Antibody for treating rheumatoid arthritis and use thereof

Abstract

The present invention provides an antibody which specifically binds to RgpA protein of Porphyromonas gingivalis. The present invention further provides a method for treating a subject suffering from rheumatoid arthritis, which comprises administering the antibody having the function of binding RgpA protein into the subject suffering from rheumatoid arthritis for treatment.

Description

ANTIBODY FOR TREATING RHEUMATOID ARTHRITIS AND USETHEREOFFIELD OF THE INVENTION

[0001] The present invention relates to a monoclonal antibody, which is characterized in that the monoclonal antibody can specifically bind to the RgpA protein of Porphyromonas gingivalis and is used for treating rheumatoid arthritis.DESCRIPTION OF PRIOR ART

[0002] Rheumatoid arthritis is a chronic systemic inflammatory autoimmune disease. The main causes of rheumatoid arthritis include genetic factors and environmental factors (such as infection and smoking). The pathogenic mechanism of rheumatoid arthritis is an invasion of the synovial membrane of the joints, leading to irreversible damages to the joints.

[0003] Previous studies show that periodontal disease is closely related to rheumatoid arthritis. Porphyromonas gingivalis is the main pathogen that causes periodontal disease. It is the only known microorganism that can produce peptidyl arginine deiminase (PAD). This enzyme can modify arginine into citrulline by citrullination of proteins such as human fibrinogen, a-enolase, etc. The produced autoantibodies, anti-cyclic citrullinated antibodies, are involved in the pathogenesis of rheumatoid arthritis. RgpA (Arg-x-specific proteinase and adhesions) in Porphyromonas gingivalis is considered to be an important virulence factor that can degrade a plurality of host proteins and infringe host defense.

[0004] Enbrel is one of the drugs currently used for treating rheumatoid arthritis. Enbrel is a soluble tumor necrosis factor (TNF) receptor fusion protein (formed by fusing the extracellular domain of human TNF receptor 2 to the Fc portion of human IgGl) that binds to and neutralizes soluble TNFa. TNFa is a key cytokine involved in inflammation and autoimmune responses. Therefore, Enbrel inhibitsactivation of inflammatory cells via inhibition of TNFa activity to reduce productions of cytokines (such as IL-1, IL-6) and prevents further recruitment of immune cells into the joints, thereby suppressing synovial inflammation, joint damages and disease progression of rheumatoid arthritis.DETAILED DESCRIPTION OF THE INVENTION

[0005] The antigen used in the present invention is chicken ovalbumin (OVA) bound to a peptide (SEQ ID NO: 1) of the RgpA protein of Porphyromonas gingivalis (P.g), a pathogen that causes periodontal disease. The antigen is injected into BALB / c mice to induce antibody production. After purification and testing, the purified monoclonal antibody of the present invention is an IgGl kappa antibody, which reacts specifically with the peptide of the RgpA protein. The monoclonal antibody has a low dissociation constant (KD=1.96xlO'9) and a high melting point (ATm=4.8). Moreover, the monoclonal antibody is highly capable of binding to FCyRIIb (KD=690 nM) and FCyR III (Kd=7.6 pM).

[0006] After sequence analysis, the monoclonal antibody purified by the present invention comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain comprises a first heavy chain complementarity determining region (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 2, a second heavy chain complementarity determining region (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 3, and a third heavy chain complementarity determining region (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 4; and the VL domain comprises a first light chain complementarity determining region (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 5, a second light chain complementarity determining region (CDR-L2) comprising the amino acid sequence of RVS, and a third light chain complementarity determining region (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6.

[0007] The therapeutic efficacy of the monoclonal antibody developed by thepresent invention is tested in a collagen-induced rheumatoid arthritis animal model. When the mice with rheumatoid arthritis are treated with the monoclonal antibody, the joint index and ankle circumference of the mice are improved, and the results of histochemical immunoassay also show that inflammation and synovial hyperplasia are reduced, and the joint clearance and cartilage formation are improved. In addition, relevant experimental results show that the monoclonal antibody is more effective in treating mice with rheumatoid arthritis than Enbrel, a drug currently used for treating rheumatoid arthritis.

[0008] The terms "a" or "an" are used herein to describe elements and components of the present invention. The term is used only for convenience and to provide basic concepts of the present invention. In addition, the description should be understood to include one or at least one and unless the context clearly indicates otherwise, the singular terms include the plural and the plural terms include the singular. When used in conjunction with the word "comprising" in the claims, the terms "a" or "an" may mean one or more than one.

[0009] The term "or" as used herein may mean "and / or".

[0010] The present invention provides an isolated antibody which comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain comprises a complementarity determining region (CDR)- HI comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 4; and the light chain variable domain comprises a CDR- L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of RVS, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0011] In one embodiment, the antibody is an IgG antibody. In a preferred embodiment, the antibody is an IgGl antibody. In a more preferred embodiment, the antibody is an IgGl kappa antibody.

[0012] As used herein, the term "antibody" is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies and antibody fragment; as long as they exhibit the desired biological activity, i.e., specific binding to an antigen, it can preferentially recognize a target antigen in a complex mixture of proteins and / or other molecules.

[0013] As used herein, the term "antibody fragment" comprises a portion of a full-length antibody, wherein the portion retains at least one, and may be up to most or all, of the functions normally associated with the portion when present in the full-length antibody, typically referring to the antigen binding site or its variable domain. Accordingly, an antibody fragment comprises the antigen binding site of the full-length antibody and thus retains the ability to bind to antigen. Alternatively, an antibody fragment may also comprise the Fc region and retain at least one biological function normally associated with the Fc region when present in the full-length antibody, such as FcRn binding, antibody half-life modulation, ADCC function, and complement binding. The antibody fragments of the present invention may exist in various forms, including, but not limited to, antigen-binding fragments (Fab, Fab', F(ab')2), and variable fragments (Fv); diabodies; linear antibodies; single-chain antibody molecules (e.g., single-chain fragment variable, scFv); single domain antibodies (for example, variable heavy chain domain (VHH); and multispecific antibodies formed by antibody fragments.

[0014] As used herein, the term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains or an antigen -binding portion thereof interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable (VH) domain and a heavy chain constant domain. Each light chain is composed of a light chain variable (VL) domain and a light chain constant domain. The VH and VL domains can be further subdivided into hypervariable domains, termed as complementarity determining regions (CDRs), and interspersed with regions that are more conserved, termed as frameworkregions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from the amino terminus to carboxyl terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4. The heavy chain variable domain and the light chain variable domain comprise binding domains that interact with antigens. The constant domain of the antibody may mediate bindings of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement pathway.

[0015] Each variable domain (VH or VL) usually has three CDRs, CDR1 , CDR2 and CDR3, respectively. As used herein, the term "complementarity determining region" (abbreviated as CDR; i.e., CDR1, CDR2 and CDR3) refers to the amino acid residues in the variable domain of an antibody, the presence of which is the main contributor to specific antigen binding. The CDRs of the VH are also referred to herein as CDR-H1, CDR-H2 and CDR-H3, respectively, wherein CDR-H1 corresponds to CDR1 of VH, CDR-H2 corresponds to CDR2 of VH, and CDR-H3 corresponds to CDR3 of VH. Likewise, the CDRs of the VL are referred to herein as CDR-L1, CDR-L2, and CDR-L3, respectively, wherein CDR-L1 corresponds to CDR1 of VL, CDR-L2 corresponds to CDR2 of VL, and CDR-L3 corresponds to CDR3 of VL.

[0016] An “isolated” antibody is an antibody that is identified and separated and / or recovered from components of its natural environment. The contaminant components of its natural environment are materials that would interfere with therapeutic uses of the antibodies of the present invention, and may include enzymes, hormones, and other proteinaceous or non -proteinaceous solutes. The isolated antibody includes an antibody in situ within a recombinant cell. The isolated antibody is generally prepared by at least one purification step.

[0017] In some aspects, the antibody has the function of binding to a RgpA protein. In one embodiment, the antibody specifically binds to a RgpA protein. In a preferred embodiment, the antibody specifically binds to a RgpA proteincomprising the amino acid sequence of SEQ ID NO: 1. In a more preferred embodiment, the antibody specifically binds to the HA4 domain in a RgpA protein. In another embodiment, the RgpA protein is from Porphyromonas gingivalis.

[0018] In some aspects, the antibodies of the present invention can treat rheumatoid arthritis.

[0019] The present invention provides a composition, which comprises the aforementioned antibody.

[0020] The present invention also provides a method for treating rheumatoid arthritis, which comprises administering a composition to a subject suffering from rheumatoid arthritis, wherein the composition comprises an antibody, and the antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 3, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 4; and the light chain variable domain comprises a CDR- L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of RVS, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0021] The present invention further provides uses of a composition for preparing drugs for treating rheumatoid arthritis, wherein the composition comprises an antibody, and the antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 3, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 4; and the light chain variable domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of RVS, and a CDR-L3comprising the amino acid sequence of SEQ ID NO: 6.

[0022] As used herein, the term "treatment" refers to all methods that can alleviate, block, suppress, control, terminate or reverse progression of the diseases described herein, but does not necessarily mean complete elimination of all symptoms of the diseases.

[0023] As used herein, "rheumatoid arthritis" refers to a type of autoimmune disease characterized by synovial joint inflammations throughout the body. The early symptoms of the disease include joint pain, which may progress into joint deformation or damages to body organs such as blood vessels, heart, lungs, skin and muscles.

[0024] As used herein, the term "subject" refers to an animal including a human. Thus, the term "subject" includes any mammal that can benefit from the methods of the present invention. The term "mammal" refers to all members of the class Mammalia. In one embodiment, the subject is a human.

[0025] In some aspects, the antibody, the composition or the drug can be delivered via any physiologically acceptable route. These route include, but are in no way limited to, parenteral administration, systemic administration, oral administration, nasal administration, rectal administration, intraperitoneal injection, intravascular injection, subcutaneous injection, transdermal administration, inhalation administration, and intramuscular injection. As used herein, the term "parenteral" includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intra-articular cavity, intrastemal, intraspinal, intralesional, and intracranial injection or infusion techniques. The appropriate routes and methods of administration may vary depending on many factors, for example, the specific therapeutic agent being used, the desired rate of absorption, the specific formulation or dosage form being used, the type or severity of conditions being treated, the specific site of action, and conditions of the patient, and can be readily selected by one skilled in the art.

[0026] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any inactive substance suitable for use in a formulation for delivery of a therapeutic agent. The carrier can be an anti-adherent, binder, coating agent, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifier, buffer and the likes. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), glucose, vegetable oils (e.g., olive oil), saline, buffer solution, buffered saline solution, and isotonic agents, for example, sugar, polyol, sorbitol, and sodium chloride.

[0027] In the present invention, the composition comprises an effective amount of the antibody of the present invention. As used herein, the term "effective amount" means an amount sufficient to improve a clinically significant condition in a subject, or to delay, minimize or alleviate one or more symptoms associated with a disease or disorder, or to cause desired beneficial physiological changes in a subject.

[0028] In one embodiment, the effective amount of the antibody ranges from 0.01 to 1000 mg / kg body weight of the subject. In a preferred embodiment, the effective amount of the antibody ranges from 0.1 to 100 mg / kg body weight of the subject. In a more preferred embodiment, the effective amount of the antibody ranges from 1 to 30 mg / kg body weight of the subject.

[0029] In one embodiment, the antibody is administered twice a week. In a preferred embodiment, the antibody is administered once a week. In another embodiment, the antibody is administered weekly for at least three weeks. In a preferred embodiment, the antibody is administered weekly for at least four weeks. In a more preferred embodiment, the antibody is administered weekly for at least six weeks.

[0030] In summary, the present invention has developed a novel monoclonal antibody that has excellent therapeutic effects in collagen-induced rheumatoid arthritis animal models. The present invention believes that this novel monoclonal antibody achieves the goal of treating rheumatoid arthritis through a new signal transduction pathway, which is different from the traditional treatment of target inflammatory factors in a way of specifically blocking TNF.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 shows the potency assay of the anti -BRI antibody of the present invention.

[0032] FIG. 2 shows that the anti-BRl antibody of the present invention can recognize HA4 antigen.

[0033] FIG. 3 shows the ankle circumference and joint index measured after the BR2 monoclonal antibody is used for treating the collagen induced arthritis (CIA) animal model. N: Normal group, n: number.

[0034] FIG. 4 shows that after being treated with the BR2 monoclonal antibody, damages to the articular cartilage of the CIA animal model are alleviated. N: Normal group. Scale bar is 100 pm.

[0035] FIG. 5 shows the cartilage tissue content of the CIA animal model evaluated by using Safranin O staining after being treated with BR2 monoclonal antibody. N: Normal group.

[0036] FIG. 6 shows the expression of inflammatory indicators of the CIA animal model after being treated with BR2 monoclonal antibody. N: Normal group.EXAMPLES

[0037] The examples of the present invention may have different implementation contents and are not limited to the examples given below. Thefollowing examples are merely representative of various aspects and features of the present invention.

[0038] Methods and results

[0039] In the present invention, 0.1 mg of chicken ovalbumin (OVA) bound to a peptide of the RgpA protein of Porphyromonas gingivalis (P.g) (abbreviated as BRI, whose sequence is YCVEVKYAAGVSPKVCVDYIPDGVA (SEQ ID NO: 1) was used as an antigen (to enhance immunity), and this antigen was administered into the body of BALB / c mice once every two weeks (8 times in total) to immunize and produce antibodies. The mouse spleen cells were fused with myeloma cells to obtain three hybridoma cell lines (Cl, C2 and C3, a total of 3 cell lines).

[0040] In the present invention, the following methods were used to test the properties and efficacy of the purified anti-BRl antibodies from the above cell lines.

[0041] Based on the antibody typing tests, the anti-BRl antibodies purified from Cl, C2 and C3 cell lines were IgGl kappa antibodies.

[0042] In the present invention, ELISA was to quantify binding abilities of the anti-BRl antibodies to BRI antigen. As shown in FIG. 1, both Cl and C3 were able to react with BRI antigen, and the EC50 was approximately 6.25 ng / mL; and the binding abilities of Cl and C3 were better than that of C2.

[0043] The present invention used Western blot to confirm whether the anti-BRl monoclonal antibodies obtained in the present invention could recognize the HA4 domain (containing the BRI peptide) of P.g bacteria and its target antigen RgpA. Proteins of various doses were subjected to SDS-PAGE for protein isolation, and after being transferred to PVDF membranes, IgG and anti-BRl antibodies were diluted at 1 :1000 and reacted with antigens. The secondary antibody used in the present invention was anti-mouse IgG conjugate HRP, which reacted with aprimary antibody and then was developed by ECL. As shown in FIG. 2, since the HA4 domain of RgpA in the pathogen P.g and its lysate had the BRI peptide for producing antibodies, it was confirmed that the monoclonal antibodies prepared by the present invention were able to specifically recognize the proteins with BRI antigens, and the group treated with IgG had no reaction with HA4.

[0044] In the present invention, the mouse antibody (abbreviated as BR2) obtained from the C3 cell line was used in subsequent experiments to analyze the antibody characteristics. Through sequence analysis, the BR2 monoclonal antibody comprised a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprised three CDR sequences, CDR-H1, CDR-H2 and CDR-H3, the CDR-H1 comprised the sequence of GYSFTGYT (SEQ ID NO: 2), the CDR-H2 comprised the sequence of IIPYNGDT (SEQ ID NO: 3), and the CDR-H3 comprised the sequence of ARLSSSGTY (SEQ ID NO: 4); and the light chain variable domain comprised three CDR sequences, CDR-L1, CDR-L2 and CDR-L3, wherein the CDR-L1 comprised the sequence of QSIVHSNGNTY (SEQ ID NO: 5), the CDR-L2 comprised the sequence of RVS, and the CDR-L3 comprised the sequence of FQGSHVPLT (SEQ ID NO: 6). Through BIAcore intermolecular interaction force analysis, it was found that the BR2 antibody specifically reacted with the immune peptide BRI, and the dissociation constant of the antigen-antibody affinity was low (Kd=l 9.6x1 O'9) and the melting point was high (ATm=4.8). In addition, it was able to bind to FCyRIIb (Kd=690 nM) and FCyR III (Kd=7.6 pM), especially FCyRIIb.

[0045] Evaluation of therapeutic effects of BR2 monoclonal antibody in rheumatoid arthritis rat models

[0046] In the present invention, type II collagen was used to induce arthritis in 6-week-old male SD rats. This animal model was a commonly used model for studying rheumatoid arthritis. It was treated after two inductions with type IIcollagen (day 0 and day 7). The experiment was divided into the following groups, and each group had 10 rats. The normal group (N) was a group of normal rats that were not treated. The other groups were rat models with collagen-induced arthritis (CIA). The control group was a group of CIA rats that were not treated and injected with phosphate-buffered saline (PBS) or IgG antibody. The comparison group was a group of CIA rats that were treated with Enbrel, a commercially available TNF biologic reagent for treating rheumatoid arthritis, wherein the amount of Enbrel administered to the CIA rats was 4.5 mg / kg, once a week, by subcutaneous injection. The experimental group was a group of CIA rats that were treated with the BR2 antibody of the present invention, wherein the BR2 antibody was administered to the CIA rats in the amount of 9 mg / kg, once a week, by subcutaneous injection. The rats were sacrificed on the 27th day after being treated, and the degree of ankle swelling was measured and the joint sections were stained for analysis.

[0047] The following method was used for post-treatment evaluation: ankle circumference, joint index, H&E staining and Safranin O staining to observe tissue morphology, and histochemical immunoassay to detect the expression of inflammatory cytokines.

[0048] (1) Quantification of ankle circumference: The ankle circumference was determined by two laboratory technicians using the following geometric formula: 2n(^a2+b2 / 2), where “a” was the lateral diameter of the ankle and “b” was the anterior-posterior diameter of the ankle.

[0049] (2) Joint index was scored on a scale from 0 to 4, where 1 = mild swelling and / or erythema, 2 = low to moderate edema, 3 = significant edema and limited joint use, and 4 = excessive edema with joint stiffness.

[0050] (3) H&E staining was used to observe tissue morphology, synovial hyperplasia thickness, and joint clearance size.

[0051] (4) Safranin O staining was used to observe cartilage tissue. Cartilage and mucoprotein were stained orange-to-red, cell nuclei were stained black and the background was stained cyan. When damages occurred, the orange-to-red stain was reduced and the cartilage content was quantified by using the imaging software Image J.

[0052] (5) Histochemical immunoassay was used for detecting protein expression. In the present invention, major inflammatory biomarkers (IL-6, TNFa, IL-17A) were selected to detect antigen expression. For the positive reaction quantification method, the same size range was selected to quantify the number of positive reaction cells in corresponding area, for example, presented as IL6 positive cells %.

[0053] Treatment results

[0054] (i) Ankle circumference and joint index: As shown in FIG. 3, BR2 monoclonal antibody treatment improved the ankle circumference (degree of swelling) and joint index (severity of disease).

[0055] (ii) Tissue morphological observation by H&E staining and Safranin O staining: The morphological observation of tissue sections was performed by H&E staining. The results showed that type II collagen induced synovial hyperplasia and cartilage destruction, while treatment with BR2 monoclonal antibody could effectively alleviate a narrowing of the joint clearance due to synovial hyperplasia and surface cartilage erosion (as shown in FIG. 4). Safranin O staining was used to observe cartilage tissues, and the BR2 monoclonal antibody was used in the present invention to treat and confirm that BR2 monoclonal antibody was able to block cartilage destruction (as shown in FIG. 5).

[0056] (iii) Detection of inflammatory factor expression by histochemical immunoassay: Collagen induced the expression of inflammatory factors, IL-6, TNFa and IL- 17 A, but the present invention was able to effectively reduce theexpression of inflammatory factors after treatment with BR2 monoclonal antibody (as shown in FIG. 6).

[0057] The present invention is appropriately described so that it may be practiced with elements or limitations not specifically disclosed herein. The terms that are used to describe are not limiting. No distinction is made between the expressions and descriptions using these terms and any equivalents thereto, but it should be recognized that the rights within the present invention may be modified. 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Claims

WHAT IS CLAIMED IS:

1. An isolated antibody which comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain comprises a CDR-HI comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 4; and the VL domain comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of RVS, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

2. The isolated antibody of claim 1, which is an IgG antibody.

3. The isolated antibody of claim 1, which has a function of binding to a RgpA protein.

4. The isolated antibody of claim 3, wherein the RgpA protein is from Porphyromonas gingivalis.

5. A composition which comprises the isolated antibody of claim 1.

6. A method for treating rheumatoid arthritis, which comprises administering a composition to a subject suffering from rheumatoid arthritis, wherein the composition comprises the isolated antibody of claim 1.

7. The method of claim 6, wherein the effective amount of the isolated antibody ranges from 0.01 to 1000 mg / kg body weight of the subject.

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