Therapeutic agent for antibody-mediated rejection after renal transplantation, containing human immunoglobulin g as active ingredient
A novel IgG treatment regimen for AMR post-kidney transplantation, involving two initial 1 g/kg doses and optional boosters, effectively treats AMR with lower IgG usage, surpassing previous combination therapies in efficacy.
Patent Information
- Application Number
- JP2024023017
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2024-02-19
- Publication Date
- 2025-08-29
AI Technical Summary
Current treatments for antibody-mediated rejection (AMR) after kidney transplantation using human immunoglobulin G (IgG) alone have not been proven effective at doses lower than 2 g/kg body weight, and the efficacy of IgG monotherapy has not been established.
A therapeutic regimen involving two initial doses of human IgG at 1 g/kg body weight, administered on separate days within 10 days of treatment onset, with optional booster doses up to 6 months later, effectively treats AMR.
The regimen achieves a 95.7% transplant kidney survival rate and significant reduction in antibody titers, outperforming previous combination therapies with lower total IgG doses.
Smart Images
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Abstract
Description
[Technical Field]
[0001] In one embodiment, the present invention provides a therapeutic agent for antibody-mediated rejection after kidney transplantation, which contains human immunoglobulin G as an active ingredient, and is useful, for example, in the field of medicine. [Background technology]
[0002] Although organ transplantation has been established as a radical treatment for organ failure, it is still acknowledged that transplanted organs are lost in significant numbers due to rejection reactions, etc. In order to ensure long-term survival of transplanted organs, it is considered extremely important to suppress this rejection reaction. Rejection reactions are divided into two types based on their pathogenesis: T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). TCMR has been dramatically reduced and largely eliminated thanks to the development of various powerful immunosuppressants. On the other hand, AMR is thought to occur as a result of vascular endothelial damage caused by anti-HLA antibodies, anti-non-HLA antibodies, and antibodies against ABO blood group antigens (anti-A antibodies, anti-B antibodies). AMR is classified as acute or chronic depending on the time of onset and histopathological findings. AMR is a major cause of graft rejection, and suppressing AMR is currently a major clinical challenge in the field of organ transplantation. According to the latest national statistics for kidney transplants, which are the most common type of transplant in Japan, the most common cause of kidney transplant rejection for which the cause is known is chronic rejection (including AMR) in 24.3% (180 / 741 cases), followed by acute rejection (including AMR) in 6.6% (49 / 741 cases).When considering the long-term prognosis of patients, how to suppress these AMRs is an important issue.
[0003] Currently, treatments for AMR, such as plasma exchange therapy to remove antibodies, administration of human immunoglobulin G, and administration of rituximab, a monoclonal antibody with immunosuppressive properties that depletes B cells in order to suppress antibody production itself, are recommended in guidelines from various countries and are used clinically. Looking at the results of AMR treatment using human immunoglobulin G, for example, in the United States, the standard treatment for AMR after kidney transplants at many facilities is a combination of plasma exchange therapy and high-dose human immunoglobulin G or rituximab. Also, UK guidelines recommend that AMR treatment in kidney, heart, and lung transplant recipients be treated with human immunoglobulin G two to three times, with a maximum dose of 2g / kg body weight per treatment, and the reality is that human immunoglobulin G therapy involves the administration of high doses. On the other hand, according to the Japanese Organ Transplantation Antibody Positivity Guidelines, antibody ablation therapy alone or in combination with human immunoglobulin G and rituximab is recommended for kidney transplants. However, the efficacy of human immunoglobulin G monotherapy has not been proven, and the dosage has not yet been established. For example, Non-Patent Documents 1 and 2, which will be described later, also report on a combination therapy of human immunoglobulin G and rituximab.
[0004] As described above, to date, no known treatment for AMR after kidney transplantation that uses human immunoglobulin G alone at a single dose of 1 g / kg body weight, lower than previously reported, has been proven to be reliably effective. [Prior art documents] [Non-patent literature]
[0005] [Non-Patent Document 1] Transplant International 25 (2012) 1165-1173 [Non-patent document 2] Clin Transplant 2015:29:439-446 Summary of the Invention [Problem to be solved by the invention]
[0006] In one embodiment, the present invention aims to provide a highly effective therapeutic agent for antibody-mediated rejection after kidney transplantation, which contains human immunoglobulin G as an active ingredient and is used so that human immunoglobulin G is administered alone at a dose of 1 g / kg body weight per administration, which is lower than previously reported doses. [Means for solving the problem]
[0007] To solve the above problems, the present inventors have intensively investigated the administration regimen of human immunoglobulin G and have established a dosage and administration method for the treatment of AMR that is reliably effective even when human immunoglobulin G is used alone, thereby completing the present invention. Specific embodiments of the present invention include, but are not limited to, the following.
[0008] [1] A therapeutic agent for antibody-mediated rejection (AMR) after kidney transplantation, containing human immunoglobulin G as an active ingredient, characterized in that it is used in such a way that a patient who has developed AMR after kidney transplantation is administered a single dose of human immunoglobulin G at a dose of 1 g / kg body weight on the day treatment begins (also referred to as the "initial administration"), and then another single dose of human immunoglobulin G at the same dose on a different day within 10 days of the date of the initial administration (also referred to as the "second administration"). [2] The therapeutic agent according to the above item [1], wherein human immunoglobulin G may be further administered up to two times (also referred to as "booster administration") at a dose of 1 g / kg body weight once per day on a different day after the second administration within 10 days of the first administration. [3] The therapeutic agent according to [2] above, wherein the additional administration of human immunoglobulin G is administered 28 days or later after the initial administration. [4] The therapeutic agent according to [2] or [3] above, wherein the additional administration of human immunoglobulin G is administered within 6 months of the initial administration. [5] The therapeutic agent according to any one of the above [1] to [4], wherein the human immunoglobulin G is administered by intravenous drip infusion. [Effects of the Invention]
[0009] In one embodiment, the present invention provides a therapeutic agent for AMR after kidney transplantation, which comprises human immunoglobulin G as an active ingredient. [Brief explanation of the drawings]
[0010] [Figure 1] FIG. 1 is a conceptual diagram showing an outline of the design of the clinical trial conducted using human immunoglobulin G described in the Examples below. DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention will be described below with reference to its embodiments. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.
[0012] One embodiment of the present invention is "[1] A therapeutic agent for antibody-mediated rejection (AMR) after kidney transplantation, containing human immunoglobulin G as an active ingredient, characterized in that it is used in such a way that a patient who has developed AMR after kidney transplantation is administered a single dose of human immunoglobulin G at a dose of 1 g / kg body weight on the day treatment begins (also referred to as the "initial administration"), and then another single dose of human immunoglobulin G at the same dose on a different day within 10 days of the date of the initial administration (also referred to as the "second administration"). is.
[0013] (About human immunoglobulin G) The "human immunoglobulin G" that is the active ingredient of the present therapeutic agent is not particularly limited, and may be, for example, human blood purified to a level suitable for use as a pharmaceutical. If necessary, it may be treated with an antiviral agent or the like. Commercially available human immunoglobulin G includes, for example, Venoglobulin IH (registered trademark) for intravenous injection, manufactured by the Japan Blood Products Organization, and such commercially available products may be used appropriately in the practice of the present invention.
[0014] (About target patients) This therapeutic agent is administered to patients who have developed AMR after kidney transplantation, and AMR includes hyperacute rejection, which occurs within a few minutes to a few hours immediately after transplantation, acute rejection, which often occurs between about one week and one month after transplantation, and chronic rejection, which occurs six months to several years after transplantation.If treatment of hyperacute or acute rejection is inadequate, there is a high possibility that it will develop into chronic rejection, so treatment at the time of acute rejection is considered important. The development of AMR after kidney transplantation is determined by a physician according to the general criteria used in medical practice, and can be determined, for example, according to the selection criteria described in the Examples section below. There are no particular limitations on when treatment should be started, but it is preferable to start treatment promptly after the onset of AMR.
[0015] (About dosage and administration) This therapeutic agent contains the above-mentioned human immunoglobulin G as its active ingredient and is a treatment for AMR after kidney transplantation. However, this agent is unique in that it is intended to be administered to patients who have developed AMR after kidney transplantation according to a specific dosage and administration regimen. (1) Basic administration "Basic administration" is an essential administration for administering this therapeutic agent to patients, and refers to a total of two administrations of human immunoglobulin G, the "initial administration" and the "second administration" described below. First, on the day treatment begins (Day 1), human immunoglobulin G is administered once at a dose of 1 g / kg body weight ("first administration"). Furthermore, on another day within 10 days (Days 2 to 10) from the day of the first administration, human immunoglobulin G is administered once more at the same dose ("second administration"). Therefore, in the basic administration cycle, human immunoglobulin G is administered to the subject patient once on Day 1 and once on another day between Days 2 and 10 at a dose of 1 g / kg body weight. (2) Additional administration The dosage and administration method for this therapeutic agent is such that the administration of human immunoglobulin G is completed with the above-mentioned basic administration. "Boost administration" refers to an optional administration in addition to the basic administration, given once a day, up to twice a day, as needed, on a different day after the second administration of the above-mentioned basic administration. Additional administration will be administered if deemed necessary by a physician. In this additional administration cycle, for example, after the physician checks the clinical test values, antibody titers, clinical symptoms, etc. after the second administration of human immunoglobulin G in the basic administration (Days 2 to 10), an additional administration can be administered up to 6 months after the start of administration (Day 168) at the physician's discretion (human immunoglobulin G is administered at a dose of 1 g / kg body weight once daily). The necessity of such a booster administration can be determined, for example, based on the criteria for booster administration described in the Examples section below. It is preferable that a booster administration not be performed until one month (Day 28) after the initial administration, whenever possible. The administration of human immunoglobulin G in both of the above administration cycles can be carried out, for example, by intravenous infusion, as described below. In principle, the additional dose is as described above, but can be increased or decreased as appropriate at the discretion of the doctor depending on the patient's symptoms, and such embodiments are also considered to be included within the scope of this embodiment. In the case of intravenous infusion, by reducing the single dose from 2 g / kg body weight to 1 g / kg body weight, the administration time can be shortened, reducing the burden on patients and medical staff.
[0016] (Regarding administration route) The route of administration of this therapeutic agent is not particularly limited as long as it is suitable for administering human immunoglobulin G to patients in the above-mentioned dosage regimen, but in clinical practice it is generally administered by intravenous injection (particularly by intravenous drip infusion).
[0017] (About dosage form) There are no particular limitations on the dosage form of this therapeutic agent, as long as it is suitable for administering human immunoglobulin G to patients by intravenous injection (particularly, intravenous drip infusion) according to the above-mentioned dosage regimen. The intravenous formulation includes a formulation in which human immunoglobulin G is dissolved in a solvent (for example, water for injection, isotonic saline, etc.). The injection may contain additives as appropriate within the scope that allows the object of the present invention to be achieved, such as solubilizing agents (e.g., amino acids, sodium carbonate, sodium citrate, etc.), isotonicity agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), and buffering agents (e.g., buffer solutions such as acetate, phosphate, citrate, etc.). Those skilled in the art can appropriately prepare the above-mentioned injections using conventional formulation methods in the art.
[0018] (Combined use with other therapeutic agents and treatment methods) As will be shown in the Examples section below, when this therapeutic agent is administered to a patient according to the above-mentioned dosage regimen, it exhibits an extremely superior therapeutic effect against AMR after kidney transplantation compared to human immunoglobulin G alone. However, this does not preclude the use of other therapeutic agents and / or other treatments in clinical practice (hereinafter collectively referred to as "administration of concomitant agents, etc.") in combination with the administration of other therapeutic agents, etc., depending on the condition of the target patient, and combination therapy with administration of concomitant agents, etc., may be carried out as needed. Such combination therapy is also encompassed within the scope of the present invention. The form of combination therapy is not particularly limited, and administration of the present therapeutic agent and administration of a concomitant agent, etc., can be combined as appropriate. For example, combination therapy can be performed in the following forms: (1) simultaneous administration of the present therapeutic agent and administration of a concomitant agent, etc.; (2) administration of the present therapeutic agent followed by administration of a concomitant agent, etc.; (3) administration of a concomitant agent, etc., followed by administration of the present therapeutic agent, etc.; (4) alternate administration of the present therapeutic agent and administration of a concomitant agent, etc.; and the preferred form can be selected as appropriate, taking into account the patient's condition. [Example]
[0019] The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Those skilled in the art may modify the embodiments of the present invention in various aspects without departing from the spirit of the present invention, and such modifications are also within the scope of the present invention.
[0020] Example: Verification of the clinical effectiveness of human immunoglobulin G administration for AMR after kidney transplantation [1] Test method The clinical trial was conducted according to the following protocol. The number of subjects was 25, of which 23 were eligible for primary evaluation. (1) Purpose To investigate the efficacy and safety of administering human immunoglobulin G to patients who developed AMR after kidney transplantation. (2) Target patients The study will target patients who have been diagnosed with AMR by antibody testing (anti-HLA antibodies, anti-non-HLA antibodies, anti-A antibodies, anti-B antibodies), pathological diagnosis, etc., and who do not meet any exclusion criteria (administration of prohibited concomitant drugs, T-cell-mediated rejection (TCMR), or other criteria). (3) Investigational drug An injection containing 5g of human immunoglobulin G per vial (50mL). (4) Usage and administration A. Basal Dosage The basic administration will be as described above, with human immunoglobulin G administered intravenously twice daily at 1g / kg body weight. However, the first administration of human immunoglobulin G will be considered Day 1, and the investigational drug will be administered within three days of case registration, with the second administration completed by Day 10. B. Booster dose Additional administration is as described above. After the second administration of human immunoglobulin G in the basic administration (Days 2-10), up to two additional intravenous infusions (1 g / kg body weight twice, for a total dose of 2 g / kg body weight) can be administered as needed. (5) Design Multicenter, open-label, phase III study (6) Concomitant use of drugs Regarding immunosuppressants, new medications and increases in dosage will be avoided as much as possible from the start of the first administration (Day 1) until the end of blood collection after the start of the second administration (Days 3 to 11). (7) Prohibited Concomitant Drugs and Therapies 1) From the time of obtaining consent until the end of the clinical trial, administration of human immunoglobulin preparations other than the investigational drug and other investigational drugs is prohibited. 2) From the time of obtaining consent until the end of blood collection after the start of the second administration of human immunoglobulin G (Days 3 to 11), administration of drugs used to treat AMR (such as rituximab) is prohibited. 3) From the start of the first human immunoglobulin G administration (Day 1) until the end of blood collection after the start of the second human immunoglobulin G administration (Days 3 to 11), administration of drugs for steroid pulse therapy and plasma exchange therapy, as well as concomitant therapy, is prohibited. (8) Evaluation items A. Primary Endpoint The transplanted kidney survival rate will be evaluated 6 months after the start of administration (Day 169). B. Secondary endpoints 1) Evaluate changes in renal function (serum creatinine, eGFR, and urinary protein) from baseline. 2) Compared to baseline, evaluate the proportion of patients whose antibody titers (if multiple antibodies are detected at baseline, the antibody with the highest MFI value will be used) have decreased. 3) Survival rate 6 months after the start of treatment (Day 169) (death due to AMR)
[0021] [2] Test results (1) The primary endpoint, the transplant kidney survival rate 6 months after the start of administration, was 95.7% (95% confidence interval: 78.1-99.9%), exceeding the target efficacy rate of 85%. The high therapeutic effect of this drug on AMR was confirmed with the dosage and administration method established in this study.
[0022] (2) Only 5 out of 23 cases required additional administration after the second administration of human immunoglobulin G (Days 2 to 10) described in Section B of (4) Dosage and Administration above (an additional administration of 1 g / kg body weight in 1 case, and an additional administration of 2 g / kg body weight in 4 cases; the average total dose of human immunoglobulin G including the basic administration and the additional administration: 2.3 g / kg body weight). Therefore, it was confirmed that human immunoglobulin G exhibits sufficient therapeutic effects against AMR with only the initial two doses (basal doses) described in A of the above section (4) Dosage and Administration. (3) The rate of decrease in antibody titer 6 months after the start of administration was 60.9% (14 of 23 cases). The rate of decrease in antibody titer 6 months after the start of administration by antibody type was 69.6% (16 of 23 cases) for anti-HLA antibodies and 65.2% (15 of 23 cases) for anti-non-HLA antibodies. From the above, it was confirmed that administration of human immunoglobulin G at the dosage and administration method established in this study showed a significant reduction in antibody titers. (4) No clinically significant changes were observed in serum creatinine levels before and after administration of human immunoglobulin G according to the dosage and administration method established in this study (1.563±0.7321 mg / dL at baseline, 1.453±0.4635 mg / dL 6 months after the start of administration). (5) These test results confirmed that human immunoglobulin G is effective in treating patients who develop AMR after kidney transplantation.
[0023] In Non-Patent Document 1, human immunoglobulin G at 1 g / kg body weight was administered once a week for 4 weeks (a total of 4 administrations; a total dose of 4 g / kg body weight) during the acute phase of AMR, and rituximab (375 mg / m 2 The effect of a combination regimen in which 100 mg / body surface area (mg / kg body surface area) was administered on AMR after kidney transplantation was examined, and it was reported that the survival rate after 6 months was 90.0% (18 out of 20 cases). Non-patent document 2 describes a single administration of 500 mg of methylprednisolone on the first day, followed by rituximab (375 mg / m 2 / body weight) once each (2 times in total) and 1g / kg body weight of human immunoglobulin G once each week in weeks 1 to 4 (4 times in total; total dose 4g / kg body weight), was administered, and the effect on AMR after kidney transplantation was investigated, and the survival rate after 6 months was reported to be 90.5% (19 out of 21 cases). As mentioned above, both "human immunoglobulin G" and "rituximab" are recommended for use in national guidelines for the treatment of AMR, and are representative AMR treatments currently in use in the medical field. Non-Patent Documents 1 and 2 examine the therapeutic effects of AMR using "combination regimens" that combine these two representative drugs, and the dosage and administration of human immunoglobulin G in these combination regimens are very similar to the dosage and administration of human immunoglobulin G established in this study. Therefore, the effects of the combination regimens described in Non-Patent Documents 1 and 2 are appropriate for comparison with the effects of the administration regimen in this study. The effects of the administration regimen in this study will be described below in comparison with the effects of the combination regimens described in Non-Patent Documents 1 and 2.
[0024] In this study, only 5 of 23 cases required additional administration, and in 18 cases, the total dose of human immunoglobulin G administered over the first 6 months of administration was 2 g / kg body weight. Even including cases requiring additional administration, the average total dose of human immunoglobulin G administered over the first 6 months of administration was 2.3 g / kg body weight, which is roughly half the total dose of human immunoglobulin G administered in the combination regimens described in Non-Patent Documents 1 and 2 (4 g / kg body weight), and AMR was controlled with this low dose. This low average total dose of human immunoglobulin G, combined with monotherapy, achieved a 95.7% engraftment rate, exceeding the results in Non-Patent Documents 1 and 2. Therefore, it is clear that the administration regimen of human immunoglobulin G in the dosage and administration method established in this study is a convenient and highly tolerable administration regimen for treating AMR using human immunoglobulin G alone, which could never be predicted from the track record of conventional AMR treatments after kidney transplantation. Therefore, the present invention provides to the medical field a novel therapeutic agent for AMR after kidney transplantation that exhibits excellent therapeutic effects based on this administration regimen. [Industrial Applicability]
[0025] In one embodiment, the present invention provides a therapeutic agent for AMR after kidney transplantation, which contains human immunoglobulin G as an active ingredient and is used so that human immunoglobulin G is administered at a dose of 1 g / kg body weight per administration, and is useful, for example, in the field of medicine.
Claims
1. A therapeutic agent for antibody-mediated rejection (AMR) after kidney transplantation, comprising human immunoglobulin G as an active ingredient, wherein the human immunoglobulin G is administered once at a dose of 1 g / kg body weight ("initial administration") on the day treatment is started to a patient who has developed AMR after kidney transplantation, and the human immunoglobulin G is further administered once more at the same dose ("second administration") on another day within 10 days from the day of the initial administration.
2. The therapeutic agent of claim 1, wherein human immunoglobulin G may be administered up to two additional times ("booster doses") at a dose of 1 g / kg body weight once per day on different days after the second administration within 10 days of the first administration.
3. The method according to claim 2, wherein the additional administration of human immunoglobulin G is administered 28 days or later after the initial administration.
4. The method according to claim 2 or 3, wherein the additional administration of human immunoglobulin G is administered within 6 months after the initial administration.
5. The therapeutic agent according to claim 1 or 2, wherein the human immunoglobulin G is administered by intravenous drip infusion.