Use of Anti-IGF-1r antibody or antigen binding portion thereof in weight loss

Abstract

Provided is a use of an anti-IGF-1R antibody or an antigen binding portion thereof in weight loss. The anti-IGF-1R antibody or the antigen binding portion thereof carries out weight loss by means of at least one of the following mechanisms: (1) inhibiting or blocking the binding between IGF-1R and IGF-1; (2) reducing, weakening or neutralizing the activity of IGF-1R; (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 portion thereof can significantly inhibit the generation and accumulation of fat, effectively inhibit the formation of collagen, and has a significant effect in treatment of obesity and weight loss.

Description

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

[0001] The present invention claims priority to Chinese patent application No. 202311122761X, filed with the Patent Office of China on September 1, 2023, entitled “Application of anti-IGF-1R antibodies or antigen-binding portions thereof in weight loss”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to the use of anti-IGF-1R antibodies or antigen-binding portions thereof in weight loss. Background Art

[0003] Obesity and obesity-related complications, including type 2 diabetes, cardiovascular disease, osteoarthritis, obstructive sleep apnea, and various 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 Obesity is associated with excessive accumulation or abnormal distribution of body fat. Abnormally distributed adipose tissue secretes various adipokines, including leptin, resistin, adiponectin, and IL-6. The adipose tissue of obese patients releases adipokines that selectively affect tissue and organ function and systemic metabolism, such as high blood pressure, high blood sugar, and high cholesterol. They may also lead to psychiatric problems, such as depression and anxiety.

[0004] 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 medication 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 2For people with obesity who have at least one obesity-related condition (such as type 2 diabetes, cardiovascular disease, or osteoarthritis), weight loss medication combined with lifestyle intervention is recommended. (Perdomo CM. Contemporary medical, device, and surgical therapies for obesity in adults. Lancet. 2023; 401(10382):1116-1130.)

[0005] Currently, the main drugs used clinically to treat obesity include early FDA-approved fat absorption inhibitors (orlistat, lorcaserin), appetite suppressants (phentermine), SGLT2 inhibitors (naltrexone), GLP-1 analogs (liraglutide), and the more recently FDA-approved PLENITY (Gelesis 100) and Imcivree (Setmelanotide). In addition, dozens of investigational drugs for obesity are currently in various stages of clinical trials and preclinical research. Their targets and mechanisms of action primarily focus on appetite regulation centers, GLP-1 receptors, gastrointestinal digestion and absorption, and other receptor agonists and inhibitors. Among these, GLP-1 analogs offer relatively good weight loss / slimming effects. GLP-1 is a gut-derived hormone that stimulates insulin secretion in a glucose-dependent manner by activating the GLP-1 receptor. The weight loss mechanism of GLP-1 receptor agonists is primarily through slowing gastrointestinal motility and suppressing appetite. They are among the most effective and safest weight loss drugs currently available.

[0006] 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 group consisting of: CH3(CH2) n CO-, where n is an integer, HOOC(CH2) m CO-, where 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 formulation containing a peptide and propylene glycol, a method for preparing the formulation, and the use of the formulation in treating diseases and conditions, 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.

[0007] GLP-1 analogs have a significant and stable anti-obesity effect, but achieving significant weight loss generally requires a higher dosage. High-dose GLP-1 derivatives are prone to gastrointestinal side effects and often have a narrow therapeutic window due to poor tolerability. Furthermore, GLP-1 analogs are peptide 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 a short half-life.

[0008] Therefore, there is an urgent need to develop safer and longer-lasting drugs for treating obesity or weight loss.

[0009] Summary of the Invention

[0010] Fat is one of the main tissues for energy storage and metabolism, helping to 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 number, causing the body fat content to exceed the normal range, thereby causing obesity. In obese patients, the number and size of fat cells will increase. These fat cells secrete a series of cytokines and hormones, such as TNF-α, IL-6, PAI-1, etc., which will affect systemic metabolism. Therefore, inhibiting the excessive differentiation of fat cells and excessive synthesis of fat, and reducing excessive fat accumulation are very important for weight loss and obesity control.

[0011] The primary function of the insulin-like growth factor 1 receptor (IGF-1R) is to mediate signaling of insulin-like growth factor 1 (IGF-1), thereby regulating various biological processes such as cell proliferation, differentiation, and survival. Studies have shown that IGF-1R activity can influence metabolic and lipogenesis processes. The role of IGF-1R in metabolism and lipogenesis is complex, and it can regulate glucose and lipid metabolism through multiple mechanisms. IGF-1R activity levels must be maintained within an appropriate range to ensure normal metabolic and lipogenesis functions. Excessive IGF-1R activation is closely associated with overweight and obesity. Excessive IGF-1R activation can lead to lipogenesis and energy homeostasis disorders through the following mechanisms: 1. Promoting adipocyte differentiation and lipogenesis: IGF-1R activation can promote adipocyte differentiation and proliferation 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 fat cells. 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 functional disorders 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.

[0012] Anti-IGF-1R antibodies have been successful in multiple therapeutic areas, such as thyroid eye disease, but have not been successfully applied to the treatment of obesity or weight loss.

[0013] In view of the deficiencies of the prior art, the present invention provides the use of an anti-IGF-1R antibody or antigen-binding portion thereof in weight loss.

[0014] The technical solution proposed by the present invention is as follows:

[0015] In one aspect, the present invention provides use of an anti-IGF-1R antibody, or an antigen-binding portion thereof, for weight loss.

[0016] In one embodiment, the anti-IGF-1R antibody, or antigen-binding portion thereof, reduces weight by at least one of the following mechanisms:

[0017] (1) Inhibit or block the binding between IGF-1R and IGF-1;

[0018] (2) reduce, weaken or neutralize the activity of IGF-1R;

[0019] (3) inhibit cell proliferation;

[0020] (4) inhibiting cellular fat synthesis and / or accumulation;

[0021] (5) Inhibit cellular collagen synthesis.

[0022] In one embodiment, the cells comprise fibroblasts.

[0023] 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.

[0024] In one embodiment, the product provides weight loss through at least one of the following mechanisms:

[0025] (1) Inhibit or block the binding between IGF-1R and IGF-1;

[0026] (2) reduce, weaken or neutralize the activity of IGF-1R;

[0027] (3) inhibit cell proliferation;

[0028] (4) inhibiting cellular fat synthesis and / or accumulation;

[0029] (5) Inhibit cellular collagen synthesis.

[0030] In one embodiment, the cells comprise fibroblasts.

[0031] In one embodiment, the antibody in the above two aspects may be a monoclonal antibody, such as a humanized antibody.

[0032] In one embodiment, the antibody or antigen-binding portion thereof of the above two aspects comprises a light chain variable region and a heavy chain variable region.

[0033] In a preferred embodiment, the light chain variable region has:

[0034] 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

[0035] 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

[0036] 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.

[0037] In a preferred embodiment, the heavy chain variable region has:

[0038] 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

[0039] 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

[0040] 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.

[0041] In one embodiment, the antibody or antigen binding portion thereof may comprise a heavy chain constant region and / or a light chain constant region.

[0042] In one embodiment, the heavy chain constant region can be an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region.

[0043] 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.

[0044] 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 can reduce or eliminate the effect of IGF-1R. + ADCC effect of cells.

[0045] 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.

[0046] In a preferred embodiment, the light chain constant region may be the human κ constant region as shown in SEQ ID NO:97.

[0047] 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.

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

[0049] 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.

[0050] In one embodiment, the heavy chain variable region has:

[0051] 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.

[0052] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:25, LCDR2 shown in SEQ ID NO:26, and LCDR3 shown in SEQ ID NO:27.

[0053] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:31, LCDR2 shown in SEQ ID NO:32, and LCDR3 shown in SEQ ID NO:33.

[0054] 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.

[0055] 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.

[0056] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:49, LCDR2 shown in SEQ ID NO:50, and LCDR3 shown in SEQ ID NO:51.

[0057] In a preferred embodiment, the light chain variable region has LCDR1 shown in SEQ ID NO:55, LCDR2 shown in SEQ ID NO:56, and LCDR3 shown in SEQ ID NO:57.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] In one embodiment, the diseases caused by obesity include fatty liver, hypertension, hyperglycemia, and high cholesterol.

[0077] In one embodiment, the products include medicines, health products, and foods.

[0078] In a preferred embodiment, the product may be a pharmaceutical 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;

[0079] The biological materials include expression vectors and host cells.

[0080] 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.

[0081] In the present invention, unless otherwise specified, the pharmaceutical dosage form is not particularly limited and can be prepared into injections, oral liquids, tablets, capsules, dripping pills, sprays, inhalants, etc., and can be prepared by conventional methods. The choice of pharmaceutical dosage form should match the mode of administration.

[0082] The anti-IGF-1R antibody or its antigen-binding portion provided by the present invention can significantly inhibit the generation and accumulation of fat and effectively inhibit the formation of collagen. It is effective in treating obesity and weight loss, with a weight change rate of more than 10% and a fat change rate of up to about 40%. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG1 shows the inhibitory efficiency of anti-IGF-1R antibodies on the proliferation of 3T3 cells stably overexpressing human IGF-1R.

[0084] Figure 2 shows the effects of anti-IGF-1R antibodies on adipogenesis and adipogenesis in fibroblasts by Oil Red O staining, wherein A is the adipogenesis induction group, B is the adipogenesis induction + IGF-1 group, and C is the adipogenesis induction + IGF-1 + AB1 group.

[0085] FIG3 shows the effects of anti-IGF-1R antibodies on adipogenesis and accumulation in fibroblasts by adipogenesis assay.

[0086] FIG4 shows the effect of anti-IGF-1R antibody on collagen production in fibroblasts by Western Blot experiment.

[0087] FIG5 shows the effect of anti-IGF-1R antibody on body weight of normal male mice (rats).

[0088] FIG6 shows the effect of anti-IGF-1R antibodies on body weight of normal female mice (rats).

[0089] FIG7 shows the effect of anti-IGF-1R antibody AB1 on the body weight of obese mice.

[0090] FIG8 shows the body weight change rate of obese mice after administration of anti-IGF-1R antibody AB1, *p<0.05, **p<0.01 (relative to the 0 mpk group).

[0091] FIG. 9 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).

[0092] FIG10 shows the effect of anti-IGF-1R antibody AB9 on the body weight of obese mice.

[0093] FIG11 shows the body weight change rate of obese mice after administration of the anti-IGF-1R antibody AB9, *p<0.05, **p<0.01 (relative to the 0 mpk group).

[0094] FIG12 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

[0095] 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.

[0096] Unless the context clearly dictates otherwise, as used herein, the expressions "a" and "an" 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.

[0097] 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.

[0098] As used herein, the term "IGF-1R" refers to the insulin-like growth factor 1 receptor. The term encompasses 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 entirely specific for human IGF-1R protein and not cross-react with proteins from other species or other types, or may cross-react with IGF-1R proteins from some other species but not all other species.

[0099] As used herein, the term "amino acid" 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 that have the same basic chemical structure as naturally occurring amino acids, i.e., carbon bonded to hydrogen, carboxyl, amino, and R groups, such as homoserine, norleucine, methionine sulfoxide, and 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 an amino acid, but function in a manner similar to naturally occurring amino acids.

[0100] The term "antibody" as used herein refers to a glycoprotein comprising heavy (H) and light (L) chains interconnected by disulfide bonds (SS). Each heavy chain is composed 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 is composed of three domains: CH1, CH2, and CH3. Each light chain is composed 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 is composed of one domain, CL. Light chains are divided into two categories: 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 and VL regions can be further divided into hypervariable regions (also called complementarity-determining regions (CDRs)), interspersed with relatively conserved framework regions or framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: 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.

[0101] 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 IGF-1R activity, and / or inactivates IGF-1R, prevents IGF-1R response or downstream pathways mediated by IGF-1R or other IGF-1R-mediated functions.

[0102] As used herein, the terms "antibody fragment," "antigen-binding fragment," "antigen-binding portion," or similar terms refer to fragments of an antibody that retain binding to a target antigen (e.g., IGF1-R) and possess 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. ScFv fragments are single polypeptide chains that include both the heavy and light chain variable regions of the antibody from which the scFv was derived.

[0103] 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 an antigen-binding molecule to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable or hypervariable regions (HVRs, also known as complementarity determining regions (CDRs)). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

[0104] 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 in VH (H1, H2, H3) and three in VL (L1, L2, L3). Based on the Chothia definition, 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 edition, 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 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 grafting (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 complementarity determining regions defined by any of the above-mentioned known schemes described herein. Although the scope of protection claimed in the present disclosure is based on the sequences shown in the Kabat definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of the present invention.

[0105] As used herein, "framework region" or "FR" refers to the variable domain residues excluding 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.

[0106] As used herein, "expression vector," "expression construct," "recombinant vector," or "recombinant expression vector" refers to the process of connecting or integrating an isolated nucleic acid molecule encoding an anti-IGFR-1 antibody to a vector. The nucleic acid sequence may be directly or indirectly connected to regulatory elements on the vector, as long as these regulatory elements are capable of regulating the translation and expression of the nucleic acid molecule. Of course, these regulatory elements may be derived directly from the vector itself or exogenously, i.e., not from the vector itself. In other words, the nucleic acid molecule and the regulatory elements are operably linked. As used herein, "operably linked" means connecting an exogenous gene to a vector so that the regulatory elements within the vector, such as transcriptional regulatory sequences and translational regulatory sequences, can perform their intended functions of regulating the transcription and translation of the exogenous gene. Of course, the polynucleotides encoding the heavy and light chains of the antibody may be independently inserted into different vectors, but are commonly inserted into the same vector. Commonly used vectors include plasmids, bacteriophages, and the like.

[0107] As used herein, the terms "cell," "host cell," or "recombinant cell" may include expression vectors. Expression vectors can be introduced into mammalian cells to obtain recombinant cells, which can then be used to express the antibodies or antigen-binding portions provided herein. The corresponding antibodies can be obtained by culturing these recombinant cells. Examples of mammalian cells that can be used include CHO cells.

[0108] As used herein, the term "pharmaceutically acceptable carrier, excipient, or adjuvant" should be compatible with the active ingredient and capable of being mixed therewith without generally reducing or significantly reducing the efficacy of the drug. Specific examples of substances that can serve as pharmaceutically acceptable carriers or adjuvants include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium methylcellulose, ethylcellulose, and methylcellulose; 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; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer. These substances 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.

[0109] As used herein, the term "EC50," "half effective dose," or "half maximal effective concentration" refers to the concentration of an antibody that elicits 50% of the maximal effect.

[0110] The term "IC50" as used herein refers to the half-inhibitory concentration of a measured antagonist. It indicates the half-dose of a drug or substance (inhibitor) that inhibits a biological process (or a substance involved in such a process, such as an enzyme, cell receptor, or microorganism).

[0111] The term "obesity" 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 latent changes in the human body. The currently 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 (weight for height). 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 The body mass index (BMI) is used to analyze the degree of obesity. The BMI cutoff values ​​established by the World Health Organization (WHO) are generally used internationally, that is, a BMI of 25.0-29.9 is considered overweight, and a BMI of 30 or more is considered obese.

[0112] The antibodies of the present invention or their antigen-binding portions thereof can be incorporated into pharmaceutical compositions suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These pharmaceutical compositions can be prepared into 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 of the present invention or their antigen-binding portions thereof can be administered by intravenous infusion, injection, intramuscular or subcutaneous injection.

[0113] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below in conjunction with the examples. In the examples, if no specific conditions are specified, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If all reagents or instruments are not specified by the manufacturer, 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 following specific embodiments. 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.

[0114] Example 1 Screening of molecules binding to IGF-1R protein

[0115] The inventors used recombinant human IGF-1R (Beijing Biopsies Biotechnology Co., Ltd., product 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 blocked with 2% BSA (Beijing Solaibao Technology Co., Ltd.) at 37°C for 2 hours. The obtained phage library was incubated with recombinant human IGF-1R, eluted, and amplified to enrich phages that bind to recombinant human IGF-1R. After repeating 3-4 times, the finally obtained phages 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 were 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 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.

[0116] Table 1 CDR sequences of 12 antibodies screened based on Kabat definition rules

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

[0118] The light chain was formed by directly splicing the light chain variable region (AB1-12) and light chain constant region (SEQ ID NO: 97) cloned in Example 1. The heavy chain was formed by directly splicing the heavy chain variable region (AB1-12) and heavy chain constant region (SEQ ID NO: 98) cloned in Example 1. The amino acid sequences of the light chain / heavy chain variable region and 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 and heavy chains and inserting the sequences of the human κ / IgG1-LALA constant region (amino acid sequences of the light and heavy chain constant regions are SEQ ID NOs: 97 and 102, respectively) between the EcoRI / HindIII restriction enzyme cleavage sites of pTT5.

[0120] Sequences encoding the variable region and human IgG1 (N297A) / κ constant region (amino acid sequences of the heavy and light chain constant regions are SEQ ID NOs: 33 and 34, respectively) were inserted into pCDNA3.1 (Invitrogen, USA) between the XhoI and BamHI restriction enzyme sites to construct an expression vector. HEK-293F cells were transfected with the obtained expression vectors using PEI. Specifically, HEK-293F cells were cultured in Free Style™ 293 Expression Medium (Gibco, Cat#: 12338-018) and transfected with each expression vector using PEI transfection. The DNA:PEI ratio was 1:3, and 1.5 μg of DNA was added per milliliter of cell culture medium. The transfected HEK-293F cells were cultured at 37°C, 5% CO2, and 120 rpm in an incubator. 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 determined by NanoDrop.

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

[0122] Table 3 Amino acid sequences of light chain and heavy chain constant regions

[0123] Example 3 Anti-IGF-1R Antibody Binding to Human IGF-1R

[0124] To determine whether anti-IGF-1R antibodies bind to human IGF-1R, the inventors used an ELISA saturation concentration method. The principle is to measure the affinity of the antibody for IGF-1R. In the presence of a small amount of IGF-1R, the antibody is serially 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 for IGF-1R.

[0125] FACS cell binding assay was performed using HEK293T cells stably overexpressing human IGF-1R. 5 HEK293T cells were plated in 96-well V-bottom plates and 50 μL of serially diluted (3-fold dilution) anti-IGF-1R antibodies were added. After incubation at 4°C for 1 hour, the 96-well plates were washed three times with PBST. Subsequently, 1000-fold diluted PE-goat anti-human IgG (purchased from BioLegend) was added. After incubation at 4°C for 1 hour, the 96-well plates were washed three times with PBS, and cell fluorescence was detected using a flow cytometer (purchased from Beckman). EC50 values ​​were calculated. The EC50 values ​​of the antibodies are shown in Table 4. The results showed that different anti-IGF-1R antibodies had different affinities for HEK293T cells overexpressing human IGF-1R.

[0126] Table 4 EC50 values ​​(equivalent to KD values) of anti-IGF-1R antibodies binding to human IGF-1R

[0127] Example 4 Anti-IGF-1R Antibodies Inhibit Human IGF-1R / IGF-1 Interaction

[0128] Using the HEK293T cells stably overexpressing human IGF-1R in Example 3, blocking assay was performed by FACS. 5 HEK293T / human IGF-1R cells were plated in 96-well V-bottom plates and 50 μL of serially diluted anti-IGF-1R antibodies were added. After incubation at 4°C for 1 hour, the plates were washed three times with PBST. Then, 100 μL of 200 μg / mL Biotinylated Human IGF-I Protein (Bipsys, Cat#: IG1-H82F7) was added. After incubation at 4°C for 1 hour, the plates were washed three times with PBST, and 1000-fold diluted Alexa Fluor 500 was added. 488 Streptavidin (Jackson, Cat#: 016-540-084). After incubation at 4°C for 1 hour, the plates were washed three times with PBST, and cell fluorescence was measured using a flow cytometer (Beckman). IC50 values ​​were calculated, and the IC50 values ​​of each antibody are shown in Table 5. The results showed that the inhibitory activity of different anti-IGF-1R antibodies on the IGF-1R / IGF-1 interaction varied, which was not completely correlated with the affinity shown in Example 3.

[0129] Table 5 IC50 values ​​of anti-IGF-1R antibodies inhibiting human IGF-1R / IGF-1

[0130] Example 5 Evaluation of Biological Activity of Anti-IGF-1R Antibodies

[0131] In this example, mouse fibroblasts 3T3 were used as the research object, 3T3 cells that stably overexpressed 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 status 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 value was calculated, and the IC50 value of each antibody is shown in Table 6. The results showed that there were differences in the inhibitory activity of different anti-IGF-1R antibodies on the proliferation of 3T3 / IGF-1R cells, which was not completely consistent with the blocking activity shown in Example 4.

[0132] Table 6 Biological activity of anti-IGF-1R antibodies

[0133] Example 6 Anti-IGF-1R Antibodies Inhibit Fibroblast Adipogenesis and Adipogenesis Accumulation

[0134] The IGF-1R signaling pathway plays an important role in cell adipogenesis and fat accumulation. In this example, isolated primary fibroblasts were used as research objects, and the role of the anti-IGF-1R antibody of the present invention in fat accumulation was evaluated by detecting the accumulation of fat. 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).

[0135] A suspension of 3T3-huIGF-1R cells overexpressing human IGF-1R was seeded in a 6-well plate and treated with a custom-prepared adipogenic induction solution to induce adipogenic differentiation. The adipogenic induction solution consisted of DMEM + 10% fetal bovine serum + 1% P / S + 0.5 mM IBMX + 0.25 μM dexamethasone + 1 μg / mL insulin. The control and experimental groups were as follows: adipogenic induction group, IGF-1 pretreatment + adipogenic induction group, and IGF-1 pretreatment + AB1-12 + adipogenic induction group. The cells were fixed with 3.5% formaldehyde for 10 minutes, rinsed twice with PBS, and incubated in 60% isopropanol with 1.5% Oil Red O stain for 1 hour. The cells were then washed six times with PBS to remove excess dye, and the lipid droplets were dissolved in the extract. The absorbance at 492 nm was read using a microplate reader. The results are shown in Figure 3. The results showed that 3T3 cells overexpressing human IGF-1R exhibited a certain degree of adipogenesis and accumulation after induction with an adipogenic induction solution. Pretreatment with IGF-1 followed by adipogenic induction resulted in the highest levels of adipogenesis and accumulation in 3T3 cells. Simultaneous treatment with AB1-12 significantly inhibited adipogenesis and accumulation in 3T3 cells to varying degrees. Therefore, the different anti-IGF-1R antibodies (AB1-AB12) described in this invention were all able to significantly inhibit adipogenesis and accumulation.

[0136] Example 7 Anti-IGF-1R Antibody Inhibits Fibroblast Collagen Production

[0137] According to some literature reports, collagen VI may cause dysfunction in adipose tissue metabolism. In this example, isolated primary fibroblasts were used as research subjects to assess the effect of the anti-IGF-1R antibodies of the present invention on collagen production by measuring collagen expression. Specifically, the isolated primary fibroblasts were cultured in DMEM medium supplemented with 10% FBS and induced to differentiate into adipocytes using adipogenic induction medium. During the culture process, TGF-β, IGF-1, and both IGF-1 and TGF-β were added to induce collagen expression. Anti-IGF-1R antibodies were also added during the induction process. Cell proteins were extracted, and collagen I expression was analyzed by immunoblotting after SDS-PAGE. The results are shown in Figure 4. The results show that the anti-IGF-1R antibodies provided by the present invention effectively inhibited collagen production after treatment. In further tests, the anti-IGF-1R antibodies provided by the present invention were able to effectively inhibit collagen production.

[0138] Example 8 Effect of anti-IGF-1R antibodies on weight control in rats

[0139] In this example, 50 SD rats (Beijing Huafukang Biotechnology Co., Ltd.) were randomly divided into 5 groups, with 10 rats in each group. After grouping, the average body weight of each group of rats showed no statistical difference at a 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. A subcutaneous control group was also set up, and the dose was consistent with the dose of the intravenous high-dose group. At the same time, an excipient control group was set up, and the excipient control formulation 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-dependency (Figures 5 and 6).

[0140] Example 9 Effect of anti-IGF-1R antibodies in a diet-induced mouse obesity model

[0141] 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 commonly 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 example, male SPF-grade C57BL / 6J mice aged 8 weeks and above, weighing 20-22g, were selected for modeling. An HFD (60% high-fat diet) was used to induce an obesity mouse model (model animal inclusion criteria: body weight of 35-40g after 16 weeks of HFD induction). Obese mice were randomly assigned to a control group and an experimental group. The experimental doses were set at 10mg / kg and 30mg / kg, and a vehicle control group was also set up. The vehicle control formulation was administered intravenously. The animals were weighed weekly before and after administration (8 weighings in total), and the body weights of the mice were recorded (Figure 7). Based on the recorded weight of the mice, the rate of change of the mouse weight was calculated to obtain the mouse weight change graph (Figure 8), where the weight change rate = (current weight - initial weight) / initial weight × 100%. The fat mass of the mice was detected by DEXA, and the total fat change of the mice was calculated to obtain the mouse total fat change graph (Figure 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 the effects of AB9 antibody on mouse weight, weight change rate, and fat change showed that in the diet-induced mouse obesity model, the weight gain of the anti-IGF-1R antibody-treated group was inhibited and the fat content was significantly reduced compared to the control group; and as the dosage increased, the inhibition of weight gain and the reduction of fat content were concentration-dependent (Figures 10-12).

[0142] 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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