use of multimodal treatments, including medications and / or surgery, to achieve weight loss goals (Bray GA. Evidence-based weight loss interventions: Individualized treatment options to maximize patient outcomes. Diabetes Obes Metab. 2021; 23 Suppl 1: 50-62.). For obesity (BMI ≥ 30 kg / m 2 ) or overweight (BMI ≥ 27 kg / m 2 ) and at least one obesity-related disease (such as type 2 diabetes, cardiovascular disease, osteoarthritis), it is recommended to use weight loss drugs combined with lifestyle intervention. (Perdomo CM. Contemporary medical, device, and surgical therapies for obesity in adults. Lancet. 2023; 401(10382): 1116-1130.).

[0004] At present, the drugs used clinically to treat obesity mainly include early FDA-approved fat absorption inhibitors (orlistat, lorcaserin), appetite suppressants (phentermine), SGLT2 inhibitors (naltrexone), GLP-1 analogs (liraglutide), and PLENITY (Gelesis100) and Imcivree (Setmelanotide) approved by the FDA in recent years. In addition, dozens of drugs under development for obesity are currently in different stages of clinical trials and preclinical studies. The targets and mechanisms of action are mainly concentrated on the appetite regulation center, GLP-1 receptors, gastrointestinal digestion and absorption, and agonists and inhibitors of other multiple receptors. Among them, the drug with relatively good weight loss / weight loss effect is GLP-1 analogs. GLP-1 is an intestinal hormone that promotes insulin secretion in a glucose-dependent manner by activating GLP-1 receptors. The weight loss mechanism of GLP-1 receptor agonists is mainly to slow down gastrointestinal motility and suppress appetite. It is a relatively good and relatively safe drug for weight loss on the market.

[0005] Chinese patent application 97198413.1 discloses a derivative of GLP-1 or a GLP-1 analogue having up to 6 amino acid changes compared to GLP-1, wherein the GLP-1 analogue has the function of human GLP-1 and the derivative has only one lipophilic substituent containing 8 to 25 carbon atoms selected from the following: CH3(CH2) n CO-, where n is an integer, HOOC(CH2) m CO-, wherein m is an integer, or lithocholyl, the lipophilic substituent being attached to an amino acid residue that is neither the N-terminus nor the C-terminus. Chinese patent application 200480034152.8 discloses a pharmaceutical preparation containing a peptide and propylene glycol, a method for preparing the preparation, and the use of the preparation in treating diseases and disorders, wherein the peptide is a GLP-1 agonist selected from GLP-1-amide, GLP-1, a GLP-1-amide analog, a GLP-1 analog, or an analog of any of these.

[0006] The anti-obesity effect of GLP-1 analogs is very significant and stable, but if you need to achieve a better weight loss effect, you generally need to increase the dosage. Large doses of GLP-1 derivatives are prone to gastrointestinal side effects, and often have a narrow therapeutic window due to poor tolerance. In addition, GLP-1 analogs are polypeptide drugs, which have relatively poor chemical and physiological stability and are particularly susceptible to degradation by proteolytic enzymes in the body, resulting in poor oral absorption, rapid metabolism, and short half-life.

[0007] Therefore, there is an urgent need to develop safer and longer-acting drugs for the treatment of obesity or weight loss. Summary of the invention

[0008] Fat is one of the main tissues for energy storage and metabolism, which can help maintain the body's energy balance and homeostasis. However, when energy intake is excessive or consumption is insufficient, fat cells will gradually increase in size and increase in number, causing the body fat content to exceed the normal range, thereby causing obesity. In obese patients, the number and size of fat cells increase. These fat cells secrete a series of cytokines and hormones, such as TNF-α, IL-6, PAI-1, etc., which have an impact on systemic metabolism. Therefore, inhibiting the excessive differentiation of adipocytes and excessive synthesis of fat, and reducing excessive fat accumulation are very important for weight loss and obesity control.

[0009] The main function of insulin-like growth factor 1 receptor (IGF-1R) is to mediate the signal transduction of insulin-like growth factor 1 (IGF-1), thereby regulating various biological processes such as cell proliferation, differentiation and survival. Studies have shown that the activity of IGF-1R can affect the process of metabolism and fat synthesis. The role of IGF-1R in metabolism and fat synthesis is complex, and it can regulate glucose and lipid metabolism through multiple mechanisms. The activity level of IGF-1R needs to be maintained within an appropriate range to ensure the normal metabolism and fat synthesis function of the body. Excessive activation of IGF-1R is closely related to overweight and obesity. Excessive activation of IGF-1R can lead to fat synthesis and energy balance disorders. Its main mechanisms are as follows: 1. Promote adipocyte differentiation and fat synthesis: IGF-1R activation can promote the differentiation and proliferation of adipocytes, and stimulate the synthesis of fatty acids and triglycerides, leading to an increase in adipose tissue. 2. Inhibit fat catabolism: IGF-1R activation can also inhibit fat catabolism and reduce the rate of fatty acid oxidation, thereby accumulating fatty acids in adipocytes. 3. Interfere with the insulin signaling pathway: IGF-1R has a similar structure and signaling pathway to the insulin receptor. Excessive activation of IGF-1R may interfere with the normal function of the insulin signaling pathway, leading to insulin resistance, abnormal glucose metabolism and increased fat synthesis. 4. Promote collagen synthesis by adipose tissue fibroblasts: According to some literature reports, collagen VI may cause dysfunction in the metabolism of adipose tissue. IGF-1R downstream signals can strongly stimulate collagen expression. Overactivated IGF-1R can strongly promote collagen synthesis by adipose tissue fibroblasts.

[0010] Anti-IGF-1R antibodies have been successful in multiple therapeutic areas, such as thyroid eye disease, etc. However, anti-IGF-1R antibodies have not been successfully applied to the treatment of obesity or weight loss.

[0011] In view of the deficiencies of the prior art, the present invention provides the use of an anti-IGF-1R antibody or an antigen-binding portion thereof in weight loss.

[0012] The technical solution proposed by the present invention is as follows:

[0013] In one aspect, the present invention provides use of an anti-IGF-1R antibody or an antigen-binding portion thereof for weight loss.

[0014] In one embodiment, the anti-IGF-1R antibody, or antigen-binding portion thereof, reduces weight by at least one of the following mechanisms:

[0015] (1) Inhibit or block the binding between IGF-1R and IGF-1;

[0016] (2) reduce, weaken or neutralize the activity of IGF-1R;

[0017] (3) Inhibit cell proliferation;

[0018] (4) inhibiting cellular fat synthesis and / or accumulation;

[0019] (5) Inhibit cellular collagen synthesis.

[0020] In one embodiment, the cells comprise fibroblasts.

[0021] In another aspect, the present invention provides use of an anti-IGF-1R antibody or an antigen-binding portion thereof in the preparation of a product for preventing or treating obesity or a disease caused by obesity.

[0022] In one embodiment, the product reduces weight by at least one of the following mechanisms:

[0023] (1) Inhibit or block the binding between IGF-1R and IGF-1;

[0024] (2) reduce, weaken or neutralize the activity of IGF-1R;

[0025] (3) Inhibit cell proliferation;

[0026] (4) inhibiting cellular fat synthesis and / or accumulation;

[0027] (5) Inhibit cellular collagen synthesis.

[0028] In one embodiment, the cells comprise fibroblasts.

[0029] In one embodiment, the antibody in the above two aspects may be a monoclonal antibody, such as a humanized antibody.

[0030] In one embodiment, the antibody or antigen binding portion thereof in the above two aspects comprises a light chain variable region and a heavy chain variable region.

[0031] In a preferred embodiment, the light chain variable region has:

[0032] LCDR1 as set forth in SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:37, SEQ ID NO:43, SEQ ID NO:49, SEQ ID NO:55, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85 or SEQ ID NO:91; and

[0033] LCDR2 as set forth in SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:50, SEQ ID NO:56, SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86 or SEQ ID NO:92; and

[0034] LCDR3 as shown in SEQ ID NO:27, SEQ ID NO:33, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:51, SEQ ID NO:57, SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81, SEQ ID NO:87 or SEQ ID NO:93.

[0035] In a preferred embodiment, the heavy chain variable region has:

[0036] HCDR1 as set forth in SEQ ID NO:28, SEQ ID NO:34, SEQ ID NO:40, SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:58, SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:88 or SEQ ID NO:94; and

[0037] HCDR2 as set forth in SEQ ID NO:29, SEQ ID NO:35, SEQ ID NO:41, SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:59, SEQ ID NO:65, SEQ ID NO:71, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:89 or SEQ ID NO:95; and

[0038] HCDR3 as shown in SEQ ID NO:30, SEQ ID NO:36, SEQ ID NO:42, SEQ ID NO:48, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:90 or SEQ ID NO:96.

[0039] In one embodiment, the antibody or antigen binding portion thereof may comprise a heavy chain constant region and / or a light chain constant region.

[0040] In one embodiment, the heavy chain constant region can be an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region.

[0041] In a preferred embodiment, the light chain of the antibody or antigen-binding portion is composed of a light chain variable region and a light chain constant region as shown in SEQ ID NO: 97; the heavy chain of the antibody or antigen-binding portion is composed of a heavy chain variable region and a heavy chain constant region as shown in any one of SEQ ID NOs: 98-104.

[0042] In a preferred embodiment, the heavy chain constant region may be a human IgG1-LALA constant region as shown in SEQ ID NO: 102, which may attenuate or eliminate the binding affinity of the heavy chain constant region to IGF-1R. + ADCC effect of cells.

[0043] In a preferred embodiment, the heavy chain constant region may be the human IgG1-YTE constant region shown in SEQ ID NO: 103, which can increase the binding affinity of the antibody to FcRn and prolong its serum half-life.

[0044] In a preferred embodiment, the light chain constant region may be a human κ constant region as shown in SEQ ID NO:97.

[0045] In a preferred embodiment, the N-terminus of the heavy chain constant region can be connected to the C-terminus of the heavy chain variable region, and the N-terminus of the light chain constant region can be connected to the C-terminus of the light chain variable region.

[0046] In one embodiment, the light chain variable region has:

[0047] An amino acid sequence as shown in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21 or SEQ ID NO:23.

[0048] In one embodiment, the heavy chain variable region has:

[0049] An amino acid sequence as shown in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22 or SEQ ID NO:24.

[0050] In a preferred embodiment, the light chain variable region has LCDR1 as shown in SEQ ID NO:25, LCDR2 as shown in SEQ ID NO:26, and LCDR3 as shown in SEQ ID NO:27.

[0051] In a preferred embodiment, the light chain variable region has LCDR1 as shown in SEQ ID NO:31, LCDR2 as shown in SEQ ID NO:32, and LCDR3 as shown in SEQ ID NO:33.

[0052] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:37, LCDR2 shown in SEQ ID NO:38, and LCDR3 shown in SEQ ID NO:39.

[0053] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:43, LCDR2 shown in SEQ ID NO:44, and LCDR3 shown in SEQ ID NO:45.

[0054] In a preferred embodiment, the light chain variable region has LCDR1 as shown in SEQ ID NO:49, LCDR2 as shown in SEQ ID NO:50, and LCDR3 as shown in SEQ ID NO:51.

[0055] In a preferred embodiment, the light chain variable region has LCDR1 as shown in SEQ ID NO:55, LCDR2 as shown in SEQ ID NO:56, and LCDR3 as shown in SEQ ID NO:57.

[0056] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:61, LCDR2 shown in SEQ ID NO:62, and LCDR3 shown in SEQ ID NO:63.

[0057] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:67, LCDR2 shown in SEQ ID NO:68, and LCDR3 shown in SEQ ID NO:69.

[0058] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:73, LCDR2 shown in SEQ ID NO:74, and LCDR3 shown in SEQ ID NO:75.

[0059] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:79, LCDR2 shown in SEQ ID NO:80, and LCDR3 shown in SEQ ID NO:81.

[0060] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:85, LCDR2 shown in SEQ ID NO:86, and LCDR3 shown in SEQ ID NO:87.

[0061] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:91, LCDR2 shown in SEQ ID NO:92, and LCDR3 shown in SEQ ID NO:93.

[0062] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:28, HCDR2 shown in SEQ ID NO:29, and HCDR3 shown in SEQ ID NO:30.

[0063] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:34, HCDR2 shown in SEQ ID NO:35, and HCDR3 shown in SEQ ID NO:36.

[0064] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:40, HCDR2 shown in SEQ ID NO:41, and HCDR3 shown in SEQ ID NO:42.

[0065] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:46, HCDR2 shown in SEQ ID NO:47, and HCDR3 shown in SEQ ID NO:48.

[0066] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:52, HCDR2 shown in SEQ ID NO:53, and HCDR3 shown in SEQ ID NO:54.

[0067] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:58, HCDR2 shown in SEQ ID NO:59, and HCDR3 shown in SEQ ID NO:60.

[0068] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:64, HCDR2 shown in SEQ ID NO:65, and HCDR3 shown in SEQ ID NO:66.

[0069] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:70, HCDR2 shown in SEQ ID NO:71, and HCDR3 shown in SEQ ID NO:72.

[0070] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:76, HCDR2 shown in SEQ ID NO:77, and HCDR3 shown in SEQ ID NO:78.

[0071] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:82, HCDR2 shown in SEQ ID NO:83, and HCDR3 shown in SEQ ID NO:84.

[0072] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:88, HCDR2 shown in SEQ ID NO:89, and HCDR3 shown in SEQ ID NO:90.

[0073] In a preferred embodiment, the heavy chain variable region has HCDR1 shown in SEQ ID NO:94, HCDR2 shown in SEQ ID NO:95, and HCDR3 shown in SEQ ID NO:96.

[0074] In one embodiment, the diseases caused by obesity include fatty liver, hypertension, hyperglycemia and high cholesterol.

[0075] In one embodiment, the products include medicines, health products, foods, etc.

[0076] In a preferred embodiment, the product may be a drug, comprising the antibody or antigen-binding portion, or a biological material comprising the antibody or antigen-binding portion or a gene thereof, and at least one pharmaceutically acceptable excipient;

[0077] The biological materials include expression vectors and host cells.

[0078] In a preferred embodiment, the excipient is selected from solvents, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, dispersants, suspending agents, isotonic agents, thickeners, emulsifiers, preservatives, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, flavoring agents, sweeteners, ion exchangers, release agents, coating agents, flavoring agents or antioxidants.

[0079] In the present invention, unless otherwise specified, the drug dosage form is not particularly limited, and can be prepared into injections, oral liquids, tablets, capsules, dripping pills, sprays, inhalants and the like, and can be prepared by conventional methods. The choice of drug dosage form should match the mode of administration.

[0080] The anti-IGF-1R antibody or its antigen binding portion provided by the present invention can significantly inhibit the generation and accumulation of fat, effectively inhibit the formation of collagen, and has a significant effect in treating obesity and weight loss. The weight change rate can reach more than 10%, and the fat change rate is as high as about 40%. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 The inhibitory efficiency of anti-IGF-1R antibodies on the proliferation of 3T3 cells stably overexpressing human IGF-1R is shown.

[0082] Figure 2The effect of anti-IGF-1R antibody on adipogenesis and accumulation of fibroblasts was shown by Oil Red O staining, wherein A is the adipogenic induction group, B is the adipogenic induction + IGF-1 group, and C is the adipogenic induction + IGF-1 + AB1 group.

[0083] Figure 3 The effect of anti-IGF-1R antibody on adipogenesis and accumulation of fibroblasts was shown by adipogenesis assay.

[0084] Figure 4 Western Blot experiments showed the effect of anti-IGF-1R antibody on collagen production in fibroblasts.

[0085] Figure 5 Shown is the effect of anti-IGF-1R antibody on body weight of normal male mice (rats).

[0086] Figure 6 Shown is the effect of anti-IGF-1R antibody on body weight of normal female mice (rats).

[0087] Figure 7 Shown is the effect of anti-IGF-1R antibody AB1 on body weight in obese mice.

[0088] Figure 8 The weight change rate of obese mice after administration of the anti-IGF-1R antibody AB1 is shown, *p<0.05, **p<0.01 (relative to the 0 mpk group).

[0089] Fig. 9 The figure shows the changes in total fat in obese mice after administration of the anti-IGF-1R antibody AB1, **p<0.01 (relative to the 0 mpk group).

[0090] Fig.10 Shown is the effect of anti-IGF-1R antibody AB9 on body weight in obese mice.

[0091] Fig.11 The body weight change rate of obese mice after administration of the anti-IGF-1R antibody AB9 is shown, *p<0.05, **p<0.01 (relative to the 0 mpk group).

[0092] Fig.12 The figure shows the changes in total fat in obese mice after administration of the anti-IGF-1R antibody AB9, *p<0.05, **p<0.01 (relative to the 0 mpk group). DETAILED DESCRIPTION

[0093] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0094] Unless the context clearly dictates otherwise, the expressions "a", "an" and "an" as used herein include plural references. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0095] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0096] The term "IGF-1R", as used herein, refers to insulin-like growth factor 1 receptor. The term includes variants, homologs, orthologs, and paralogs. For example, an antibody specific for human IGF-1R may, in some cases, cross-react with an IGF-1R protein from another species, such as monkey. In other embodiments, an antibody specific for human IGF-1R protein may be completely specific for human IGF-1R protein and not cross-react with proteins of other species or other types, or may cross-react with IGF-1R proteins of some other species but not all other species.

[0097] The term "amino acid" as used herein refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are amino acids encoded by the genetic code, as well as modified amino acids, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds having the same basic chemical structure as naturally occurring amino acids, i.e., carbon is bound to hydrogen, carboxyl, amino, and R groups, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. These analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetics refer to compounds that have a structure that is different from the general chemical structure of amino acids, but function in a manner similar to naturally occurring amino acids.

[0098] The term "antibody" as used herein refers to a glycoprotein comprising a heavy chain (H) and a light chain (L) interconnected by disulfide bonds (SS). Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). The heavy chain constant region consists of three domains CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region (abbreviated herein as VH). The light chain constant region consists of one domain CL. Light chains are divided into two categories, namely kappa-type light chains and lambda-type light chains (for example, the light chain constant region Cκ / λ in the present invention indicates that the light chain constant region is a kappa-type light chain or a lambda-type light chain). The VH region and the VL region can be further divided into hypervariable regions (also called complementary determining regions (CDRs)), with more conservative framework regions or framework regions (FRs) inserted therebetween. 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. Antibodies include monospecific antibodies, bispecific antibodies, and multispecific antibodies, as long as they exhibit the desired biological activity or function.

[0099] The term "anti-IGF-1R antibody" or "IGF-1R antibody" as used herein refers to an antibody that specifically binds to IGF-1R and partially or completely neutralizes, inhibits or weakens the activity of IGF-1R, and / or inactivates IGF-1R, prevents IGF-1R response or downstream pathways mediated by IGF-1R or other IGF-1R-mediated functions.

[0100] The terms "antibody fragment", "antigen binding fragment", "antigen binding portion" or similar terms used herein refer to fragments of an antibody that retain binding to a target antigen (e.g., IGF1-R) and have the same activity as the full-length antibody. Such fragments include, for example, single-chain antibodies, single-chain Fv fragments (scFv), Fd fragments, Fab fragments, Fab' fragments, or F(ab')2 fragments. The scFv fragment is a single polypeptide chain that includes the heavy and light chain variable regions of the antibody from which the scFv is derived.

[0101] The term "variable region" or "variable domain" as used herein refers to the domain of the antibody heavy chain or light chain that participates in the binding of the antigen-binding molecule to the antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, wherein each domain comprises four conserved framework regions (FR) and three hypervariable regions or hypervariable regions (HVR, also referred to as complementarity determining regions CDR). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

[0102] The terms "hypervariable region", "hypervariable region", "complementarity determining region", "HVR" or "CDR" as used herein refer to regions in the variable domain region of an antibody that are highly variable in sequence and / or form structurally defined loops ("hypervariable loops"). Typically, a natural four-chain antibody comprises six HVRs or CDRs: three present in VH (H1, H2, H3) and three present in VL (L1, L2, L3). Based on the Chothia definition rules, exemplary CDRs (LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3) are located at amino acid residues L26-L32 (L1), L50-L52 (L2), L91-L96 (L3), H26-H32 (H1), H52-H56 (H2) and H96-H101 (H3) (Chothia et al., J. Mol. Biol. 196: 901-917 (1987)). Based on the Kabat definition rules, exemplary CDRs (LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3) are located at amino acid residues L24-L34 (L1), L50-L56 (L2), L89-L97 (L3), H31-H35 (H1), H50-H65 (H2) and H95-H102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, the fifth edtion, Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Based on the IMGT definition rules, exemplary CDRs (LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3) are located at amino acid residues L27-L32 (L1), L50-L51 (L2), L89-L97 (L3), H26-H33 (H1), H51-H56 (H2) and H93-H102 (H3) (Honjo, T. and Alt, FW (1995) Immunoglobulin genes. Academic Press pp. 3-443). It is well known to those skilled in the art that the CDRs of antibodies can be defined in the art by a variety of methods, such as the Kabat definition rules based on sequence variability, the Chothia definition rules based on the position of the structural loop region and the reference tool for antibody humanization design based on CDR transplantation (see J Mol Biol. 273: 927-48, 1997).It will be understood by those skilled in the art that, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass the complementary determining region defined by any of the above-mentioned known schemes described in the present invention. Although the scope of protection claimed in the present disclosure is based on the sequence shown in the Kabat definition rule, the amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of the present invention.

[0103] As used herein, "framework region" or "FR" refers to variable domain residues other than the hypervariable region (HVR) residues. The FR of a variable domain is typically composed of the following four FR domains: FR1, FR2, FR3, and FR4. Thus, HVR and FR sequences typically appear in the following sequence in VH (or VL): FR1-H1 (L1)-FR2-H2 (L2)-FR3-H3 (L3)-FR4.

[0104] As used herein, "expression vector", "expression construct", "recombinant vector" or "recombinant expression vector" means that when the isolated nucleic acid molecule encoding the anti-IGFR-1 antibody is connected or integrated into a vector, the nucleic acid sequence can be directly or indirectly connected to the regulatory elements on the vector, as long as these regulatory elements can regulate the translation and expression of the nucleic acid molecule. Of course, these regulatory elements can come directly from the vector itself, or they can be exogenous, that is, not from the vector itself. In other words, the nucleic acid molecule is operably connected to the regulatory element. "Operably connected" herein means connecting the exogenous gene to the vector so that the regulatory elements in the vector, such as transcription regulatory sequences and translation regulatory sequences, etc., can play their intended function of regulating the transcription and translation of the exogenous gene. Of course, the polynucleotides used to encode the heavy chain and light chain of the antibody can be inserted into different vectors separately and independently, and it is common to insert them into the same vector. Commonly used vectors can be, for example, plasmids, bacteriophages, etc.

[0105] The terms "cell", "host cell" or "recombinant cell" as used herein may include expression vectors. The expression vectors may be introduced into mammalian cells to obtain recombinant cells, which are then used to express the antibodies or antigen-binding portions provided by the present disclosure. The corresponding antibodies may be obtained by culturing the recombinant cells. These usable mammalian cells may be, for example, CHO cells.

[0106] The term "pharmaceutically acceptable carrier, excipient or adjuvant" as used herein should be compatible with the active ingredient and can be mixed with it without reducing or significantly reducing the effect of the drug under normal circumstances. Specific examples of some substances that can be used as pharmaceutically acceptable carriers or adjuvants are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols, such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate; colorants; flavorings; tablets, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer, etc. These materials are used as needed to aid in the stability of the formulation or to help increase the activity or its bioavailability or to create an acceptable taste or smell in the case of oral administration to improve patient compliance with treatment.

[0107] As used herein, the terms "EC50," "half effective dose," or "half maximal effective concentration" refer to the concentration of an antibody that elicits 50% of the maximal effect.

[0108] The term "IC50" as used herein refers to the half-inhibitory concentration of the measured antagonist. It indicates the half amount of a drug or substance (inhibitor) in inhibiting a certain biological process (or certain substances contained in this process, such as enzymes, cell receptors or microorganisms).

[0109] The term "obesity" as used in this article refers to a certain degree of obvious overweight and excessive fat layer. It is a state caused by excessive accumulation of body fat, especially triglycerides. It does not refer to a simple increase in weight, but a state of excessive accumulation of adipose tissue in the body. Excessive accumulation of body fat due to excessive food intake or changes in body metabolism causes excessive weight gain and causes pathological, physiological changes or latency in the human body. The commonly used body mass index (BMI) is abbreviated as BMI, also translated as body mass index. It is an index that calculates the ratio of height to weight. The specific calculation method is to divide the weight (kilograms, kg) by the square of the height (meters, m), that is, BMI = weight / height / height (kg / m 2 ). When analyzing the degree of obesity based on body mass index, the body mass index cutoff values ​​set by the World Health Organization (WHO) are usually used internationally, that is, a body mass index of 25.0-29.9 is considered overweight, and a body mass index of 30 or more is considered obese.

[0110] The antibodies or antigen-binding portions thereof of the present invention can be incorporated into pharmaceutical compositions suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These pharmaceutical compositions can be prepared in various forms, such as liquid, semisolid and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions), dispersants or suspensions, tablets, pills, powders, liposomes and suppositories. Typical pharmaceutical compositions are in the form of injection solutions or infusion solutions. The antibodies or antigen-binding portions thereof of the present invention can be administered by intravenous infusion, injection, intramuscular or subcutaneous injection.

[0111] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiment. If the specific conditions are not specified in the embodiment, it is carried out according to the conditions recommended by normal conditions or manufacturers. If the manufacturer is not specified in all reagents or instruments, they are all conventional products that can be purchased commercially. In order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention. Such structures and technologies are also described in many publications.

[0112] Example 1 Screening of molecules binding to IGF-1R protein

[0113] The inventor used recombinant human IGF-1R (Beijing Biopsies Biotechnology Co., Ltd., item number: IGR-H5229) as an antigen to coat a high-affinity ELISA plate at 4°C overnight, with a coating amount of 50 ng per well, and used 2% BSA (Beijing Solebold Technology Co., Ltd.) for blocking at 37°C for 2 hours. The obtained phage library was incubated with recombinant human IGF-1R, eluted, and amplified to enrich the phages that bind to recombinant human IGF-1R. After repeating 3-4 times, the phages finally obtained were cloned and amplified, and clones with positive binding to human IGF-1R were obtained according to the phage ELISA detection method. After sequencing the positive clones, molecules with complete variable region sequences as shown in Table 1 below were obtained. Among them, the heavy chain variable region CDR and light chain variable region CDR of the antibody or its antigen-binding portion of the present application are determined by the Kabat numbering system, and the CDR region amino acid sequences are listed in Table 1. It is well known in the art that the heavy chain variable region and light chain variable region CDRs can be identified by, for example, the Kabat, Chothia, IMGT, AbM or Contact numbering systems / methods.

[0114] Table 1 CDR sequences of 12 antibodies screened based on Kabat definition rules

[0115]

[0116]

[0117] Example 2 Construction and expression of anti-IGF-1R antibody

[0118] The light chain variable region (AB1-12) and the light chain constant region (SEQ ID NO: 97) cloned in Example 1 were directly spliced ​​to form the light chain, and the heavy chain variable region (AB1-12) and the heavy chain constant region (SEQ ID NO: 98) cloned in Example 1 were directly spliced ​​to form the heavy chain. The amino acid sequences of the light chain / heavy chain variable region and the light chain / heavy chain constant region are shown in Tables 2 and 3.

[0119] An expression vector was constructed by codon-optimizing the amino acid sequences of the light chain and heavy chain and inserting the sequence of the human κ / IgG1-LALA constant region (the amino acid sequences of the light chain constant region and the heavy chain constant region are SEQ ID NO: 97 and 102, respectively) between the restriction enzyme cleavage sites EcoRI / HindIII of pTT5.

[0120] The sequences encoding the variable region and the human IgG1 (N297A) / κ constant region (the amino acid sequences of the heavy chain constant region and the light chain constant region are SEQ ID NO: 33 and 34, respectively) were inserted into the restriction enzyme sites XhoI / BamHI of pCDNA3.1 (Invitrogen, USA) to construct an expression vector. The expression vector obtained above was transfected into HEK-293F cells using PEI. Specifically, HEK-293F cells were cultured in Free StyleTM 293 expression medium (Gibco, Cat#: 12338-018), and each expression vector was transfected into the cells using PEI transfection. The ratio of DNA to PEI was 1:3, and the amount of DNA added to each milliliter of cell culture medium was 1.5 μg. The transfected HEK-293F cells were cultured at 120 rpm in an incubator at 37°C and 5% CO2. After 10-12 days, the cell culture supernatant was collected. The monoclonal antibody was enriched and purified by pre-equilibrated protein-G affinity column (GE, Cat#: 17040501) and eluted with elution buffer (20 mM citric acid, pH 3.0-3.5). Afterwards, the antibody was stored in PBS (pH 7.0) and the antibody concentration was detected by NanoDrop.

[0121] Table 2 Amino acid sequences of light chain and heavy chain variable regions

[0122]

[0123]

[0124] Table 3 Light chain and heavy chain constant region amino acid sequences

[0125]

[0126]

[0127]

[0128] Example 3 Anti-IGF-1R Antibody Binding to Human IGF-1R

[0129] In order to determine whether the anti-IGF-1R antibody binds to human IGF-1R, the inventors used the ELISA saturation concentration method, the principle of which is: to determine the affinity of the antibody relative to IGF-1R, in the presence of a small amount of IGF-1R, the antibody is graded diluted, and the concentration of the antibody / IGF-1R complex is detected. When the concentration of the antibody / IGF-1R complex accounts for half of the total IGF-1R concentration, the corresponding concentration value (EC50) of the antibody is the KD value of the antibody relative to IGF-1R.

[0130] FACS cell binding assay was performed using HEK293T cells stably overexpressing human IGF-1R. 5 HEK293T cells were plated on a 96-well V-bottom plate, and 50 μL of gradient dilution (3-fold dilution) of anti-IGF-1R antibody was added. After incubation at 4°C for 1 hour, the 96-well plate was washed 3 times with PBST. After that, 1000-fold diluted PE-goat anti-human IgG (purchased from BioLegend) was added. After incubation at 4°C for 1 hour, the 96-well plate was washed 3 times with PBS, and then the cell fluorescence was detected using a flow cytometer (purchased from Beckman), and the EC50 value was calculated. The EC50 value of the antibody is shown in Table 4. The results show that there are differences in the affinity of different anti-IGF-1R antibodies to HEK293T cells overexpressing human IGF-1R.

[0131] Table 4 EC50 value (equivalent to KD value) determination of anti-IGF-1R antibody binding to human IGF-1R

[0132]

[0133]

[0134] Example 4 Anti-IGF-1R Antibodies Inhibit Human IGF-1R / IGF-1 Interaction

[0135] Using the HEK293T cells stably overexpressing human IGF-1R in Example 3, blocking detection was performed by FACS. 5HEK293T / human IGF-1R cells were plated in a 96-well V-bottom plate and 50 μL of serially diluted anti-IGF-1R antibody was added. After incubation at 4°C for 1 hour, the plate was washed 3 times with PBST. Then, 100 μL of 200 μg / mL Biotinylated Human IGF-I Protein (Biopsy, Cat#: IG1-H82F7) was added and incubated at 4°C for 1 hour. The plate was washed 3 times with PBST and 1000-fold diluted Alexa Fluor 488Streptavidin (Jackson, Cat#: 016-540-084). After incubation at 4°C for 1 hour, the plate was washed three times with PBST, and the cell fluorescence was detected by flow cytometry (Beckman), and the IC50 value was calculated. The IC50 value of each antibody is shown in Table 5. The results show that the inhibitory activity of different anti-IGF-1R antibodies on the IGF-1R / IGF-1 interaction is different, which is not completely related to the affinity strength in Example 3.

[0136] Table 5 IC50 values ​​of anti-IGF-1R antibodies inhibiting human IGF-1R / IGF-1

[0137] Antibody ID IC50(nM) AB1 1.72 AB2 4.32 AB3 2.48 AB4 1.03 AB5 8.25 AB6 6.52 AB7 1.84 AB8 0.97 AB9 4.27 AB10 5.31 AB11 3.72 AB12 2.52

[0138] Example 5 Evaluation of Biological Activity of Anti-IGF-1R Antibodies

[0139] In this example, mouse fibroblasts 3T3 were used as the research object, 3T3 cells stably overexpressing human IGF-1R were constructed, and the fibroblast proliferation activity was used as the biological activity characterization of the anti-IGF-1R antibody. To this end, the activity of the anti-IGF-1R antibody of the present invention can be evaluated by detecting the cell proliferation of 3T3 / IGF-1R cells. The CCK8 method was used to detect the inhibitory efficiency of the anti-IGF-1R antibody on the proliferation of 3T3 / IGF-1R cells ( Figure 1 ). The IC50 values ​​were calculated, and the IC50 values ​​of each antibody are shown in Table 6. The results showed that the inhibitory activities of different anti-IGF-1R antibodies on 3T3 / IGF-1R cell proliferation were different, which were not completely consistent with the blocking activities shown in Example 4.

[0140] Table 6 Biological activity of anti-IGF-1R antibodies

[0141] Antibody ID IC50(nM) AB1 8.25 AB2 133.27 AB3 567.87 AB4 89.07 AB5 9.72 AB6 219.87 AB7 19.58 AB8 7.60 AB9 61.61 AB10 16.65 AB11 9.11 AB12 20.45

[0142] Example 6 Anti-IGF-1R Antibodies Inhibit Fibroblast Adipogenesis and Adipogenesis Accumulation

[0143] The IGF-1R signaling pathway plays an important role in cellular adipogenesis and fat accumulation. In this example, isolated primary fibroblasts were used as the research object, and the role of the anti-IGF-1R antibody in the present invention in fat accumulation was evaluated by detecting the fat accumulation. Specifically, the isolated primary fibroblasts were cultured in a DMEM medium containing 10% FBS, and the fibroblasts were induced to differentiate into adipocytes using a fat induction medium. During the differentiation induction process, IGF-1 was added alone, and IGF-1 and anti-IGF-1R antibodies were added together for treatment. Oil red staining was used to observe the formation of fat cells. The results showed that the anti-IGF-1R antibody can significantly inhibit the formation and accumulation of fat ( Figure 2 ).

[0144] The 3T3-huIGF-1R cell suspension overexpressing human IGF-1R was inoculated in a 6-well plate and treated with a self-prepared adipogenic induction solution to induce cell adipogenic differentiation. The adipogenic induction solution is: DMEM + 10% fetal bovine serum + 1% P / S + 0.5mM IBMX + 0.25μM dexamethasone + 1μg / mL insulin. The control group and experimental group were set up as follows: adipogenic induction group, IGF-1 pretreatment + adipogenic induction group, IGF-1 pretreatment + AB1-12 + adipogenic induction group. The cells were fixed with 3.5% formaldehyde solution for 10 minutes, rinsed twice with PBS, and incubated in 60% isopropanol for 1 hour with 1.5% Oil Red O dye solution. The cells stained with Oil Red O were washed with PBS to remove excess dye (washed 6 times), the fat droplets were dissolved in the extract, and the absorbance at 492nm was read with an enzyme reader. The results are as follows. Figure 3 As shown. The results showed that 3T3 cells overexpressing human IGF-1R showed a certain degree of fat production and accumulation after being induced by adipogenic induction solution. After IGF-1 pretreatment and then adipogenic induction, the degree of fat production and accumulation of 3T3 cells was the highest. After adding AB1-12 treatment at the same time, the fat production and accumulation of 3T3 cells were significantly inhibited to varying degrees. Therefore, the different anti-IGF-1R antibodies (AB1-AB12) in the present invention can significantly inhibit the production and accumulation of fat.

[0145] Example 7 Anti-IGF-1R Antibody Inhibits Fibroblast Collagen Production

[0146] According to some literature reports, collagen VI may cause dysfunction in the metabolism of adipose tissue. In this example, isolated primary fibroblasts were used as the research object, and the role of the anti-IGF-1R antibody in the present invention in collagen production was evaluated by detecting the expression of collagen. Specifically, the isolated primary fibroblasts were cultured in a DMEM medium containing 10% FBS, and the fibroblasts were induced to differentiate into adipocytes using a fat induction medium. During the culture process, TGF-β, IGF-1 were added separately, and IGF-1 and TGF-β were added together to induce collagen expression. During the induction process, anti-IGF-1R antibodies were added simultaneously for treatment. Cell proteins were extracted, and the expression of collagen I was detected by immunoblotting after SDS-PAGE. The results are shown as follows. Figure 4 The results show that the anti-IGF-1R antibody provided by the present invention effectively inhibits the production of collagen after treatment. In more tests, the anti-IGF-1R antibody provided by the present invention can effectively inhibit the production of collagen.

[0147] Example 8 Effect of anti-IGF-1R antibody on weight control in rats

[0148] In this embodiment, 50 SD rats (Beijing Huafukang Biotechnology Co., Ltd.) were randomly assigned to 5 groups, 10 rats in each group. After grouping, the average body weight of each group of rats had no statistical difference at the test level of 5.0%. The antibody molecule administered was AB1, and the dose of this experiment was set at 20, 60 and 200 mg / kg. In addition, a subcutaneous control group was set, and the dose was consistent with the dose of the intravenous high-dose group. At the same time, an excipient control group was set, and the excipient reference substance was administered intravenously. The information of each experimental group is as follows: Group 1: excipient control group, intravenous administration; Group 2: 20mpk (Milligrams Per Kilograms) AB1, intravenous administration; Group 3: 60mpk AB1, intravenous administration; Group 4: 200mpk AB1, intravenous administration; Group 5: 200mpk AB1, subcutaneous administration. The rats were weighed once a week before and after administration (8 weighings in total), and the weights of male and female rats were counted separately. The results showed that compared with the control group, the weight gain of the intravenous administration group was inhibited; and as the dosage increased, the inhibition of weight gain had a certain concentration dependence ( Figure 5 and Figure 6 ).

[0149] Example 9 Effect of anti-IGF-1R antibody in diet-induced mouse obesity model

[0150] Diet-induced animal obesity models are similar to human obesity and can better reflect the pathogenesis of human obesity. C57BL / 6J mice (Beijing Huafukang Biotechnology Co., Ltd.) are often used in diet-induced obesity (DIO) models because they are prone to developing severe obesity, fat accumulation, glucose intolerance and moderate insulin resistance. In this embodiment, male SPF-grade C57BL / 6J mice aged 8 weeks and above, weighing 20-22g, were selected for modeling. HFD (60% high-fat diet) induced mice to establish an obese mouse model (model animal inclusion criteria: body weight of 35-40g at 16 weeks of HFD induction). Obese mice were randomly assigned to a control group and an experimental group. The test dose was set at 10mg / kg and 30mg / kg, and an excipient control group was set at the same time, and an excipient reference substance was administered intravenously. The animal weight was weighed once a week before and after administration (8 weighings in total), and the weight of the mouse was recorded ( Figure 7 ). The change rate of mouse weight was calculated based on the mouse weight records, and the mouse weight change graph was obtained ( Figure 8 ), weight change rate = (current weight - initial weight) / initial weight × 100%. The fat mass of mice was detected by DEXA, and the total fat change of mice was calculated to obtain the total fat change graph of mice ( Fig. 9 ). Total fat change = (current fat mass - initial fat mass) / initial fat mass × 100%. At the end of the experiment (day 56), the results of AB9 antibody on mouse body weight, weight change rate and fat change showed that in the diet-induced mouse obesity model, compared with the control group, the weight gain of the anti-IGF-1R antibody group was inhibited and the fat content was significantly reduced; and with the increase of the dosage, the inhibition of weight gain and the reduction of fat content had a certain concentration dependence ( Figure 10-12 ).

[0151] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. Use of anti-IGF-1R antibodies or antigen-binding portions thereof in weight loss.

2. The use according to claim 1, characterized in that: The anti-IGF-1R antibody or antigen-binding portion thereof reduces weight by at least one of the following mechanisms: (1) Inhibit or block the binding between IGF-1R and IGF-1; (2) reduce, weaken or neutralize the activity of IGF-1R; (3) Inhibit cell proliferation; (4) inhibiting cellular fat synthesis and / or accumulation; (5) Inhibit cellular collagen synthesis.

3. Use of an anti-IGF-1R antibody or an antigen-binding portion thereof in the preparation of a product for preventing or treating obesity or diseases caused by obesity.

4. The use according to claim 2, characterized in that: The product prevents or treats obesity or obesity-related diseases through at least one of the following mechanisms: 1) Inhibit or block the binding between IGF-1R and IGF-1; 2) reduce, weaken or neutralize the activity of IGF-1R; 3) Inhibit cell proliferation; 4) Inhibit cellular fat synthesis and / or accumulation; 5) Inhibit collagen synthesis in cells.

5. The use according to claim 2 or 4, characterized in that: The cells include fibroblasts.

6. The use according to claim 1 or 3, characterized in that: The antibody, or antigen-binding portion thereof, comprises a light chain variable region and a heavy chain variable region.

7. The use according to claim 6, characterized in that: The light chain variable region has: LCDR1 as set forth in SEQ ID NO:25, SEQ ID NO:31, SEQ ID NO:37, SEQ ID NO:43, SEQ ID NO:49, SEQ ID NO:55, SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85 or SEQ ID NO:91; and LCDR2 as set forth in SEQ ID NO:26, SEQ ID NO:32, SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:50, SEQ ID NO:56, SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86 or SEQ ID NO:92; and LCDR3 as shown in SEQ ID NO:27, SEQ ID NO:33, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:51, SEQ ID NO:57, SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81, SEQ ID NO:87 or SEQ ID NO:

93.

8. The use according to claim 6, characterized in that: The heavy chain variable region has: HCDR1 as set forth in SEQ ID NO:28, SEQ ID NO:34, SEQ ID NO:40, SEQ ID NO:46, SEQ ID NO:52, SEQ ID NO:58, SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:88 or SEQ ID NO:94; and HCDR2 as set forth in SEQ ID NO:29, SEQ ID NO:35, SEQ ID NO:41, SEQ ID NO:47, SEQ ID NO:53, SEQ ID NO:59, SEQ ID NO:65, SEQ ID NO:71, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:89 or SEQ ID NO:95; and HCDR3 as shown in SEQ ID NO:30, SEQ ID NO:36, SEQ ID NO:42, SEQ ID NO:48, SEQ ID NO:54, SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:90 or SEQ ID NO:

96.

9. The use according to claim 7 or 8, characterized in that: The light chain of the antibody or antigen-binding portion is composed of a light chain variable region and a light chain constant region as shown in SEQ ID NO: 97; the heavy chain of the antibody or antigen-binding portion is composed of a heavy chain variable region and a heavy chain constant region as shown in any one of SEQ ID NOs: 98-104.

10. The use according to claim 6, characterized in that: The light chain variable region has: An amino acid sequence as shown in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21 or SEQ ID NO:

23.

11. The use according to claim 6, characterized in that: The heavy chain variable region has: An amino acid sequence as shown in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22 or SEQ ID NO:

24.

12. The use according to claim 7, characterized in that: The light chain variable region has: LCDR1 as shown in SEQ ID NO:25, LCDR2 as shown in SEQ ID NO:26, and LCDR3 as shown in SEQ ID NO:27; Or, LCDR1 as shown in SEQ ID NO:31, LCDR2 as shown in SEQ ID NO:32, LCDR3 as shown in SEQ ID NO:33; or, LCDR1 as shown in SEQ ID NO:37, LCDR2 as shown in SEQ ID NO:38, LCDR3 as shown in SEQ ID NO:39; Or, LCDR1 as shown in SEQ ID NO:43, LCDR2 as shown in SEQ ID NO:44, LCDR3 as shown in SEQ ID NO:45; or, LCDR1 as shown in SEQ ID NO:49, LCDR2 as shown in SEQ ID NO:50, LCDR3 as shown in SEQ ID NO:51; or, LCDR1 as shown in SEQ ID NO:55, LCDR2 as shown in SEQ ID NO:56, LCDR3 as shown in SEQ ID NO:57; Or, LCDR1 as shown in SEQ ID NO:61, LCDR2 as shown in SEQ ID NO:62, LCDR3 as shown in SEQ ID NO:63; or, LCDR1 as shown in SEQ ID NO:67, LCDR2 as shown in SEQ ID NO:68, LCDR3 as shown in SEQ ID NO:69; or, LCDR1 as shown in SEQ ID NO:73, LCDR2 as shown in SEQ ID NO:74, LCDR3 as shown in SEQ ID NO:75; or, LCDR1 as shown in SEQ ID NO:79, LCDR2 as shown in SEQ ID NO:80, LCDR3 as shown in SEQ ID NO:81; or, LCDR1 as shown in SEQ ID NO:85, LCDR2 as shown in SEQ ID NO:86, LCDR3 as shown in SEQ ID NO:87; Or, LCDR1 as shown in SEQ ID NO:91, LCDR2 as shown in SEQ ID NO:92, LCDR3 as shown in SEQ ID NO:

93.

13. The use according to claim 7, characterized in that: The heavy chain variable region has: HCDR1 as shown in SEQ ID NO:28, HCDR2 as shown in SEQ ID NO:29, and HCDR3 as shown in SEQ ID NO:30; Or, HCDR1 as shown in SEQ ID NO:34, HCDR2 as shown in SEQ ID NO:35, and HCDR3 as shown in SEQ ID NO:36; Or, HCDR1 as shown in SEQ ID NO:40, HCDR2 as shown in SEQ ID NO:41, and HCDR3 as shown in SEQ ID NO:42; Or, HCDR1 as shown in SEQ ID NO:46, HCDR2 as shown in SEQ ID NO:47, and HCDR3 as shown in SEQ ID NO:48; Or, HCDR1 as shown in SEQ ID NO:52, HCDR2 as shown in SEQ ID NO:53, and HCDR3 as shown in SEQ ID NO:54; Or, HCDR1 as shown in SEQ ID NO:58, HCDR2 as shown in SEQ ID NO:59, and HCDR3 as shown in SEQ ID NO:60; Or, HCDR1 as shown in SEQ ID NO:64, HCDR2 as shown in SEQ ID NO:65, and HCDR3 as shown in SEQ ID NO:66; Or, HCDR1 as shown in SEQ ID NO:70, HCDR2 as shown in SEQ ID NO:71, and HCDR3 as shown in SEQ ID NO:72; Or, HCDR1 as shown in SEQ ID NO:76, HCDR2 as shown in SEQ ID NO:77, and HCDR3 as shown in SEQ ID NO:78; Or, HCDR1 as shown in SEQ ID NO:82, HCDR2 as shown in SEQ ID NO:83, and HCDR3 as shown in SEQ ID NO:84; Or, HCDR1 as shown in SEQ ID NO:88, HCDR2 as shown in SEQ ID NO:89, and HCDR3 as shown in SEQ ID NO:90; Or, HCDR1 shown in SEQ ID NO:94, HCDR2 shown in SEQ ID NO:95, and HCDR3 shown in SEQ ID NO:

96.

14. The use according to claim 3, characterized in that: The diseases caused by obesity include fatty liver, high blood pressure, high blood sugar and high cholesterol.

15. The use according to claim 3, characterized in that: The products include medicines, health products and food.

16. The use according to claim 15, characterized in that The product comprises the antibody or antigen-binding portion, or a biological material comprising the antibody or antigen-binding portion or a gene thereof, and at least one pharmaceutically acceptable excipient; The biological materials include expression vectors and host cells.

17. The use according to claim 16, characterized in that The auxiliary material is selected from solvents, diluents, disintegrants, precipitation inhibitors, surfactants, glidants, adhesives, lubricants, dispersants, suspending agents, isotonic agents, thickeners, emulsifiers, preservatives, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, flavoring agents, sweeteners, ion exchangers, release agents, coating agents, flavoring agents or antioxidants.

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