Use of FcRn inhibitors in the preparation of drugs that eliminate donor-specific antibodies

Abstract

This invention belongs to the field of biomedical technology, specifically relating to the application of FcRn inhibitors in the preparation of drugs for clearing anti-HLA antibodies (especially donor-specific antibodies DSA). Preferably, the FcRn inhibitor is egamod. Research results show that egamod, through its mechanism of targeting the neonatal Fc receptor (FcRn), has the advantages of rapid onset of action, efficient clearance of target antibodies, and good safety, making it a novel intervention approach for clearing HLA antibodies and / or DSA in gene therapy for thalassemia or other disease treatments, as well as for preventing and treating diseases such as transplant rejection and platelet transfusion ineffectiveness.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of FcRn inhibitors in the preparation of drugs that clear anti-HLA antibodies (especially donor-specific antibodies DSA). Background Technology

[0002] In the clinical transfusion and transplantation fields, anti-HLA antibodies (especially donor-specific antibodies (DSA)) are a core factor mediating platelet transfusion ineffectiveness and graft rejection. Epidemiological studies show that approximately 30% of patients who have received multiple transfusions (especially those with hematologic malignancies and those undergoing stem cell transplantation) develop anti-HLA antibodies. These antibodies can recognize and attack the donor's HLA molecules, activating an immune response and leading to rejection. Furthermore, these antibodies can cause platelet transfusion ineffectiveness, with women (69%), those with a high estimated population response rate (median 95%), and those with a history of multiple pregnancies being high-risk groups. Antibody characterization analysis shows that when the cumulative DSA-MFI ≥ 10,000, the 2-hour corrected platelet count increment (CCI) decreases sharply (P<0.001), and 87% activate complement C1q; when MFI ≥ 6,000, the median post-transfusion CCI drops to 0, and the clearance difficulty of anti-HLA-DQ antibodies is significantly higher than that of anti-DR antibodies (median clearance time 74 days). vs (18 days).

[0003] To address the harm caused by DSA, the clearance strategy focuses on triple intervention: plasma exchange (5 times) + IVIG (2 g / kg) + rituximab (375 mg / m²). 2 The baseline regimen is 4 weeks (×4 weeks). Early intervention (≤ 7 days) can achieve an 88% clearance rate, while delayed treatment (>433 days) significantly reduces efficacy (P=0.0002). Innovative technologies such as computer algorithms optimize donor matching by accumulating DSA-MFI, reducing screening time from 15 minutes to <2 minutes; virtual crossmatching (such as HLA-Matchmaker) expands the scope of "permissible mismatches." Notably, early clearance of asymptomatic DSA can achieve 8-year survival rates comparable to the DSA-negative group in transplant patients (P=0.37), but high MFI (>10,000), anti-HLA-A / DQ antibodies, and complement activation remain the main causes of clearance failure. Current challenges lie in elucidating drug resistance mechanisms and the synergistic weakening effect of ABO incompatibility on low MFI-DSA, necessitating the exploration of targeted drugs to improve clearance efficiency.

[0004] Current DSA clearance strategies face multiple efficacy defects: antibody clearance efficiency exhibits significant site-specific differences, with HLA-A / B antibody clearance exceeding 70% while HLA-C / DP clearance is less than 40%. This difference is directly related to antigen expression levels—platelet surface HLA-A / B molecules exceed 10-1. 4HLA-C counts are only about 3,000 per cell, making low-expressed antigens more likely to escape clearance. Epitope immunogenicity further restricts clearance efficacy; highly immunogenic epitopes such as 41T, 62GE, and 145KHA induce antibodies that form stable immune complexes that resist proteolytic degradation. Among these, anti-DQ antibody clearance takes a median of 74 days with a 1-year relapse rate exceeding 30%, while anti-DR antibody clearance takes only 18 days. The drug mechanism has a fundamental limitation—rituximab only targets CD20. + B cells cannot eliminate long-lived plasma cells; bortezomib can inhibit plasma cells but causes thrombocytopenia with a side effect rate as high as 53%; IVIG accelerates antibody degradation through the FcRn saturation mechanism but is ineffective against high-affinity IgG (K). d <10 -10 M) is ineffective; drug resistance is a prominent issue. Patients who remain positive after clearing C1q-positive DSA (MFI>10,000) have a platelet recovery correction index (CCI) that is consistently <5,000, and anti-DQ antibodies are prone to rebound through memory B cell reactivation. These defects collectively lead to a desensitization failure rate of over 30%, necessitating the development of epitope-specific clearance technologies. Summary of the Invention

[0005] To overcome the defects and shortcomings of existing technologies, this invention provides the use of FcRn inhibitors in the preparation of drugs that clear anti-HLA antibodies (especially donor-specific antibodies DSA). Aigamod accelerates antibody degradation by targeting FcRn and blocking the recovery process of IgG antibodies.

[0006] Specifically, the present invention is achieved through the following technical solutions: This invention provides the use of FcRn inhibitors in the preparation of drugs that eliminate anti-HLA antibodies.

[0007] Alternatively, in the above-described uses, the anti-HLA antibody is a donor-specific antibody (DSA).

[0008] Alternatively, in the above-described uses, the FcRn inhibitor is agamod.

[0009] Alternatively, in the above-described uses, the use is to clear HLA antibodies and / or DSA in gene therapy for thalassemia or in the treatment of other diseases.

[0010] Alternatively, in the above-described uses, the removal of HLA antibodies and / or DSA refers to the removal of DSA or the reduction of DSA or HLA antibodies.

[0011] Alternatively, in the above-described uses, the drug may be a subcutaneous or intravenous formulation.

[0012] Alternatively, in the above-described uses, the intravenous administration dose is 10 mg / kg, administered intravenously over 1 hour, once a week for a total of 2 weeks.

[0013] Alternatively, in the above-described uses, the subcutaneous administration formulation may further contain hyaluronidase.

[0014] Alternatively, in the above-described uses, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0015] Alternatively, in the above-described uses, the purpose is to prevent or treat HLA antibody-mediated platelet transfusion ineffectiveness and transplant rejection.

[0016] Efgartigimod, as the world's first FcRn antagonist, is innovative in clearing pathogenic antibodies (such as anti-HLA antibodies, especially DSA) mainly in the following aspects: (1) Unique Mechanism of Action: Egamod targets and binds to the neonatal Fc receptor (FcRn), blocking its recycling process with immunoglobulin G (IgG). Under physiological conditions, FcRn protects IgG from lysosomal degradation, prolonging its half-life; while Egamod competitively binds to FcRn, preventing the recovery of pathogenic IgG antibodies, thereby accelerating their degradation in vivo and significantly reducing serum antibody levels. This mechanism mimics the effect of "biological plasma exchange," but avoids the blood-source dependence and infection risk of traditional plasma exchange. High Selectivity and Safety Advantages: Unlike traditional immunosuppressants (such as glucocorticoids), Egamod specifically targets only IgG antibodies, with no significant effect on other immunoglobulins such as IgA and IgM, thus avoiding widespread immunosuppression and reducing the risk of infection. Clinical studies show that its adverse reactions are mainly mild to moderate (such as headache and respiratory infection), with an incidence rate comparable to placebo, and without the typical risks of traditional treatments such as liver and kidney toxicity or bone marrow suppression. Safety data for long-term use also show that the risk of infection does not increase with the duration of treatment.

[0017] (2) Rapid onset of action and sustained response: Aigamod has a rapid onset of action in clearing antibodies. The global Phase III clinical trial (ADAPT) showed that within the first treatment cycle (4 weeks), 77.8% of patients with acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG) showed an improvement of ≥2 points in the Daily Living Scale (MG-ADL), 74.2% showed an improvement of ≥3 points in the muscle strength score (QMG), and 40% reached the minimum clinical manifestation. In its application for DSA, it can also rapidly reduce antibody titers, providing a timely intervention for organ transplant rejection. In addition, although its antibody clearance effect is reversible, antibody levels can be continuously controlled through periodic administration (every 4 weeks is one cycle).

[0018] (3) Innovative Treatment Concept: Aigamod propels autoimmune diseases into a new era of "precise elimination of pathogenic antibodies." Traditional treatments rely on non-specific immunosuppression (such as hormones or chemotherapy drugs), which have significant side effects and limited efficacy; while Aigamod directly eliminates pathogenic antibodies, realizing a paradigm shift from "comprehensive immune suppression" to "precise targeted elimination." This mechanism is not only applicable to gMG, but also provides new ideas for other antibody-mediated diseases (such as transplant rejection and immune thrombocytopenic purpura). Clinical Convenience and Patient Benefits: Its intravenous infusion time is only 1 hour / time (traditional immunoglobulin infusion requires 4-6 hours), and the future development of subcutaneous formulations will further improve the convenience of medication. Patients can significantly improve their quality of life through periodic treatment, achieving "dual goals" (symptom control + minimal side effects) and returning to a normal life.

[0019] In summary, Aigamod, with its core FcRn targeting mechanism, represents a groundbreaking innovation in the treatment of autoimmune diseases through its efficient antibody clearance, safety advantages, and rapid and sustained clinical response, providing a new pathway for the intervention of related diseases mediated by anti-HLA antibodies. Attached Figure Description

[0020] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings: Figure 1 Scatter plot comparing DSA antibody MFI values ​​before and after egamod treatment.

[0021] Figure 2 Bar chart showing the percentage decrease in average MFI corresponding to the specificity of the top 10 antibodies.

[0022] Figure 3 Pie chart showing the decrease in DSA antibody MFI after egamod treatment.

[0023] Figure 4 Histogram showing the percentage decrease in DSA antibody MFI after egamod treatment. Detailed Implementation

[0024] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0025] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0026] The present invention will be further illustrated below with reference to the embodiments: Example: The inventors presented DSA test results from 15 patients with thalassemia (from the Cell and Gene Therapy Center of Guangzhou First People's Hospital), and observed a visible decrease in DSA or HLA antibodies after using eigamod. The specific administration method was 10 mg / kg of the product, administered intravenously over 1 hour, once a week for a total of 2 weeks. The MFI values ​​of different DSA or HLA subtypes before and after eigamod infusion were compared. The experiment used the Luminex method, with LabScreen Single Antigen as the detection reagent. The MFI value is the fluorescence intensity of the microbead reaction, representing the reaction intensity of the microbead. Standardized relative fluorescence intensity values ​​were used for the MFI values. Interpretation criteria: MFI value > 8000 was strongly positive; MFI value 5000–8000 was moderately positive; MFI value 2000–5000 was positive; MFI value 1000–2000 was suspiciously positive; MFI value < 1000 was negative.

[0027] Figures 1 to 4 This study presents comparative data on DSA levels in patients before and after treatment with eigamod. Overall, the results indicate that DSA levels significantly decreased after eigamod treatment.

[0028] Figure 1 This is a scatter plot comparing DSA antibody MFI values ​​before and after eigenmod treatment. The plot presents the correlation between pre-treatment MFI values ​​(horizontal axis, reflecting pre-treatment DSA antibody levels) and post-treatment MFI values ​​(vertical axis, reflecting post-treatment DSA antibody levels) in patients receiving eigenmod treatment. Two key reference lines are included: the red dashed line represents no change (slope = 1), signifying "post-treatment MFI = pre-treatment MFI" (the ideal state of no treatment effect); points below the dashed line indicate a decrease in antibody levels after treatment (effective drug clearance), while points above indicate an increase in antibody levels. The blue solid line is the trend line (slope = 0.87), which shows the overall trend by fitting all data points: a slope < 1 indicates that, overall, post-treatment MFI values ​​increase with pre-treatment levels, but the increase is weaker than in the "no change" state, suggesting that eigenmod has a clearing effect on DSA antibodies. The scatter plot (green dots) represents the combination of MFI values ​​before and after treatment for a single patient. Most of the dots are below the line of no change (especially in people with high MFI values ​​before treatment), which further supports the conclusion that "Agamod can effectively reduce DSA antibody levels in most patients". A few dots near or above the dashed line may reflect individual differences or poor drug response.

[0029] Figure 2This is a bar chart showing the average percentage decrease in MFI for the top 10 antibody specificities. The chart displays the average percentage decrease in MFI for the top 10 common antibody specificities (horizontal axis, such as A24 (A24:02), A23 (A23:01), etc.) in patients treated with egamod (vertical axis, reflecting the relative reduction in antibody levels after treatment; higher values ​​indicate a stronger clearing effect of the drug on that antibody specificity). Different colored bars distinguish different antibody specificities, and the specific percentages marked at the top of the bars (e.g., A24 (A24:02) reaches 99.5%, A69 (A69:01) is 89.7%) visually present the average decrease in the specificity of each antibody: the average decrease percentage of the first few antibody specificities (such as A24 subtype, A23, A25, etc.) is close to or exceeds 97%, indicating that iatrovid has a particularly significant clearing effect on these common DSA antibody specificities; although the decrease percentage of the latter few (such as B39, A1, A69, etc.) is slightly lower, it still remains above 89.7%, which overall reflects the effective clearing effect of the drug on multiple DSA antibody specificities.

[0030] Figure 3 This is a pie chart categorizing the decrease in DSA antibody MFI after eigamod treatment. The chart shows the distribution of the decrease in DSA antibody MFI (mean fluorescence intensity) among patients treated with eigamod (divided into four categories based on the percentage decrease). The sectors and their corresponding percentages are as follows: Gray sector: decrease <10%, 12.0% (indicating that a small number of patients have almost no or minimal decrease in antibody levels); Purple sector: decrease 10-30%, 8.2% (indicating that a small number of patients have a slight decrease in antibody levels); Green sector: decrease 30-50%, 18.4% (indicating that some patients have a moderate decrease in antibody levels); Orange sector: decrease 50-80%, 35.4% (indicating that nearly one-third of patients have a significant decrease in antibody levels); Blue sector: decrease >80%, 25.9% (indicating that about one-quarter of patients have almost completely cleared antibody levels). Overall, over 80% of patients (35.4% + 25.9% + 18.4%) experienced a decrease in MFI of ≥30%, with patients experiencing a decrease of 50-80% and >80% accounting for a combined 61.3%, indicating that egamod has a significant clearance effect on DSA antibodies in most patients; only 20.2% (12.0% + 8.2%) of patients experienced a decrease of <30%, reflecting that the drug's antibody clearance effect was relatively limited in this group of patients.

[0031] Figure 4This is a histogram showing the distribution of the percentage decrease in DSA antibody MFI after eigamod treatment. The horizontal axis represents the "MFI decrease percentage (%)", indicating the reduction in antibody levels after treatment relative to pre-treatment levels; the vertical axis represents the "frequency", indicating the number of patients within the corresponding percentage decrease range. The red dashed line in the figure marks the average MFI decrease percentage (55.2%) for all patients, visually reflecting the central trend of overall clearance efficacy. From the distribution perspective: the highest frequency (12 cases) was in the range of approximately 40% decrease, indicating that the antibody level decrease was concentrated in this range for a large number of patients; the frequency of the 85% to 90% decrease range was also relatively high (approximately 11 cases), reflecting that the antibodies in some patients were almost completely cleared; the overall distribution showed a multi-peak characteristic (such as peaks around 40%, 60%, and 85%), indicating heterogeneity in the response to the drug among patients, but the average value of 55.2% and the frequency distribution of most ranges (such as the dense frequency in the 50% to 80% range) still support the conclusion that "Agamod has a significant clearance effect on DSA antibodies in most patients".

[0032] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Use of FcRn inhibitors in the preparation of drugs that eliminate anti-HLA antibodies.

2. The use according to claim 1, characterized in that: The anti-HLA antibody is a donor-specific antibody (DSA).

3. The use according to claim 1 or claim 2, characterized in that: The FcRn inhibitor is iatrovid.

4. The use according to claim 1 or claim 2, characterized in that: The intended use is to clear HLA antibodies and / or DSA in gene therapy for thalassemia or in the treatment of other diseases.

5. The use according to claim 4, characterized in that: The removal of HLA antibodies and / or DSA refers to the removal of DSA or the reduction of DSA or HLA antibodies.

6. The use according to claim 3, characterized in that: The drug is a subcutaneous or intravenous administration preparation.

7. The use according to claim 6, characterized in that: The intravenous administration dose is 10 mg / kg, administered via intravenous infusion over 1 hour, once a week for a total of 2 weeks.

8. The use according to claim 6, characterized in that: The subcutaneous administration formulation also contains hyaluronidase.

9. The use according to claim 8, characterized in that: The hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

10. The use according to any one of claims 1 to 3, characterized in that: The intended use is to prevent or treat HLA antibody-mediated platelet transfusion ineffectiveness and transplant rejection.

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