Method for treating psoriasis plaque by using anti-IL23p19 antibody in subjects who have previously undergone biological treatment on psoriasis plaque

Abstract

A method of treating a psoriasis plaque subject who has previously been treated with a biological agent, comprising administering to the subject an effective amount of an anti-IL-23p19 subunit antibody, and to the use of an anti-IL-23p19 antibody to treat a psoriasis plaque subject who has previously been treated with a biological agent.

Description

Methods for switching patients with plaque psoriasis who have previously received biologics to anti-IL23p19 antibodies Technical Field

[0001] The present invention relates to the use of anti-IL-23p19 antibodies to treat plaque psoriasis subjects who have previously received biologic treatment. The present invention also relates to a method for treating plaque psoriasis subjects who have previously received biologic treatment for plaque psoriasis, comprising administering an effective amount of anti-IL-23p19 antibodies to the subject. Background Art

[0002] IL-23 is a heterodimeric cytokine that is a member of the IL-12 family and consists of a p40 subunit and a p19 subunit. IL-23 activates signaling pathways by binding to the IL-23 receptor (IL-23R) and the β1 subunit of the IL-12 receptor (IL-12Rβ1). Although IL-23 and IL-12 are closely related in structure, these two cytokines have distinct biological functions, with IL-12 and IL-23 driving Th1 and Th17 cell responses, respectively. Alone or with the help of other cytokines, such as transforming growth factor (TGF)-β, IL-6, or IL-1β, IL-23 can induce the differentiation of naive CD4+ T cells into Th17 cells and promote the proliferation, differentiation, and maintenance of Th17 and innate immune cells. Th17 cells stimulate the production of IL-17, IL-22, tumor necrosis factor (TNF)-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulate local tissue inflammation and other immune-mediated pathological processes through a broad immune-mediated inflammatory state. Chronic inflammation caused by dysregulated IL-23 / Th17 / IL-17 responses is the pathophysiological basis of multiple autoimmune diseases, including psoriasis, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, and asthma.

[0003] Psoriasis is a chronic, recurrent, inflammatory, systemic disease mediated by immune factors, caused by a combination of genetics and the environment. It can occur in all age groups, regardless of gender. Typical clinical manifestations include scaly erythema or plaques, which can be localized or widespread. Psoriasis is non-contagious, difficult to treat, and often lifelong. Psoriasis can be divided into psoriasis vulgaris (including guttate psoriasis and plaque psoriasis), pustular psoriasis, erythrodermic psoriasis, and arthritic psoriasis.

[0004] Currently, the main systemic drug treatments for psoriasis in China include methotrexate (MTX), cyclosporine A, retinoids, and biologics. In recent years, monoclonal antibody biologics targeting inflammatory cytokines have been used to treat severe psoriasis that is poorly treated with traditional systemic drugs, severely impacts quality of life, and is accompanied by significant joint symptoms. These include tumor necrosis factor α (TNF-α) antagonists (etanercept, infliximab, adalimumab); IL-12 / 23 antagonists (ustekinumab); and IL-17A antagonists (secukinumab). Guselkumab (Johnson & Johnson), Risankizumab (AbbVie), and Tildrakizumab (Merck) are humanized IgG1 monoclonal antibodies that bind to the IL-23p19 subunit and have been developed in recent years. They have shown significant efficacy in the treatment of plaque psoriasis and have been used in many countries to treat moderate to severe plaque psoriasis.

[0005] With biologics, some patients experience a loss of response, or recurrence of symptoms, after a certain period of treatment. This necessitates the introduction of new treatments to effectively treat these patients. Currently, the use of biologics by psoriasis patients in China remains very low, and there remains a significant demand for effective, safe, and cost-effective domestic biologics. Furthermore, for patients whose symptoms have been alleviated with existing biologics, switching to a treatment with a simpler, more convenient route of administration and the ability to maintain symptom relief would increase patient compliance and be more beneficial.

[0006] SUMMARY OF THE INVENTION

[0007] The purpose of the present invention is to provide a method for switching subjects who have previously received biologics for the treatment of plaque psoriasis to recombinant anti-interleukin IL-23p19 antibodies for the treatment of plaque psoriasis, so as to meet the unmet needs in the art.

[0008] use

[0009] The present invention provides a use of a recombinant anti-interleukin IL23p19 antibody in switching a subject who has previously received a biological agent for plaque psoriasis to the antibody for the treatment of plaque psoriasis.

[0010] In a first aspect, the present invention relates to use of a recombinant anti-interleukin IL23p19 antibody in the preparation of a medicament for treating plaque psoriasis in a subject.

[0011] In a second aspect, the present invention relates to a recombinant anti-interleukin IL23p19 antibody for use in treating plaque psoriasis in a subject.

[0012] For the first and second aspects, further embodiments thereof are as follows:

[0013] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region comprises SEQ ID NO.1 or consists of SEQ ID NO.2, the amino acid sequence of CDR3 of the heavy chain variable region comprises SEQ ID NO.3 or consists of SEQ ID NO.4; the amino acid sequence of CDR1 of the light chain variable region comprises SEQ ID NO.4, the amino acid sequence of CDR2 of the light chain variable region comprises SEQ ID NO.5, and the amino acid sequence of CDR3 of the light chain variable region comprises SEQ ID NO.6 or consists of SEQ ID NO.6.

[0014] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0015] In some embodiments, the recombinant anti-interleukin IL23p19 antibody is an IgG1 antibody, preferably comprising SEQ ID NO: 9 or a heavy chain sequence at least 90%, 95%, 98% or 99% identical thereto and SEQ ID NO: 10 or a light chain sequence at least 90%, 95%, 98% or 99% identical thereto.

[0016] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises the heavy chain shown in SEQ ID NO:9 and the light chain shown in SEQ ID NO:10.

[0017] In some embodiments, the subject has previously received a biologic for plaque psoriasis. In some embodiments, the subject has previously received a biologic for plaque psoriasis and is then switched to an antibody of the invention for plaque psoriasis treatment.

[0018] In some embodiments, the subject may be a user who has been using the biologic according to the prescribed dosage regimen (for at least 4 months) or a user who has not been using the biologic according to the prescribed dosage regimen (for at least 4 months between the last biologic and the first biologic).

[0019] In some embodiments, the subject has lost or had an inadequate response to a previous biologic therapy. In some embodiments, the subject is currently receiving biologic therapy but has lost or had an inadequate response. In some embodiments, the subject has an sPGA score of ≥2, or a cumulative body surface area of ​​lesions of ≥3%, or has not achieved a 75% improvement in PASI after receiving a biologic.

[0020] In some embodiments, for subjects who have lost response or responded poorly to previous biologic treatment, the administration of the antibodies of the present invention includes a treatment phase and a maintenance phase. In some embodiments, during the treatment phase, the frequency of administration of the antibodies of the present invention is once a day, twice a week, once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or longer. The administration cycle of the antibodies of the present invention can be one week, two weeks, three weeks, one month, two months, three months or longer, and the interval between each administration cycle can be the same or different. In a preferred embodiment, the treatment phase includes administering an anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively. In some embodiments, during the maintenance phase, the frequency of administration of the antibodies of the present invention is once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer. In some embodiments, the maintenance phase lasts for at least 24, 28, 32, 36, 40, 44, 48 weeks or longer. In a preferred embodiment, the maintenance phase is administered once every 12 weeks until the final administration at the end of week 32. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic treatment, anti-IL-23p19 antibodies are administered at weeks 0, 4, and 8, respectively, and then administered once every 12 weeks. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic treatment, anti-IL-23p19 antibodies are administered at weeks 0, 4, and 8, respectively, and then administered once every 12 weeks until the final administration at the end of week 32.

[0021] In some embodiments, the dose per administration is selected from 100 mg-1000 mg, preferably 150 mg-800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the dose per administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose per administration is 200 mg.

[0022] In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, followed by 200 mg of anti-IL-23p19 antibody every 12 weeks thereafter. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, followed by 200 mg of anti-IL-23p19 antibody every 12 weeks thereafter until the final dose at week 32.

[0023] In some embodiments, the subject is a responder to a prior biologic. In some embodiments, the subject is currently receiving a biologic and is still responding. In some embodiments, the subject has an sPGA score of 0 or 1 and a cumulative body surface area of ​​lesions <3%, or has achieved a PASI improvement of 75% or greater after taking a biologic.

[0024] In some embodiments, for subjects who have previously responded to biologic therapy, the antibodies of the present invention are administered daily, twice a week, weekly, every two weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, or longer. The administration period for the antibodies of the present invention can be one week, two weeks, three weeks, one month, two months, three months, or longer, and the intervals between each administration period can be the same or different. In a preferred embodiment, the anti-IL-23p19 antibody is administered at week 0. In some embodiments, after administration at week 0, the administration interval is maintained at once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer. In some embodiments, the maintenance administration continues for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In a preferred embodiment, the maintenance administration is administered every 12 weeks thereafter. In a preferred embodiment, for subjects who have previously responded to biologic therapy, the anti-IL-23p19 antibody is administered at week 0 and every 12 weeks thereafter. In one embodiment, for subjects who have previously responded to biologic therapy, the anti-IL-23p19 antibody is administered at week 0 and every 12 weeks thereafter until the final dose at week 36.

[0025] In some embodiments, the dose per administration is selected from 100 mg-1000 mg, preferably 150 mg-800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the dose per administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose per administration is 200 mg.

[0026] In some embodiments, for subjects who have previously responded to biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at week 0, and 200 mg of anti-IL-23p19 antibody is administered every 12 weeks thereafter. In some embodiments, for subjects who have previously responded to biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at week 0, and 200 mg of anti-IL-23p19 antibody is administered every 12 weeks thereafter until the final dose at week 36.

[0027] In some embodiments, the biologic agent comprises a tumor necrosis factor alpha (TNF-α) inhibitor / antagonist and / or an IL-17A inhibitor / antagonist.

[0028] In some embodiments, the TNF-α inhibitor / antagonist drugs include etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab pegol (Cimzia).

[0029] In some embodiments, the IL-17A inhibitor / antagonist drugs include secukinumab (Cosentyx) and ixekizumab (Taltz).

[0030] In some embodiments, the anti-IL-23p19 antibodies of the present invention are formulated and administered as liquid pharmaceutical compositions. Suitable carriers and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils may be used as solvents or suspending media, where appropriate. For this purpose, any mixture of non-volatile mineral or non-mineral oils, including synthetic mono- or diglycerides, may be utilized. Furthermore, fatty acids such as oleic acid may also be used to prepare injectables.

[0031] In some embodiments, the pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention is a solution or dry powder formulation for injection. For example, the composition is a lyophilized powder, which can be reconstituted in a pharmaceutically acceptable liquid carrier to form an injection. The pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution.

[0032] In some embodiments, the anti-IL-23p19 antibodies of the invention are administered topically.

[0033] In some embodiments, the anti-IL-23p19 antibodies of the invention are administered by subcutaneous injection.

[0034] In some embodiments, following administration, the subject experiences no serious adverse events.

[0035] In some embodiments, following administration, the subject experiences adverse events at a rate comparable to that of subjects receiving a placebo.

[0036] In some embodiments, the subject is a human.

[0037] In some embodiments, administering the anti-IL-23p19 antibodies of the present invention to a subject can improve psoriasis lesions and improve the quality of life of such subjects who have previously lost response or responded poorly to biologic treatment. In some embodiments, administering the anti-IL-23p19 antibodies of the present invention to a subject can enable such subjects who have previously responded to biologic treatment to continue to maintain their response to treatment or improve their response (e.g., improve their lesions) and maintain or improve their current quality of life.

[0038] In a preferred embodiment, the anti-IL-23p19 antibody of the present invention can achieve one or more of the following effects in a subject:

[0039] Previously, the longest dosing interval for IL-17 and TNF drugs was once every four weeks, which was relatively frequent and could easily cause inconvenience to patients. However, when the anti-IL-23p19 antibody of the present invention is administered using the administration method of the present invention, the dosing frequency is reduced, making administration simpler and more convenient, while also improving patient compliance and quality of life.

[0040] Research data showed that after subjects with baseline clinical response switched to anti-IL23P19 antibody treatment, 85.3% of subjects still maintained clinical response (cumulative body surface area of ​​lesions <3%, and static physician global score sPGA 0 or 1) at week 16, and the rate remained at around 85% from week 16 to week 36 of observation; after subjects with baseline clinical non-response switched to anti-IL23P19 antibody treatment, some subjects began to respond, and the response rate gradually increased to 52.1% by week 16, and remained at a similar rate after week 16.

[0041] Treatment

[0042] In a third aspect, the present invention relates to a method for treating plaque psoriasis in a subject, the method comprising administering to the subject an effective amount of a recombinant anti-interleukin IL23p19 antibody.

[0043] In a fourth aspect, the present invention provides a method for switching a subject who has previously received a biologic agent for plaque psoriasis to a recombinant anti-interleukin IL23p19 antibody for the treatment of plaque psoriasis.

[0044] For the third and fourth aspects, further embodiments are as follows:

[0045] In some embodiments, the anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region comprises SEQ ID NO.1 or consists of SEQ ID NO.2, the amino acid sequence of CDR3 of the heavy chain variable region comprises SEQ ID NO.3 or consists of SEQ ID NO.4; the amino acid sequence of the light chain variable region CDR1 of the antibody comprises SEQ ID NO.4 or consists of SEQ ID NO.5, the amino acid sequence of the light chain variable region CDR2 comprises SEQ ID NO.5, and the amino acid sequence of the light chain CDR3 variable region comprises SEQ ID NO.6 or consists of SEQ ID NO.6.

[0046] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90%, 95%, 98% or 99% identity thereof, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence having at least 90%, 95%, 98% or 99% identity thereof.

[0047] In some embodiments, the recombinant anti-interleukin IL23p19 antibody is an IgG1 antibody, preferably comprising SEQ ID NO: 9 or a heavy chain sequence at least 90%, 95%, 98% or 99% identical thereto and SEQ ID NO: 10 or a light chain sequence at least 90%, 95%, 98% or 99% identical thereto.

[0048] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises the heavy chain shown in SEQ ID NO:9 and the light chain shown in SEQ ID NO:10.

[0049] In some embodiments, the subject has previously received a biologic for plaque psoriasis. In some embodiments, the subject has previously received a biologic for plaque psoriasis and is then switched to an antibody of the invention for plaque psoriasis treatment.

[0050] In some embodiments, the subject may be a user who has been using the biologic according to the prescribed dosage regimen (for at least 4 months) or a user who has not been using the biologic according to the prescribed dosage regimen (for at least 4 months between the last biologic and the first biologic).

[0051] In some embodiments, the method comprises administering an anti-IL-23p19 antibody to a subject who has previously received a biologic for plaque psoriasis.

[0052] In some embodiments, the subject has lost or had an inadequate response to a previous biologic therapy. In some embodiments, the subject is currently receiving biologic therapy but has lost or had an inadequate response. In some embodiments, the subject has an sPGA score of ≥2, or a cumulative body surface area of ​​lesions of ≥3%, or has not achieved a 75% improvement in PASI after receiving a biologic.

[0053] In some embodiments, for subjects who have lost response or responded poorly to previous biologic treatment, the methods of the present invention include administering the antibodies of the present invention in two stages: a treatment phase and a maintenance phase. In some embodiments, during the treatment phase, the antibodies of the present invention are administered daily, twice a week, weekly, biweekly, four weeks, five weeks, six weeks, seven weeks, eight weeks, or longer. The administration cycle for the antibodies of the present invention can be one week, two weeks, three weeks, one month, two months, three months, or longer, and the intervals between each administration cycle can be the same or different. In a preferred embodiment, the treatment phase includes administering the anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively. In some embodiments, during the maintenance phase, the antibodies of the present invention are administered once every four weeks, eight weeks, twelve weeks, sixteen weeks, twenty weeks, or longer. In some embodiments, the maintenance phase lasts for at least 24, 28, 32, 36, 40, 44, or 48 weeks or longer. In a preferred embodiment, the maintenance phase is administered once every 12 weeks until the final administration at the end of week 32. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic treatment, anti-IL-23p19 antibodies are administered at weeks 0, 4, and 8, respectively, and then administered once every 12 weeks. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic treatment, anti-IL-23p19 antibodies are administered at weeks 0, 4, and 8, respectively, and then administered once every 12 weeks until the final administration at the end of week 32.

[0054] In some embodiments, the dose per administration is 100 mg-1000 mg, preferably 150 mg-800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the dose per administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose per administration is 200 mg.

[0055] In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, followed by 200 mg of anti-IL-23p19 antibody every 12 weeks thereafter. In some embodiments, for subjects who have lost response or have had an inadequate response to previous biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, followed by 200 mg of anti-IL-23p19 antibody every 12 weeks thereafter until the final dose at week 32.

[0056] In some embodiments, the subject is a responder to prior biologic therapy. In some embodiments, the subject is currently receiving biologic therapy and is still responding. In some embodiments, the subject has an sPGA score of 0 or 1 and a cumulative body surface area of ​​lesions <3%, or has achieved a PASI improvement of 75% or greater after taking a biologic.

[0057] In some embodiments, for subjects who have previously responded to biologic therapy, the frequency of administration of the antibodies of the present invention is once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer. The administration cycle of the antibodies of the present invention can be one week, two weeks, three weeks, one month, two months, three months, or longer, and the intervals between each administration cycle can be the same or different. In a preferred embodiment, the anti-IL-23p19 antibody is administered at week 0. In some embodiments, after administration at week 0, administration is maintained at once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer. In some embodiments, the maintenance administration continues for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In a preferred embodiment, the maintenance administration is administered once every 12 weeks for at least 24, 28, 32, 36, 40, 44, 48 weeks, or longer. In a preferred embodiment, for subjects who have previously responded to biologic therapy, the anti-IL-23p19 antibody is administered at week 0 and then every 12 weeks thereafter for at least 24, 28, 32, 36, 40, 44, 48 weeks or longer. In one embodiment, for subjects who have previously responded to biologic therapy, the anti-IL-23p19 antibody is administered at week 0 and then every 12 weeks thereafter until the final dose at week 36.

[0058] In some embodiments, the dose per administration is selected from 100 mg-1000 mg, preferably 150 mg-800 mg, for example 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg. In some embodiments, the dose per administration is 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg of anti-IL-23p19 antibody. In a preferred embodiment, the dose per administration is 200 mg.

[0059] In some embodiments, for subjects who have previously responded to biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at week 0, and 200 mg of anti-IL-23p19 antibody is administered every 12 weeks thereafter. In some embodiments, for subjects who have previously responded to biologic therapy, 200 mg of anti-IL-23p19 antibody is administered at week 0, and 200 mg of anti-IL-23p19 antibody is administered every 12 weeks thereafter until the final dose at week 36.

[0060] In some embodiments, the biologic agent comprises a tumor necrosis factor alpha inhibitor / antagonist and / or an IL-17A inhibitor / antagonist.

[0061] In some embodiments, the TNF-α inhibitor / antagonist drugs include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

[0062] In some embodiments, the IL-17A inhibitor / antagonist drugs include secukinumab and ixekizumab.

[0063] In some embodiments, the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

[0064] In some embodiments, the anti-IL-23p19 antibodies of the present invention are formulated and administered as liquid pharmaceutical compositions. Suitable carriers and solvents include water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils may be used as solvents or suspending media, where appropriate. For this purpose, any mixture of non-volatile mineral or non-mineral oils, including synthetic mono- or diglycerides, may be utilized. Furthermore, fatty acids such as oleic acid may also be used to prepare injectables.

[0065] In some embodiments, the pharmaceutical composition comprising the anti-IL-23p19 antibody of the present invention is a solution or dry powder formulation for injection. For example, the composition is a lyophilized powder, which can be reconstituted in a pharmaceutically acceptable liquid carrier to form an injection. The pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution.

[0066] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the invention is administered topically.

[0067] In some embodiments, the anti-IL-23p19 antibody or pharmaceutical composition of the invention is administered by subcutaneous injection.

[0068] In some embodiments of the aforementioned methods, following administration, the subject does not experience a serious adverse event.

[0069] In some embodiments of the above methods, following administration, the subject experiences an adverse event at a rate comparable to that of subjects receiving a placebo.

[0070] In some embodiments of the above methods, the subject is a human.

[0071] The method of the present invention for treating plaque psoriasis by converting a subject who has previously received biologic treatment for plaque psoriasis to a recombinant anti-interleukin IL23p19 subunit antibody can treat plaque psoriasis subjects who are currently receiving biologic treatment but have lost response or have poor efficacy, thereby improving psoriasis lesions and quality of life in such subjects. In addition, it can also treat plaque psoriasis subjects who are currently receiving biologic treatment and are still responding, thereby allowing such subjects to continue to maintain a responsive state or improve their response (e.g., improve psoriasis lesions) to treatment and continue to maintain or improve their current quality of life.

[0072] Compared to similar products, the method of the present invention can include both psoriasis subjects who have failed to respond to biologic treatment and those who have responded. Furthermore, the actual clinical use of biologics does not always follow the instructions in the package insert. The method of the present invention has a certain therapeutic effect on subjects who follow the instructions and switch to the anti-IL23p19 antibody of the present invention, as well as subjects who do not follow the instructions and switch to the anti-IL23p19 antibody of the present invention, thus covering a wider range of subjects.

[0073] In a preferred embodiment, the anti-IL-23p19 antibody of the present invention can achieve one or more of the following effects in a subject:

[0074] Previously, the longest dosing interval for IL-17 and TNF drugs was once every four weeks, which was relatively frequent and could easily cause inconvenience to patients. However, when the anti-IL-23p19 antibody of the present invention is administered using the administration method of the present invention, the dosing frequency is reduced, making administration simpler and more convenient, while also improving patient compliance and quality of life.

[0075] Research data showed that after subjects with baseline clinical response switched to anti-IL23P19 antibody treatment, 85.3% of subjects still maintained clinical response (cumulative body surface area of ​​lesions <3%, and static physician global score sPGA 0 or 1) at week 16, and the rate remained at around 85% from week 16 to week 36 of observation; after subjects with baseline clinical non-response switched to anti-IL23P19 antibody treatment, some subjects began to respond, and the response rate gradually increased to 52.1% by week 16, and remained at a similar rate after week 16.

[0076] It should be understood that the technical solutions obtained by any combination of any technical features recorded in the first to second aspects above and any technical features of the technical solutions recorded in the third to fourth aspects are also included in the present invention.

[0077] Single-dose drug unit or complete drug packaging box

[0078] In a fifth aspect, the present invention relates to a single pharmaceutical dosage unit, characterized in that it comprises the anti-IL23p19 antibody of the present invention.

[0079] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region comprises SEQ ID NO.1 or consists of SEQ ID NO.2, the amino acid sequence of CDR3 of the heavy chain variable region comprises SEQ ID NO.3 or consists of SEQ ID NO.4; the amino acid sequence of CDR1 of the light chain variable region comprises SEQ ID NO.4, the amino acid sequence of CDR2 of the light chain variable region comprises SEQ ID NO.5, and the amino acid sequence of CDR3 of the light chain variable region comprises SEQ ID NO.6 or consists of SEQ ID NO.6.

[0080] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0081] In some embodiments, the recombinant anti-interleukin IL23p19 antibody is an IgG1 antibody, preferably comprising SEQ ID NO: 9 or a heavy chain sequence at least 90%, 95%, 98% or 99% identical thereto and SEQ ID NO: 10 or a light chain sequence at least 90%, 95%, 98% or 99% identical thereto.

[0082] In some embodiments, the recombinant anti-interleukin IL23p19 antibody comprises the heavy chain shown in SEQ ID NO:9 and the light chain shown in SEQ ID NO:10.

[0083] In some embodiments, the single pharmaceutical dosage unit comprises the following dose of the anti-IL-23p19 antibody: 10 mg-1000 mg, preferably 50 mg-800 mg, more preferably 50 mg-500 mg fixed dose, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 610 mg, 620 mg, 630 mg, 640 mg 0mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or 1000mg.

[0084] In some embodiments, the single-dose unit is a single-dose unit packaged in a prefilled autoinjector pen.

[0085] In a sixth aspect, the present invention relates to a complete pharmaceutical packaging kit, characterized in that it comprises the anti-IL23p19 antibody of the present invention as described in any one of the above-mentioned single pharmaceutical dosage unit embodiments.

[0086] In a seventh aspect, the present invention relates to use of the single-dose pharmaceutical unit as described above or the complete pharmaceutical kit as described above in the preparation of a medicament for treating plaque psoriasis.

[0087] In some embodiments, a single pharmaceutical dosage unit as described above or a kit of parts as described above is used to treat plaque psoriasis.

[0088] It should be understood that the technical solutions obtained by any combination of any technical features recorded in the fifth to seventh aspects above and any technical features of the technical solutions recorded in the first to fourth aspects are also included in the present invention.

[0089] Other embodiments of the present invention will become apparent by reference to the detailed description which follows.

[0090] Detailed Description of the Invention

[0091] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be varied. In addition, the terminology used herein is only for describing specific embodiments and is not intended to be limiting.

[0092] definition

[0093] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

[0094] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0095] The term "and / or" when used to link two or more alternatives should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0096] As used herein, the terms "comprising" or "including" are intended to include the recited elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms "comprising" or "including" are used, unless otherwise indicated, the context of consisting of the recited elements, integers, or steps is also encompassed. For example, when reference is made to an antibody variable region "comprising" a specific sequence, it is intended to encompass an antibody variable region consisting of that specific sequence.

[0097] The p19 subunit of IL-23 (also referred to herein as "IL-23p19" and "p19 subunit") is a 189 amino acid polypeptide containing a 21-amino acid leader sequence (Oppmann et al., Immunity 13:715 (2000), SEQ ID NO:181) and comprises four packed α-helices, designated A, B, C, and D, with an up-up-down-down topology. The four helices are connected by three polypeptide loops. The AB and CD loops are made relatively long because they connect the parallel helices. The short BC loop connects the antiparallel B and C helices. The p19 subunit of IL-23 is a member of the IL-6 family of helical cytokines. This family of cytokines binds to its cognate receptor via three conserved epitopes (sites I, II, and III; Bravo and Heath (2000) EMBO J. 19:2399-2411). The p19 subunit interacts with three cytokine receptor subunits to form a competent signaling complex. When expressed in cells, the p19 subunit initially forms a complex with the p40 subunit, which it shares with IL-12. The p19p40 complex is secreted from cells as a heterodimeric protein and is referred to as IL-23. In one embodiment, the IL-23p19 of the present invention is derived from humans (NCBI: AAG37232) or cynomolgus monkeys (NCBI: AEY84629).

[0098] As used herein, the terms "anti-IL-23p19 antibody," "anti-IL-23p19," "recombinant anti-interleukin IL23p19 antibody," "IL-23p19 antibody," or "antibody that binds to IL-23p19" refer to an antibody that is capable of binding to a (human or cynomolgus monkey) IL-23p19 subunit or fragment thereof with sufficient affinity such that the antibody can be used as a diagnostic and / or therapeutic agent in targeting (human or cynomolgus monkey) IL-23p19.

[0099] As used herein, the term "antibody" is used in the broadest sense to refer to a protein that contains an antigen binding site, encompassing natural antibodies and artificial antibodies of various structures, including but not limited to complete antibodies and antigen-binding fragments of antibodies.

[0100] The terms "whole antibody," "full-length antibody," "complete antibody," and "intact antibody" are used interchangeably herein to refer to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. 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. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, which are complementarity determining regions (CDRs), interspersed with more conserved regions, which are 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. The constant region is not directly involved in binding the antibody to the antigen, but exhibits various effector functions.

[0101] "Complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms structurally determined loops ("hypervariable loops") and / or contains antigen contact residues ("antigen contact points"). CDRs are primarily responsible for binding to antigenic epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, and are numbered sequentially starting from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3.

[0102] In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment systems, including, for example, Chothia based on the three-dimensional structure of antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0103] Unless otherwise indicated, in the present invention, when referring to residue positions in the variable region of an antibody (including heavy chain variable region residues and light chain variable region residues), the numbering refers to the position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0104] In one embodiment, the CDRs of an antibody of the invention have boundaries defined by the AbM rule.

[0105] "Antibody fragments" refer to molecules other than intact antibodies that comprise a portion of an intact antibody and bind to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies; bivalent or bispecific antibodies or fragments thereof; camelid antibodies; and bispecific or multispecific antibodies formed from antibody fragments.

[0106] "Treat" or "treat" means to slow, interrupt, arrest, alleviate, stop, reduce, or reverse the progression or severity of an existing symptom, disorder, condition, or disease.

[0107] The term "effective amount" refers to the amount or dosage of a formulation or antibody of the present invention that, when administered to a patient in single or multiple doses, produces the desired effect in the treated patient. An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering a variety of factors, such as the species of mammal; its size, age, and general health; the specific disease involved; the extent or severity of the disease; the response of the individual patient; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; and the use of any concomitant therapy.

[0108] A "therapeutically effective amount" is an amount effective to achieve the desired therapeutic result, at the required dosage and for the required period of time. A therapeutically effective amount of an agent, antibody or antibody fragment, or conjugate or composition of the invention can vary depending on a variety of factors, such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or deleterious effects of the agent, antibody or antibody fragment, or conjugate or composition are outweighed by the therapeutically beneficial effects.

[0109] "Formulation" or "pharmaceutical composition" refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to an animal, preferably a mammal (including a human). "Liquid formulation" or "liquid composition" refers to a formulation in liquid form. The liquid composition of the present invention comprises (i) an antibody according to the present invention; (ii) a buffer; and (iii) a solvent. The composition of the formulation of the present invention may be as shown in the embodiment related to the liquid pharmaceutical composition above. The liquid formulation of the present invention is preferably an injectable.

[0110] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0111] As used herein, "buffer" refers to a pH buffer. For example, the buffer is selected from histidine, glutamate, phosphate, acetate, citrate, and tris.

[0112] As used herein, the term "solvent" refers to a liquid used to dissolve or suspend active ingredients and inactive ingredients to form a liquid formulation. The solvents that can be used in the present invention include, but are not limited to, water for injection, organic solvents for injection, but are not limited to, oil for injection, ethanol, propylene glycol, etc., or a combination thereof.

[0113] "sPGA" stands for static Physician's Global Assessment, which records the physician's assessment of a subject's psoriasis status and includes the following aspects: induration, scaling, and erythema. It is used to assess the condition of a subject's psoriasis lesions at a given time point. All lesions are graded based on the following scales: induration, erythema, and scaling. The sPGA score is calculated by dividing the total score of these three items by 3, as shown below.

[0114] Induration (I) (average of all lesions; measured using the National Psoriasis Foundation Reference card)

[0115] 0 = No evidence of raised plaques

[0116] 1 = small raised plaque, 0.25 mm

[0117] 2 = mild plaque elevation, 0.5 mm

[0118] 3 = Moderately raised plaque, 0.75 mm

[0119] 4 = obvious raised plaque, 1 mm

[0120] 5 = Severely raised plaque, ≥1.25 mm

[0121] Erythema (E) (average of all lesions)

[0122] 0 = No evidence of erythema, hyperpigmentation may be present

[0123] 1 = Faint erythema

[0124] 2 = Mild red

[0125] 3 = Medium red

[0126] 4 = Bright red

[0127] 5 = dark red to deep red

[0128] Scaling (S) (average of all lesions)

[0129] 0 = No evidence of scaling

[0130] 1 = Microscaly; occasional scaling in < 5% of total lesions

[0131] 2 = Mild; mainly fine scales

[0132] 3 = Moderate; mainly coarse scales

[0133] 4 = obvious; mainly thick, non-stubborn scales

[0134] 5 = Severe; predominantly very thick, stubborn scales

[0135] sPGA total average score = I + E + S / 3

[0136] sPGA (static Physician Global Assessment) is evaluated based on the total average score:

[0137] 0 = Clear, removes some residual discoloration

[0138] 1 = Minimal; most lesions are scored as 1 point individually

[0139] 2 = Mild, most lesions are scored as 2 points individually

[0140] 3 = Moderate, most lesions are scored as 3 points individually

[0141] 4 = obvious, most lesions are scored as 4 points individually

[0142] 5 = severe, most lesions scored individually as 5 points

[0143] Note: Scores should be rounded to the nearest integer. If the total score is <1.50, score = 1; if the total score is ≥1.50, score = 2.

[0144] sPGA-G uses the sPGA evaluation criteria to perform local evaluation of perineal psoriasis, with a score of 0-5.

[0145] "PASI" stands for Psoriasis Area and Severity Index, a systematic tool used to assess and grade the severity of psoriasis lesions and their response to treatment. PASI scores range from 0 to 72. It linearly combines the percentage of body surface area involved with the severity of erythema, induration, and scaling in four body regions. This endpoint is based on the percentage reduction from baseline and is usually summarized as a binomial distribution based on achieving X% reduction (or PSAIx), where X can be 50, 75, 90, and 100. To calculate PASI, the areas of four major body regions are assessed: head (h), trunk (t), upper extremities (u), and lower extremities (l), representing 10%, 30%, 20%, and 40% of the same body area, respectively.

[0146] The area of ​​psoriasis affecting these four parts is expressed numerically:

[0147] 0 = not involved;

[0148] 1 = <10%;

[0149] 2 = 10% - < 30%;

[0150] 3 = 30% - < 50%;

[0151] 4 = 50% - < 70%;

[0152] 5 = 70% - < 90%;

[0153] 6 = 90% - 100%

[0154] The severity of the lesions was assessed using a scale of 0 to 4, with 0 representing no skin involvement, 1 being mild, 2 being moderate, 3 being severe, and 4 being very severe. The scores for the four sites were presented separately.

[0155] To assist with area estimation, note the following:

[0156] a. The neck belongs to the head

[0157] b. The armpits and groin belong to the trunk

[0158] c. Buttocks belong to the lower limbs

[0159] PASI=0.1*(Eh+Ih+Sh)Ah+0.3*(Et+It+St)At+0.2*(Eu+Iu+Su)Au+0.4*(El+Il+Sl)Al.

[0160] "DLQI" stands for Dermatology Life Quality Index. It is a dermatology-related quality of life tool used to assess the impact of the disease on the subject's quality of life (AY Finlay and GK Khan). It is a 10-question questionnaire that assesses six different aspects of quality of life: symptoms and feelings, daily activities, leisure activities, work or school standards, personal relationships, and treatment. The DLQI has a one-week recall period. Response categories include no relationship (0), not at all (0), a little (1), a lot (2), and very much (3). The answer to question 7 is "yes" / "no", with "yes" being scored as 3 points.

[0161] The DLQI was completed by the subjects themselves at the visits indicated in the flow chart.

[0162] DLQI is analyzed through the following six aspects:

[0163] Score corresponding to the option

[0164] For question 7, if you choose “Yes”, you will get the highest score of 3 points. If you choose “No”, you will get the score in the table based on the options.

[0165] The DLQI total score is calculated by summing the scores of each question, with the result ranging from 0 to 30. The higher the score, the more impaired the quality of life.

[0166] 0-1 points: no impact on the subject's life,

[0167] 2-5 points: small impact,

[0168] 6-10 points: moderate impact,

[0169] 11-20 points: Very big impact,

[0170] 21-30 points: Has a significant impact on the subject's life.

[0171] If one answer to a question in a dimension is missing, the dimension is considered missing. If two or more questions are missing, the total DLQI score is considered missing. A change of 5 points from baseline is considered a clinically important difference.

[0172] As used herein, the term "single pharmaceutical dosage unit" refers to a single pharmaceutical dosage form comprising an antibody of the present invention to be administered to a subject at the time of administration, such as an injection vial, ampoule, prefilled needle or prefilled syringe containing a solution or lyophilized powder of the drug.

[0173] Treatment

[0174] The present invention provides a method for switching a subject who has previously received a biological agent to treat plaque psoriasis to an anti-IL23p19 antibody to treat plaque psoriasis.

[0175] In some specific embodiments of the present invention, the amino acid sequence of the heavy chain CDR1 of the anti-IL23p19 antibody includes SEQ ID NO.1, the amino acid sequence of the heavy chain CDR2 includes SEQ ID NO.2, and the amino acid sequence of the heavy chain CDR3 includes SEQ ID NO.3; the amino acid sequence of the light chain CDR1 of the antibody includes SEQ ID NO.4, the amino acid sequence of the light chain CDR2 includes SEQ ID NO.5, and the amino acid sequence of the light chain CDR3 includes SEQ ID NO.6.

[0176] In a specific embodiment of the present invention, the method comprises that the anti-IL-23p19 antibody is an antibody that specifically binds to IL-23p19 and comprises the following 6 CDRs,

[0177] - heavy chain VH CDR1 of GYTFTSYLMH (SEQ ID NO: 1);

[0178] - Heavy chain VH CDR2 of YINPYNEGTN (SEQ ID NO: 2);

[0179] - heavy chain VH CDR3 of NWDLPY (SEQ ID NO: 3);

[0180] - Light chain VL CDR1 of RASQSISDYLH (SEQ ID NO: 4);

[0181] - light chain VL CDR2 of YASQSMS (SEQ ID NO: 5); and

[0182] -Light chain VL CDR3 of QQGHSFPFT (SEQ ID NO: 6).

[0183] In a specific embodiment, the anti-IL-23p19 antibody comprises a heavy chain variable region, VH, and a light chain variable region, VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8, or a sequence at least 90%, 95%, 98% or 99% identical thereto:

[0184] Sequence (SEQ ID NO:7)

[0185] Sequence (SEQ ID NO:8)

[0186] In a specific embodiment, the IL-23p19 antibody is an IgG1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9, or a sequence at least 90%, 95%, 98% or 99% identical thereto, and wherein the light chain comprises the sequence of SEQ ID NO: 10, or a sequence at least 90%, 95%, 98% or 99% identical thereto.

[0187] Sequence (SEQ ID NO:9)

[0188] Sequence (SEQ ID NO:10)

[0189] Preferably, the IL-23p19 antibody is the anti-IL-23p19 antibody 17D1-YTE disclosed in PCT application number PCT / CN2019 / 121261 (international application date: November 27, 2019), which consists of a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10.

[0190] In some embodiments, the anti-IL-23p19 antibody is recombinantly expressed in HEK 293 cells or CHO cells.

[0191] In some specific embodiments, the formulation of the IL-23p19 antibody can be prepared according to the preparation containing anti-IL-23p19 antibodies, its preparation method and use disclosed in PCT application number PCT / CN2021 / 093219 (international application date: May 12, 2021).

[0192] In some embodiments of the present invention, the method comprises administering an anti-IL-23p19 antibody to a subject who has previously received a biologic for plaque psoriasis treatment, and for subjects who have lost response or have responded poorly to biologic treatment, administering the anti-IL-23p19 antibody at weeks 0, 4, and 8, respectively, and then every 12 weeks thereafter.

[0193] The dosage per administration is 100 mg to 1000 mg. For example, the dosage per administration is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. Preferably, the dosage per administration is 200 mg.

[0194] Among them, poor response was defined as: sPGA ≥ 2 points, or cumulative body surface area of ​​lesions ≥ 3%, or PASI improvement after using biological agents did not reach 75%.

[0195] In some embodiments of the invention, the method comprises administering an anti-IL-23p19 antibody to a subject who has previously received a biologic for plaque psoriasis treatment, wherein the anti-IL-23p19 antibody is administered at week 0 and every 12 weeks thereafter to a subject who has responded to biologic treatment.

[0196] The dosage per administration is 100 mg to 1000 mg. Specifically, the dosage per administration is 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. Preferably, the dosage per administration is 200 mg.

[0197] Response was defined as: an sPGA score of 0 or 1 with cumulative body surface area of ​​lesions < 3%; or a PASI improvement of 75% or more after the use of biologics.

[0198] In some embodiments of the present invention, the administration method is subcutaneous injection.

[0199] In some embodiments of the present invention, the biologic agent includes a tumor necrosis factor α inhibitor / antagonist and / or an IL-17A inhibitor / antagonist. TNF-α inhibitors / antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. IL-17A inhibitors / antagonists include secukinumab and ixekizumab.

[0200] Furthermore, TNF-α inhibitors / antagonists include but are not limited to etanercept, infliximab, and adalimumab. IL-17A inhibitors / antagonists include but are not limited to secukinumab.

[0201] For example, previous treatment with biologics:

[0202] a. Patients receiving treatment according to the prescribed dosage rules shall meet the following requirements:

[0203] - Use of an IL-17 inhibitor for at least 4 months: secukinumab 300 mg subcutaneously at weeks 0, 1, 2, 3, 4, and every 4 weeks thereafter; ixekizumab 160 mg subcutaneously at week 0, 80 mg subcutaneously at weeks 2, 4, 6, 8, 10, 12, and every 4 weeks thereafter;

[0204] - Use of TNF inhibitors for at least 4 months: Adalimumab 80 mg subcutaneously at week 0, 40 mg subcutaneously at week 1 and every 2 weeks thereafter; Etanercept 25 mg twice weekly for the first 3 months, 50 mg once weekly or 25 mg twice weekly thereafter; Infliximab 5 mg / kg intravenously at weeks 0, 2, and 6, and the same dose every 8 weeks thereafter;

[0205] or

[0206] b. Those who are not treated according to the prescribed dosage rules refer to those who do not meet the previous dosage and dosing interval requirements, but at least 4 months have passed between the last biologic administration and the first biologic administration.

[0207] Single dose unit

[0208] A single dose unit comprising: an effective amount of an anti-IL-23p19 antibody of the present invention, preferably comprising a fixed dose selected from 100 mg-1000 mg; preferably 50 mg-800 mg, more preferably 50 mg-500 mg fixed dose, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg , 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg, preferably, 50, 60, 70, 80, 90, 100, 150, 200, 300, 350, 400 or 500 mg of anti-IL-23p19 antibody.

[0209] In some embodiments, the single-dose unit is a single-dose unit packaged in a prefilled autoinjector pen.

[0210] Complete set of medicine boxes

[0211] A kit comprising an effective amount of an anti-IL-23p19 antibody of the present invention, preferably comprising a fixed dose of 100 mg to 1000 mg; more preferably comprising 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg of the anti-IL-23p19 antibody, and specifically, further comprising a package insert printed with instructions for using the anti-IL-23p19 antibody to prevent or treat plaque psoriasis in a subject.

[0212] In some embodiments, the kit comprises the anti-IL-23p19 antibody in the form of a single-dose unit. In other embodiments, the single-dose unit is packaged in a prefilled autoinjector pen.

[0213] application

[0214] Use of the anti-IL-23p19 antibody, single-dose unit, and complete drug kit of the present invention in preparing a medicament for preventing or treating plaque psoriasis. Example

[0215] Example 1. Preparation and purification of IL-23p19 antibody

[0216] The antibody 17D1-YTE, which specifically binds to IL-23p19, was obtained according to PCT application number PCT / CN2019 / 121261. The antibody has a heavy chain sequence of SEQ ID NO: 9 and a light chain sequence of SEQ ID NO: 10. PCT application number PCT / CN2019 / 121261 is hereby incorporated by reference in its entirety.

[0217] Briefly, the antibody was recombinantly expressed in CHO cells and purified by affinity chromatography to obtain the IL-23p19 antibody sample used in the present invention, and the IL-23p19 antibody sample used in the formulation screening experiment of the present invention was purified by cation exchange chromatography.

[0218] Example 2. Clinical study

[0219] Preclinical pharmacokinetic (PK), pharmacodynamic (PD), and toxicology studies demonstrate that the anti-IL-23p19 antibody has a clear target, a well-defined mechanism of action, and significant anti-inflammatory effects. It is expected to reduce or even clear skin lesions, improve the severity of lesions, and reduce the cumulative body surface area of ​​lesions in subjects with plaque psoriasis. The anti-IL-23p19 antibody exhibits linear PK characteristics in cynomolgus monkeys, a long half-life, and high bioavailability. It demonstrates high safety in cynomolgus monkeys after repeated short-term and long-term dosing, and demonstrates no risk of hemolysis or cytokine release in vitro.

[0220] The anti-IL-23p19 antibody of the present invention has completed a Phase I randomized, double-blind, placebo-controlled safety and tolerability clinical study in healthy subjects with single-dose escalation. The results showed that the anti-IL-23p19 antibody is safe and well tolerated in healthy subjects.

[0221] The anti-IL-23p19 antibody of this invention has completed a Phase II multicenter, randomized, double-blind, placebo-controlled clinical study across a dose range in moderate-to-severe plaque psoriasis and achieved the primary efficacy endpoint. The Phase II study results demonstrated that the anti-IL-23p19 monoclonal antibody significantly improved skin lesions in subjects with moderate-to-severe plaque psoriasis, with an overall good safety and tolerability profile.

[0222] The results of the above two studies verified the significant efficacy and safety of anti-IL-23P19 antibodies in Chinese subjects with moderate to severe plaque psoriasis. The benefits outweigh the risks, and the data support the continuation of clinical research on this product.

[0223] This study is a multicenter, open-label study of anti-IL-23p19 monoclonal antibodies, which aims to evaluate the effectiveness of the anti-IL-23p19 monoclonal antibody of the present invention in subjects with plaque psoriasis who have been previously treated with biologics.

[0224] 3.1 Research Objectives

[0225] Main purpose:

[0226] To evaluate the effectiveness of switching subjects who have previously received biologics for plaque psoriasis to treatment with the anti-IL23p19 antibody of the present invention.

[0227] Secondary purpose

[0228] - To evaluate the safety of switching patients with plaque psoriasis who are being treated with biologics to anti-IL-23p19 antibodies;

[0229] To evaluate the effects of switching from biologic therapy to anti-IL-23p19 antibody therapy on health-related quality of life in participants with plaque psoriasis;

[0230] To evaluate the immunogenicity of subjects with plaque psoriasis who were switched from biologic therapy to anti-IL-23p19 antibody therapy.

[0231] 3.2 Study Endpoints

[0232] Primary efficacy endpoint

[0233] The proportion of subjects achieving a static Physician's Global Assessment (sPGA) score of clear (0) or nearly clear (1) and a BSA <3% at Week 16.

[0234] Secondary efficacy endpoints

[0235] - The proportion of subjects achieving a static Physician Global Assessment (sPGA) score of 0 at Week 16;

[0236] - Proportion of participants with a Dermatology Life Quality Index (DLQI) score of 0 / 1 at Week 16;

[0237] - the proportion of participants with an sPGA of 0 or 1, an sPGA of 0, and a DLQI of 0 or 1 at Week 44;

[0238] - The proportion of subjects with an sPGA of 0 or 1, an sPGA of 0, and a DLQI of 0 or 1 at Week 16 who maintained their scores at Week 44.

[0239] Other efficacy endpoints

[0240] - Change from baseline in DLQI;

[0241] - Change from baseline in Psoriasis Area and Severity Index (PASI);

[0242] - Change from baseline in Boby Surface Area (BSA);

[0243] - proportion of subjects with BSA ≤1% and ≤3%;

[0244] - Proportion of participants with PASI ≤1 and ≤3 (suboptimal responders at baseline only);

[0245] -Time to sPGA 0 or 1 (only for those with poor baseline responders);

[0246] - Time to reach sPGA score of 0 (poor responders at baseline only);

[0247] Safety endpoints

[0248] All adverse events, including serious adverse events, etc. Changes in vital signs, physical examinations, laboratory tests, electrocardiograms, etc. before and after administration.

[0249] Immunogenicity evaluation

[0250] The production of anti-drug antibodies (ADA) and neutralizing antibodies (NAb).

[0251] 3.3 Research design

[0252] This study is a multicenter, open-label study that primarily evaluates the effectiveness of switching subjects with plaque psoriasis treated with biologics to treatment with the anti-IL23p19 antibody of the present invention.

[0253] The target population is male or female subjects aged 18 to 75 years with plaque psoriasis who have previously used biologics for plaque psoriasis, including IL-17 inhibitors and tumor necrosis factor α (TNF-α) inhibitors, prior to screening. Subjects can be either regular users of biologics (for at least four months) or non-regular users (with at least four months between the last biologic dose and the first biologic dose).

[0254] Approximately 160 subjects are planned to be enrolled, with at least 30% of the enrolled subjects experiencing suboptimal responses at baseline. Suboptimal responders (sPGA ≥ 2, cumulative body surface area of ​​lesions ≥ 3%, or PASI improvement less than 75% after biologic therapy) will be switched to the anti-IL23p19 antibody of this invention, administered subcutaneously at weeks 0, 4, and 8, and every 12 weeks thereafter until the end of week 32. Responders (sPGA 0 or 1, cumulative body surface area of ​​lesions < 3%, or PASI improvement of 75% or greater after biologic therapy) will be switched to the anti-IL23p19 antibody of this invention, administered at week 0 and every 12 weeks thereafter until the end of week 36. Switching to the anti-IL23p19 antibody should occur within one week of the planned biologic therapy dose. The screening period of the study shall not exceed 4 weeks, and qualified subjects shall be switched to the anti-IL23p19 antibody treatment of the present invention, and follow-up shall be completed until the end of the 44th week after the last administration.

[0255] 3.4 Inclusion Criteria

[0256] Eligible subjects must meet all of the following inclusion criteria:

[0257] (1) Male or female aged 18 years or younger than 75 years;

[0258] (2) the investigator assessed the subject as suitable for continued biologic therapy for plaque psoriasis;

[0259] (3) Previous treatment with biological agents

[0260] a. Patients receiving treatment according to the prescribed dosage rules shall meet the following requirements:

[0261] - Use of an IL-17 inhibitor for at least 4 months: secukinumab 300 mg subcutaneously at weeks 0, 1, 2, 3, 4, and every 4 weeks thereafter; ixekizumab 160 mg subcutaneously at week 0, 80 mg subcutaneously at weeks 2, 4, 6, 8, 10, 12, and every 4 weeks thereafter;

[0262] - Use of TNF inhibitors for at least 4 months: Adalimumab 80 mg subcutaneously at week 0, 40 mg subcutaneously at week 1 and every 2 weeks thereafter; Etanercept 25 mg twice weekly for the first 3 months, 50 mg once weekly or 25 mg twice weekly thereafter; Infliximab 5 mg / kg intravenously at weeks 0, 2, and 6, and the same dose every 8 weeks thereafter;

[0263] or

[0264] b. Patients not receiving treatment according to the prescribed dosage regimen refer to those who do not meet the dosage and dosing interval requirements of the previous item, but the period from the last biologic to the first biologic is at least 4 months;

[0265] (4) Patients who responded or responded poorly to biologics at screening and baseline:

[0266] a. Response is defined as: an sPGA score of 0 or 1 with cumulative lesions <3% of the total body surface area; or a PASI improvement of 75% or greater after treatment with a biologic agent;

[0267] b. Poor response is defined as: sPGA ≥ 2 points, or cumulative body surface area of ​​lesions ≥ 3%, or PASI improvement of less than 75% after use of biologics;

[0268] (5) Have a full understanding of the purpose of the trial, and a basic understanding of the pharmacological effects of the trial drugs and possible adverse reactions; voluntarily sign the informed consent form in accordance with the spirit of the Declaration of Helsinki.

[0269] 3.5 Exclusion criteria

[0270] Eligible subjects must not meet any of the following exclusion criteria:

[0271] (1) Patients with previous or current diagnosis of pustular psoriasis, erythrodermic psoriasis, or drug-induced psoriasis (e.g., psoriasis caused by beta-blockers, calcium channel inhibitors, etc.); or patients with guttate psoriasis before screening or first administration;

[0272] (2) those who had previously used anti-IL23p19 antibodies or IL-23 preparations;

[0273] (3) those who had received two biologics for the treatment of psoriasis within 4 months before screening;

[0274] (4) Patients who had used topical treatment for psoriasis within 2 weeks before the first dose, or had used non-biological systemic treatment or phototherapy within 4 weeks before the first dose;

[0275] (5) Use of Natalizumab, or B cell or T cell regulators (such as rituximab, abatacept, or visilizumab) within 12 months before the first medication;

[0276] (6) Unwilling to avoid continuous sun exposure and other ultraviolet light sources during the study period;

[0277] (7) Received treatment with an investigational biologic within 6 months before the first use of the study drug, or received any investigational treatment within 30 days, or within 5 half-lives of the study drug, or is currently participating in a clinical study;

[0278] (8) There is evidence that the subject has serious, progressive, uncontrolled (including but not limited to) cardiovascular disease, neuromuscular disease, blood disease, respiratory disease, liver or digestive disease, urinary disease, neurological or psychiatric disease;

[0279] (9) had opportunistic infections within 6 months before screening [such as herpes zoster (severe or recurrent), active cytomegalovirus, Pneumocystis carinii, Histoplasma, Aspergillus, Mycobacterium, etc.];

[0280] (10) Known history of recurrent or chronic infection, including but not limited to chronic kidney infection, chronic chest infection (such as bronchiectasis), recurrent urinary tract infection, open, draining or infected wounds of the skin;

[0281] (11) A history of severe infection (e.g., sepsis, pneumonia, pyelonephritis), or hospitalization for infection within 2 months before screening;

[0282] (12) having a malignant tumor or a history of malignant tumor (except for skin squamous cell carcinoma, basal cell carcinoma, or localized cervical carcinoma in situ that has been successfully removed and has no evidence of recurrence or metastasis within 5 years);

[0283] (13) have or have had a lymphoproliferative disease, or have symptoms or signs suggestive of a lymphoproliferative disease within 5 years prior to screening, such as lymphadenopathy and / or splenomegaly;

[0284] (14) Subjects with a known history of active tuberculosis, or suspected tuberculosis by clinical manifestations or imaging evidence (including but not limited to pulmonary tuberculosis, lymphadenopathy, tuberculous pleurisy, etc.), or the tuberculosis status of subjects tested by the Interferon Gamma Release Assay (IGRA) during the screening period. For subjects without active tuberculosis symptoms and imaging evidence of tuberculosis:

[0285] - Negative IGRA test result, eligible for enrollment;

[0286] - Inconclusive IGRA test results can be retested. Those with inconclusive results after retesting are not eligible for enrollment;

[0287] - Patients with positive IGRA test results may be re-screened and evaluated after receiving at least one month of preventive anti-tuberculosis treatment. Patients who have no tuberculosis symptoms, tolerate tuberculosis drugs well, and are willing to receive complete preventive anti-tuberculosis treatment during the study period may be included in the study group upon evaluation by the investigator;

[0288] - Participants with a positive IGRA result before receiving biologics, who have received a complete course of preventive anti-tuberculosis treatment and have no symptoms of active tuberculosis and no radiographic evidence of tuberculosis are eligible for enrollment.

[0289] (15) BCG vaccination within 12 months before the first use of study drug, or plan to receive BCG vaccination during the study or within 12 months after the last study treatment;

[0290] (16) Received a live vaccine or bacterial vaccine within 3 months before the first use of the study drug, or planned to receive a live vaccine or bacterial vaccine during the study or within 3 months after the last study treatment;

[0291] (17) The results of routine blood tests and blood biochemistry tests during the screening and baseline periods meet the following conditions:

[0292] - Any index of hemoglobin, red blood cells, white blood cells, neutrophils, or platelets is less than the lower limit of normal value (LLN), and the abnormality is judged by the investigator to be clinically significant;

[0293] - Alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), or direct bilirubin (DBIL) > 2 times the upper limit of normal value (ULN);

[0294] - Creatinine (Cr) > ULN; if it reaches the range required by the protocol after re-examination, the patient can also be included in the study.

[0295] (18) Virus test results during screening meet any of the following conditions:

[0296] - Positive for human immunodeficiency virus (HIV) antibodies;

[0297] - Hepatitis C virus (HCV) antibody positive with no history of successful treatment, where successful treatment is defined as completion of antiviral therapy for at least 24 weeks with negative HCV RNA status;

[0298] - Hepatitis B virus (HBV) screening should include at least hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and hepatitis B core antibody (HBcAb). If the test results of the above three indicators are: HBsAg positive; or if only HBcAb is positive when HBsAg is negative, HBV DNA testing is required and the test result is positive;

[0299] - Positive syphilis-specific antibodies (except for those whose non-specific syphilis antibodies titer turns negative after regular syphilis treatment).

[0300] (19) The following clinically significant 12-lead electrocardiogram (ECG) abnormalities at screening: QTcF>450ms, shortened or delayed PR interval, second-degree or third-degree atrioventricular block, preexcitation syndrome, long QT syndrome; or severe arrhythmia requiring treatment;

[0301] (20) Those who have had severe drug or food allergic reactions in the past, and / or those who are allergic to the experimental drugs or their ingredients;

[0302] (21) history of alcohol and drug abuse within 12 months before screening;

[0303] (22) Female subjects are pregnant or lactating, or female subjects of childbearing age have a positive pregnancy test before screening and administration;

[0304] (23) Those who have plans to have children during the study period and within 6 months after the administration of the study drug, or those who are unwilling to take contraceptive measures (such as condoms, etc.) deemed appropriate by the doctor during the trial;

[0305] (24) Those who the researcher considers are not suitable to participate in this clinical trial due to various reasons.

[0306] 3.6 Study Drug, Dosage, and Administration

[0307] Poor responders: subcutaneous injection of 200 mg of the anti-IL23p19 antibody of the present invention at week 0, 4, 8, 20, and 32;

[0308] Responders: 200 mg of the anti-IL23p19 antibody of the present invention was injected subcutaneously at weeks 0, 12, 24, and 36.

[0309] The study drug is administered as an injection. The dosage form is 100 mg (1 ml) per vial. The formulation is: 100.0 mg / ml recombinant anti-interleukin-23p19 subunit antibody, 0.76 mg / ml histidine, 1.08 mg / ml histidine hydrochloride, 50.00 mg / ml sorbitol, 0.5 mg / ml polysorbate 80, pH 6.0.

[0310] Subjects are prohibited from receiving the following treatments during the study treatment period:

[0311] ·Drugs and treatments prohibited before the first dose follow the relevant provisions of the exclusion criteria and are still prohibited during the study. The drugs / treatments prohibited during the study are shown in the table below:

[0312] Table: Medications / treatments prohibited during the study

[0313] If a subject is using a contraindicated drug that has been assessed to have a significant impact on efficacy and safety (e.g., use of biologics, potent or super-potent local treatments for more than 1 week, or non-biologic systemic drugs), treatment should be discontinued.

[0314] During administration, patients should avoid taking hepatotoxic drugs.

[0315] 3.7 Treatment compliance

[0316] Patients received study treatment at the study center, and treatment compliance was monitored using medication delivery and receipt records, subject medical records, and eCRFs.

[0317] 3.8 Indicators related to efficacy evaluation

[0318] A. Psoriasis Area and Severity Index (PASI)

[0319] Whenever possible, the physician who performed the PASI assessment on the subject at screening / baseline should also perform the PASI assessment on the subject at subsequent follow-up visits.

[0320] PASI 90 refers to a ≥90% improvement in PASI score from baseline; PASI 75 refers to a ≥75% improvement in score from baseline; and PASI 100 refers to a 100% improvement from baseline.

[0321] B. Static Physician Global Assessment (sPGA)

[0322] sPGA records the doctor's assessment of the subject's psoriasis status, including the following aspects: nodules, scaling, and erythema.

[0323] Whenever possible, the physician who performed the sPGA assessment on the subject at Screening / Baseline should perform the sPGA assessment on that subject at the subsequent follow-up visit.

[0324] C. Dermatology Life Quality Index (DLQI)

[0325] For visits involving DLQI assessment, DLQI assessment was performed before all other visit contents (examination, procedure, psoriasis assessment, adverse events and concomitant medication collection, etc.) during the study.

[0326] D. Take photos of skin lesions

[0327] In order to obtain more data for efficacy evaluation, each time the efficacy evaluation is conducted, the subject's skin condition (except the perineum) is photographed.

[0328] 3.9 Safety Assessment

[0329] I. Laboratory tests

[0330] Routine laboratory safety assessments include the laboratory tests listed in the table below.

[0331] Routine laboratory examination contents

[0332] HBcAb: hepatitis B core antibody; HBeAb: hepatitis B E antibody; HBeAg: hepatitis B E antigen; HBsAb: hepatitis B surface antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus.

[0333] Laboratory-related examinations were performed in the fasting state.

[0334] II. Clinical Examination

[0335] Clinical examinations include general physical examination, vital signs examination (including temperature, pulse and blood pressure), 12-lead electrocardiogram (12-lead ECG), chest X-ray, severe allergic reactions, injection site reactions, cardiovascular events (including major cardiovascular events known in the art (such as cardiovascular and cerebrovascular-related death, non-fatal myocardial infarction and non-fatal stroke) and other cardiovascular events), and psychiatric events.

[0336] 3.10 Immunogenicity

[0337] About 5 ml of whole blood was collected, serum was separated, and aliquots were frozen for ADA and NAb analysis.

[0338] 3.11 Statistical Analysis Methods

[0339] A. General Methods of Statistical Analysis

[0340] This trial will summarize efficacy and safety data separately based on whether the subjects have responded to previous biologics.

[0341] No intergroup comparisons were performed in this trial. Quantitative data were described using number of cases, mean, standard deviation, median, Q1, Q3, minimum, and maximum values; and enumeration data were described using frequency and percentage.

[0342] All statistical analyses were performed using SAS v 9.4 (or higher).

[0343] B. Baseline Characteristics of Subjects

[0344] Descriptive statistics include demographic characteristics or baseline characteristics of the subjects, diagnosis and treatment information of the study disease, medical history, previous concomitant treatment, etc.

[0345] C. Efficacy Analysis

[0346] The evaluation of efficacy indicators was based on the safety analysis set and summarized by the presence or absence of response.

[0347] 1) Primary efficacy endpoint analysis

[0348] The primary efficacy endpoint of this study was the proportion of subjects achieving an sPGA score of 0 (clear) or 1 (nearly clear) at Week 16. Subjects without a Week 16 sPGA score or who used other psoriasis treatments that affected efficacy assessment before Week 16 were considered to have failed to meet the Week 16 sPGA target.

[0349] The number and percentage of subjects achieving sPGA 0 / 1 were calculated, and the 95% CI was calculated using the Clopper-Pearson method.

[0350] 2) Analysis of secondary efficacy endpoints

[0351] Binary variable analysis

[0352] Secondary efficacy endpoints of dichotomous variables included the proportion of subjects with an sPGA score of 0 and a DLQI score of 0 / 1 at week 16; the proportion of subjects with an sPGA score of 0 / 1, an sPGA score of 0, and a DLQI score of 0 / 1 at week 44; the proportion of subjects with an sPGA score of 0 / 1, an sPGA score of 0, and a DLQI score of 0 / 1 at week 16 who maintained these scores at week 44; the proportion of subjects with a BSA score of ≤1% and ≤3%; and the proportion of subjects with a PASI score of ≤1 and ≤3 (only those with an inadequate responder at baseline).

[0353] The analysis method is the same as the primary efficacy endpoint analysis.

[0354] Continuous variable analysis

[0355] Secondary efficacy endpoints of continuous variables included the changes in DLQI, PASI, and cumulative skin lesion area (BSA) from baseline at each visit.

[0356] Descriptive statistics for each continuous efficacy endpoint were summarized by visit, including the number of cases, mean, standard deviation, median, Q1, Q3, minimum, and maximum values. The 95% CI for the mean was also calculated. Changes in the mean over time were also plotted.

[0357] Time-to-event variable analysis (poor responders at baseline only)

[0358] Secondary efficacy endpoints of event-onset variables included time to reach sPGA 0 / 1 score and sPGA 0 score, which was defined as the time from the first dose of study drug to reaching sPGA 0 / 1 score or sPGA 0 score. If a subject did not reach the corresponding sPGA score at the time of completion / termination of the study, the score was censored at the time of the subject's last efficacy assessment.

[0359] The number and percentage of subjects who achieved the corresponding sPGA score and those who were censored were summarized. The median time and its 95% CI were calculated using the Kaplan-Meier method, and KM curves were drawn.

[0360] D. Security Analysis

[0361] The security analysis will be based on the security analysis set.

[0362] 1) Drug exposure

[0363] Summarize the subjects' exposure to study drugs, medication duration, compliance, etc. during the study.

[0364] 2) Adverse events

[0365] Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects experiencing each category of adverse events (AEs), including treatment-emergent adverse events, drug-related adverse events, AESIs, and SAEs, were summarized. The occurrence of each AE was further summarized according to the MedDRA system organ class and preferred term. The relationship between each adverse event and the study drug and the severity of each event were also analyzed.

[0366] 3). Laboratory examination

[0367] The number of cases, mean, standard deviation, median, Q1, Q3, minimum and maximum values ​​were used to describe the actual measured values ​​and changes compared with the baseline at each time point for routine blood tests, blood biochemistry and other indicators according to the visit. A cross-classification table was used to describe the normal and abnormal changes before and after administration.

[0368] Urinalysis will use a cross-classification table to describe the normal and abnormal changes before and after treatment.

[0369] 4). 12-lead electrocardiogram

[0370] Descriptive statistics were used to summarize the measured values ​​and changes from baseline of ECG quantitative indices. Cross-classification tables were used to summarize the changes in normal and abnormal values ​​before and after treatment.

[0371] 5) Vital signs, physical examination, and other safety-related examinations

[0372] Descriptive statistics were presented for the examination results of vital signs and the changes compared with baseline.

[0373] Use a list to describe the subjects whose physical examinations and other safety examinations have abnormal changes compared with baseline.

[0374] E. Immunogenicity

[0375] Descriptive statistics were used to summarize the positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against IL-23P19 antibody during the entire trial period.

[0376] 3.12 Results

[0377] The above results indicate that the method of switching to the anti-IL23p19 antibody treatment of the present invention has excellent efficacy and safety for subjects who have previously received biological agents for plaque psoriasis.

[0378] ● Anti-IL-23P19 antibodies have a good safety profile: In single-dose studies in healthy subjects and multiple-dose studies in people with psoriasis, the subjects showed good overall safety, with no significant increase in the incidence of adverse events compared with the placebo group, and no dose-dependent safety events were observed.

[0379] ●Increasing the loading dose exposure (average concentration) can improve the PASI90 compliance rate at week 16: increasing the average concentration of anti-IL-23p19 antibodies within 16 weeks (C avg,16w ) can increase the PASI 90 achievement rate in patients with psoriasis at week 16. According to the robust PopPK / PASI model simulation results, approximately 57.5% of patients with psoriasis achieved PASI 90 at week 16 using a 200mg subcutaneous injection of anti-IL-23p19 antibody at weeks 0, 4, and 8.

[0380] ● Long-interval (Q12W) maintenance dosing can maintain long-term benefits for people with psoriasis: Based on the results of a robust PopPK / PASI model simulation, the long-term (Week 52) PASI90 compliance rate was approximately 88% using a 200mg Q12W maintenance dosing regimen. This long-term maintenance dosing regimen is expected to provide the most convenient treatment option and a stable efficacy treatment option for people with psoriasis.

[0381] Effectiveness of switching to the anti-IL23p19 antibody of the present invention for subjects who have previously received interleukin-17 antagonists or anti-tumor necrosis factor antagonists for plaque psoriasis

[0382] Subjects who were judged to have a clinical response at baseline received a 200mg subcutaneous injection of anti-IL23p19 antibody every 12 weeks; subjects who were judged to have an inadequate clinical response at baseline received a 200mg subcutaneous injection of anti-IL23p19 antibody at weeks 0, 4, and 8, and every 12 weeks thereafter. The results are shown in the following table:

[0383] Research data showed that after subjects with a baseline clinical response switched to treatment with the anti-IL23p19 antibody of the present invention, 85.3% of the subjects still maintained a clinical response (cumulative body surface area of ​​lesions <3% and a static physician global score sPGA of 0 or 1) at week 16, and this percentage remained at around 85% from week 16 to week 36 of observation. After subjects with a baseline clinical non-response switched to treatment with the anti-IL23p19 antibody, the proportion of subjects who responded gradually increased, reaching 52.1% at week 16, and a similar response ratio was maintained thereafter.

[0384] It can be seen that the anti-IL23p19 antibody of the present invention can effectively treat subjects with plaque psoriasis who have previously received interleukin-17 antagonists or anti-tumor necrosis factor antagonists for treatment.

[0385] While the exemplary embodiments of the present invention have been described above, it should be understood by those skilled in the art that these disclosures are merely exemplary and that various other substitutions, adaptations, and modifications may be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A method for treating plaque psoriasis in a subject, comprising administering to the subject an effective amount of an anti-IL23p19 antibody, wherein: The anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of CDR1 of the heavy chain variable region includes SEQ ID NO.1, the amino acid sequence of CDR2 of the heavy chain variable region includes SEQ ID NO.2, and the amino acid sequence of CDR3 of the heavy chain variable region includes SEQ ID NO.3; the amino acid sequence of CDR1 of the light chain variable region of the antibody includes SEQ ID NO.4, the amino acid sequence of CDR2 of the light chain variable region includes SEQ ID NO.5, and the amino acid sequence of CDR3 of the light chain variable region includes SEQ ID NO.

6.

2. The method of claim 1, wherein the anti-IL23p19 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90%, 95%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence having at least 90%, 95%, 98% or 99% identity thereto.

3. The method according to claim 1 or 2, wherein the anti-IL23p19 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the sequence shown in SEQ ID NO: 9 or comprises a sequence having at least 90% identity with SEQ ID NO: 9, and the light chain comprises the sequence shown in SEQ ID NO: 10 or comprises a sequence having at least 90% identity with SEQ ID NO:

10.

4. The method of any one of claims 1-3, wherein the subject has received a biologic agent for plaque psoriasis prior to treatment.

5. The method according to any one of claims 1-4, wherein the subject is a person who uses a biologic according to a prescribed dosage regimen (e.g., for at least 4 months).

6. The method according to any one of claims 1-4, wherein the subject is a person who does not use biologics according to the prescribed dosage pattern (e.g., at least 4 months from the last biologic to the first biologic administration).

7. The method according to any one of claims 1-6, wherein the subject has lost response or has had a poor response to previous biologic therapy.

8. The method according to claim 7, wherein the subject has an sPGA of ≥2 points, or a cumulative body surface area of ​​skin lesions of ≥3%, or a PASI improvement of less than 75% after the use of a biological agent.

9. The method according to any one of claims 1 to 8, wherein for subjects who have lost response or have responded poorly to previous biologic treatment, the anti-IL23p19 antibody is administered by a two-stage administration regimen comprising a treatment phase and a maintenance phase.

10. The method of claim 9, wherein during the treatment period, the anti-IL23p19 antibody is administered once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, or once every twelve weeks.

11. The method of claim 9 or 10, wherein the treatment phase comprises administering the anti-IL-23p19 antibody at weeks 0, 4, and 8.

12. The method of any one of claims 9-11, wherein during the maintenance phase, the anti-IL-23p19 antibody is administered once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer, and continues for at least 24, 28, 32, 36, 40, 44, 48 weeks or longer.

13. The method according to any one of claims 9 to 12, wherein the maintenance phase is administered once every 12 weeks until the last administration at the end of the 32nd week.

14. The method according to any one of claims 1 to 13, wherein for subjects who have lost response or have a poor response to biologic treatment, anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, and then administered once every 12 weeks, for example, anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, respectively, and then administered once every 12 weeks until the last administration at the end of the 32nd week, for another example, 200 mg of anti-IL-23p19 antibody is administered at weeks 0, 4, and 8, respectively, and then 200 mg of anti-IL-23p19 antibody is administered once every 12 weeks until the last administration at the end of the 32nd week.

15. The method according to any one of claims 1-6, wherein the subject has responded to previous biologic treatment, or the subject is currently being treated with a biologic and is still responding.

16. The method according to claim 15, wherein the subject's sPGA is 0 or 1, and the cumulative body surface area of ​​lesions is <3%, or the PASI improvement after the use of biological agents reaches 75% or more.

17. The method of any one of claims 15-16, wherein the anti-IL-23p19 antibody is administered at week 0.

18. The method of any one of claims 15-17, wherein the anti-IL23p19 antibody is administered once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, or longer.

19. The method of any one of claims 15-18, wherein the anti-IL-23p19 antibody is administered at week 0 and every 12 weeks thereafter.

20. The method of any one of claims 15-19, wherein the anti-IL-23p19 antibody is administered at week 0 and every 12 weeks thereafter for at least 24, 28, 32, 36, 40, 44, 48 weeks or more to subjects who have previously responded to biologic therapy.

21. The method according to any one of claims 1 to 20, wherein the anti-IL-23p19 antibody is administered in a dose selected from 100 mg-1000 mg, preferably 150 mg-800 mg, such as 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg, preferably a dose of 200 mg per administration.

22. The method according to any one of claims 1-21, wherein the biological agent comprises a tumor necrosis factor alpha inhibitor / antagonist drug and / or an IL-17A inhibitor / antagonist drug.

23. The method according to claim 22, wherein the TNF-α inhibitor / antagonist drugs include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

24. The method according to claim 22, wherein the IL-17A inhibitor / antagonist drugs include secukinumab and ixekizumab.

25. The method of any one of claims 1-24, wherein the anti-IL-23p19 antibody is formulated for administration as a liquid pharmaceutical composition.

26. The method of claim 25, wherein the liquid pharmaceutical composition is an injection.

27. The method of any one of claims 1-26, wherein the anti-IL-23p19 antibody or pharmaceutical composition is administered by subcutaneous injection.

28. Use of an anti-IL-23p19 antibody or a pharmaceutical composition comprising an anti-IL-23p19 antibody for the preparation of a medicament for treating plaque psoriasis in a subject who has previously received a biologic for plaque psoriasis, wherein the anti-IL-23p19 antibody is as described in any one of claims 1 to 3.

29. The use of claim 28, wherein the subject is as described in any one of claims 4-8 and 15-16.

30. A single pharmaceutical dosage unit comprising the anti-IL-23p19 antibody of any one of claims 1-3.

31. The single pharmaceutical dosage unit according to claim 30, wherein the single pharmaceutical dosage unit comprises the anti-IL-23p19 antibody in a dose of 10 mg to 1000 mg, preferably 50 mg to 800 mg, more preferably 50 mg to 500 mg fixed dose, for example 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg, preferably 50, 60, 70, 80, 90, 100, 150, 200, 300, 350, 400 or 500 mg of an anti-IL-23p19 antibody.

32. The single pharmaceutical dose unit according to claim 30 or 31, wherein the single dose unit is a single dose unit packaged in a prefilled autoinjector pen.

33. A pharmaceutical kit comprising a single pharmaceutical dosage unit according to any one of claims 30 to 32, and optionally, a package insert having instructions for use of an anti-IL-23p19 antibody for preventing or treating plaque psoriasis in a patient.

34. Use of a single pharmaceutical dosage unit according to any one of claims 30 to 32 or a kit of parts according to claim 33 for the preparation of a medicament for treating plaque psoriasis.

35. A single pharmaceutical dosage unit as claimed in any one of claims 30 to 32 or a kit of parts as claimed in claim 33 for use in the treatment of plaque psoriasis.

36. The use according to claim 34, or the single pharmaceutical dosage unit according to any one of claims 30-32 or the kit of parts according to claim 33 for use according to claim 35, for use in a subject according to any one of claims 4-8 and 15-16.