Monoclonal antibodies targeting human complement c5 and uses thereof

Abstract

The present application relates to a kind of monoclonal antibody targeting human complement C5 and its application, the monoclonal antibody includes heavy chain variable region and light chain variable region, the heavy chain variable region includes HCDR1, HCDR2 and HCDR3, the light chain variable region includes LCDR1, LCDR2 and LCDR3.This antibody or its antigen binding fragment has strong binding capacity with human complement C5, and blocks the cleavage activation of C5 convertase to complement C5.Moreover, the C5 activation mediated by the activation of complement classical pathway and alternative pathway can be blocked simultaneously.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological medicine, and relates to a monoclonal antibody targeting human complement C5 and application thereof. BACKGROUND

[0002] As an important part of natural immunity, the complement system participates in host defense, inflammation regulation and tissue homeostasis through a cascade reaction. Among them, complement component C5, as a key node of the terminal complement pathway, plays a core role in various pathological processes through its cleavage products C5a (a strong chemotactic factor) and C5b (a precursor of membrane attack complex C5b-9). Abnormal activation of C5 can drive the progression of various immune-related diseases through mechanisms such as recruitment of inflammatory cells, mediation of endothelial damage and direct lysis of target cells. Studies have shown that overactivation of the C5 signaling pathway is closely related to diseases such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (gMG), neuromyelitis optica spectrum disorder (NMOSD), and is significantly associated with chronic inflammatory diseases, ischemia-reperfusion injury and age-related macular degeneration (AMD).

[0003] At present, targeted therapy for C5 (such as anti-C5 monoclonal antibodies Eculizumab, Ravulizumab and Crovalimab, etc.) has shown significant clinical efficacy by blocking C5 cleavage, but its application still faces many challenges: including the decline in patient compliance caused by frequent administration, the heterogeneity of drug response in some patients due to genetic polymorphism, and the risk of infection caused by long-term inhibition of C5. Therefore, the development of new C5 inhibitors with improved pharmacokinetic properties, higher target affinity or the ability to overcome individual differences has become an important research direction to improve clinical efficacy and expand the scope of indications. The C5 monoclonal antibody inhibitor of the present application aims to provide a better therapeutic window and disease indication control potential through innovative epitope selection and antibody engineering technology. SUMMARY

[0004] In view of the deficiencies in the prior art, the purpose of the present application is to provide a monoclonal antibody targeting human complement C5 and application thereof.

[0005] To achieve this application purpose, the following technical solutions are adopted in the present application:

[0006] In a first aspect, the present application provides a monoclonal antibody targeting human complement C5, the monoclonal antibody comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, and the light chain variable region comprising LCDR1, LCDR2 and LCDR3,

[0007] the amino acid sequence of the HCDR1 comprises the sequence set forth in SEQ ID NO. 1, the amino acid sequence of the HCDR2 comprises the sequence set forth in SEQ ID NO. 2, and the amino acid sequence of the HCDR3 comprises the sequence set forth in SEQ ID NO. 3;

[0008] the amino acid sequence of the LCDR1 comprises the sequence set forth in SEQ ID NO. 4, the amino acid sequence of the LCDR2 comprises the sequence set forth in SEQ ID NO. 5, and the amino acid sequence of the LCDR3 comprises the sequence set forth in SEQ ID NO. 6.

[0009] Optionally, the amino acid sequence of the heavy chain variable region comprises the sequence set forth in SEQ ID NO. 7.

[0010] Optionally, the amino acid sequence of the light chain variable region comprises the sequence set forth in SEQ ID NO. 8.

[0011] In a second aspect, the present application provides a nucleic acid molecule encoding the monoclonal antibody targeting human C5 according to the first aspect.

[0012] In a third aspect, the present application provides an expression vector comprising the nucleic acid molecule according to the second aspect.

[0013] In a fourth aspect, the present application provides a host cell comprising the expression vector according to the third aspect.

[0014] In a fifth aspect, the present application provides use of the monoclonal antibody targeting human complement C5 according to the first aspect or the expression vector according to the third aspect in the preparation of a detection reagent, wherein the target of the detection reagent is human complement C5.

[0015] In a sixth aspect, the present application provides a pharmaceutical composition comprising the monoclonal antibody targeting human complement C5 according to the first aspect, and a pharmaceutically acceptable carrier and / or diluent.

[0016] In a seventh aspect, the present application provides use of any one or at least two of the monoclonal antibody targeting human complement C5 according to the first aspect, the expression vector according to the third aspect, the host cell according to the fourth aspect, or the pharmaceutical composition according to the sixth aspect in the preparation of a medicament for preventing, ameliorating, or treating an autoimmune disease or a medicament for inhibiting immune rejection.

[0017] Compared with the prior art, the present application has the following beneficial effects:

[0018] The antibody or antigen binding fragment thereof has strong binding ability with human complement C5, and blocks the enzymatic cleavage of complement C5 convertase on C5. Meanwhile, it can inhibit the signal transduction pathway of complement classical pathway and alternative pathway and downstream regulatory signal, and can block the activation of upstream activation signal on C5. The antibody does not have ADCC effect, ADCP effect and CDC effect, and avoids causing immune cell killing and phagocytosis of target cells containing C5 after binding with C5. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 is the detection result of the binding activity of humanized antibody 6E3-H1L1 with complement C5;

[0020] Figure 2 is the ability of humanized antibody 6E3-H1L1 to block the activation of complement classical pathway;

[0021] Figure 3 is the ability of humanized antibody 6E3-H1L1 to block the activation of alternative classical pathway;

[0022] Figure 4 is the ADCC ability mediated by humanized antibody 6E3-H1L1. DETAILED DESCRIPTION

[0023] The technical solutions of the present application are further illustrated by specific embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present application, and should not be regarded as specific limitations on the present application.

[0024] Example 1

[0025] Preparation of human complement C5 murine antibody

[0026] The full-length protein sequence of human complement C5 (P01031) was used as an immunizing antigen to immunize 8-week-old female Balb / c mice. The first immunization was performed by subcutaneous injection of the purified antigen and complete Freund's adjuvant, 50 μL per point, 6 injection points. The second, third and fourth immunizations were performed by subcutaneous injection of the antigen and incomplete adjuvant, 50 μL per point, 6 injection points. On the 7th day after the fourth immunization, the mice were bled from the tail vein for titer detection. The mouse with the highest titer was selected for booster immunization by intraperitoneal injection of the antigen, 25 μg per mouse. Three days later, the mouse spleen was taken in a sterile environment. The mouse spleen was subjected to histological separation, chopped and made into a single cell suspension. The two cells were mixed at a ratio of spleen cells: SP2 / 0 = 10:1, and the collected spleen cells were washed twice with IMEM medium. After centrifugation of the mixed cells, the supernatant was removed, PEG1500 was slowly added to the cell mass, and after incubation for 2 minutes, IMEM 2 mL was added to terminate the cell fusion reaction, and then IMEM 10 mL was slowly added at 800 rpm to discard the supernatant. Then, sufficient IMEM containing double antibodies and 15% FBS (1×HAT) was added to resuspend the cells. According to 300 μL of cell suspension per well, it was added to a 96-well cell culture plate. The 96-well plate was placed in a 37°C cell culture incubator for culture, and hybridoma clones were obtained after 10 days. The positive clones were obtained by limiting dilution method to obtain single cell positive clones, and the positive clones were cultured to harvest the cell culture supernatant. The cell supernatant was purified by Protein A / G affinity chromatography column to obtain anti-human complement C5 protein antibody, and the human complement C5 murine antibody m6E3 was obtained.

[0027] The amino acid sequence of the heavy chain variable region of m6E3 is shown in SEQ ID NO. 11.

[0028] SEQ ID NO. 11:

[0029] EVQLQQSGPELVKPGASVKISCKTS GYTFTENT MLWVKQSHGKSLEWIGG IIPNNGDT DYNQKFKGKATLTVDRSSSTAYMELRSLTSEDSAVYYC ARSLLRLLPFDY WGQGTTLTVSS.

[0030] The amino acid sequence of HCDR1 in the heavy chain variable region is shown in SEQ ID NO. 1, the amino acid sequence of HCDR2 is shown in SEQ ID NO. 2, and the amino acid sequence of HCDR3 is shown in SEQ ID NO. 3.

[0031] SEQ ID NO. 1: GYTFTENT .

[0032] SEQ ID NO. 2: IIPNNGDT .

[0033] SEQ ID NO. 3: ARSLLRLLPFDY .

[0034] The nucleotide sequence of the heavy chain variable region of m6E3 is shown in SEQ ID NO. 12.

[0035] SEQ ID NO. 12:

[0036] GATATTGTGATGACCCAGAGCCATAAATTTATGAGCACCAGCGTGGGCGATCGCGTGAGCATTACCTGCAAAGCGAGCCAGGATGTGAGCACCGCGGTGGCGTGGTATCAGCAGAAACCGGGCCTGAGCCCGAAACTGCTGATTTATTGGGCGAGCACCCGCCATACCGGCGTGCCGGATCGCTTTACCGGCAGCGGCAGCGGCACCGATTTTACCCTGACCATTAGCAGCGTGCAGGCGGAAGATCTGGAACTGTATTATTGCCAGCAGCATTATGATACCCCGTGGACCTTTGGCGGCGGCACCAAACTGGATATTAAACGC.

[0037] The amino acid sequence of the light chain variable region of m6E3 is shown in SEQ ID NO. 13.

[0038] SEQ ID NO. 13:

[0039] DIVMTQSHKFMSTSVGDRVSITCKAS QDVSTA VAWYQQKPGLSPKLLIY WAS TRHTGVPDRFTGSGSGTDFTLTISSVQAEDLELYYC QQHYDTPWT FGGGTKLDIKR.

[0040] The amino acid sequence of LCDR1 in the light chain variable region is shown in SEQ ID NO. 4, the amino acid sequence of LCDR2 is shown in SEQ ID NO. 5, and the amino acid sequence of LCDR3 is shown in SEQ ID NO. 6.

[0041] SEQ ID NO. 4: QDVSTA .

[0042] SEQ ID NO.5: WAS .

[0043] SEQ ID NO.6: QQHYDTPW .

[0044] The nucleotide sequence of the light chain variable region of m6E3 is shown in SEQ ID NO.14.

[0045] SEQ ID NO.14:

[0046] GAAGTGCAGCTGCAGCAGAGCGGCCCGGAACTGGTGAAACCGGGCGCGAGCGTGAAAATTAGCTGCAAAACCAGCGGCTATAACCTTTACCGAAAACACCATGCTGTGGGTGAAACAGAGCCATGGCAAAAGCCTGGAATGGATTGGCGGCATTATTCCGAACAACGGCGATACCGATTA TAACCAGAAATTTAAAGGCAAAGCGACCCTGACCGTGGATCGCAGCAGCAGCACCGCGTATATGGAACTGCGCAGCCTGACCAGCGAAGATAGCGCGGTGTATTATTGCGCGCGCAGCCTGCTGCGCCTGCTGCCGTTTGATTGGGGCCAGGGCACCACCCTGACCGTGAGCAGC.

[0047] Example 2

[0048] Preparation of human complement C5 humanized antibody

[0049] For the variable regions of the heavy and light chains of the m6E3 antibody, a human antibody framework most closely related to its murine frame sequence was selected for CDR region transplantation. Humanization mutations were performed on some amino acid sequences in the FW region, and reversion mutations were performed on residues that significantly affect the conformation of VH and VL, resulting in humanized antibodies 6E3-HwLw, 6E3-H1L1, and 6E3-H2L1. The heavy chain sequence of the humanized antibody 6E3-H1L1 is shown in SEQ ID NO. 15, and the amino acid sequence of the light chain variable region includes the sequence shown in SEQ ID NO. 16.

[0050] SEQ ID NO.15:

[0051] QVQLVQSGAEVKKPGASVKVSCKTSGYTFTENTMLWVKQAPGQGLEWIGGIIPNNGDTDYNQKFKGRVTLTRDTSSSTAYMELSRLTSEDTAVYYCARSLLRLLPFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.

[0052] SEQ ID NO. 16:

[0053] DIVMTQSPDSLAVSLGERATINCKASQDVSTAVAWYQQKPGQPPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVEVYYCQQHYDTPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

[0054] The nucleotide sequences of the heavy and light chains of 6E3-H1L1 shown are set forth in SEQ ID NO. 17 and SEQ ID NO. 18.

[0055] SEQ ID NO. 17

[0056]

[0057] SEQ ID NO.18

[0058] GATATTGTGATGACCCAGAGCCCGGATAGCCTGGCGGTGAGCCTGGGCGAACGCGCGACCATTAACTGCAAAGCGAGCCAGGATGTGAGCACCGCGGTGGCGTGGTATCAGCAGAAACCGGGCCAGCCGCCGAAACTGCTGATTTATTGGGCGAGCACCCGCCATACCGGCGTGCCGGATCGCTTTAGCGGCAGCGGCAGCGGCACCGATTTTACCCTGACCATTAGCAGCCTGCAGGCGGAAGATGTGGAAGTGTATTATTGCCAGCAGCATTATGATACCCCGTGGACCTTTGGCGGCGGCACCAAACTGGAAATTAAACGCACCGTGGCGGCGCCGAGCGTGTTTATTTTTCCGCCGAGCGATGAACAGCTGAAAAGCGGCACCGCGAGCGTGGTGTGCCTGCTGAACAACTTTTATCCGCGCGAAGCGAAAGTGCAGTGGAAAGTGGATAACGCGCTGCAGAGCGGCAACAGCCAGGAAAGCGTGACCGAACAGGATAGCAAAGATAGCACCTATAGCCTGAGCAGCACCCTGACCCTGAGCAAAGCGGATTATGAAAAACATAAAGTGTATGCGTGCGAAGTGACCCATCAGGGCCTGAGCAGCCCGGTGACCAAAAGCTTTAACCGCGGCGAATGC。

[0059] Example 3

[0060] Binding activity of human complement C5 antibody to C5

[0061] ELISA method was used to detect the binding activity of complement C5 humanized antibody. C5 protein was diluted to 1 μg / mL with CBS buffer, coated in an enzyme-labeled plate at 50 μL / well, and placed at 4°C overnight. The plate was washed with PBST buffer 200 μL / well for 3 times. Then 1% BSA dissolved in PBS was added, 200 μL / well, and incubated at 37°C for 1 hour. After incubation, the plate was washed with PBST 3 times, 200 μL / well. The positive control PcAb (Crovalimab, self-made, expressed by Roche antibody sequence) and complement humanized antibody were diluted to 3 μg / mL, gradient diluted by 3 times dilution method, and 100 μL was transferred to the enzyme-labeled plate by a syringe and incubated at 37°C for 1 h. After incubation, the plate was washed with PBST 3 times, 200 μL / well, and dried. HRP-labeled anti-human (or mouse) IgG antibody (both diluted 1:10,000) was diluted with 1% BSA dissolved in PBS, 100 μL / well. Incubate at 37°C for 1 h; after incubation, wash the plate with PBST 3 times, 200 μL / well, and dry. Add 50 μL TMB color developing solution to each well for color development reaction for 5 min, then add 50 μL / well hydrochloric acid to stop the reaction. The absorbance at 450 nm (OD450) was detected by the absorption mode of the enzyme-labeled instrument. The ELISA detection results are shown in Figure 1 .

[0062] As can be seen from Figure 1 , the complement C5 humanized antibodies 6E3-HwLw, 6E3-H1L1, 6E3-H2L1 and m6E3 have strong binding capacity with complement C5 protein, and the EC50 of the obtained antibodies are: 6E3-HwLw = 0.039 μg / mL, 6E3-H1L1 = 0.019 μg / mL, 6E3-H2L1 = 0.020 μg / mL, and Crovalimab = 0.058 μg / mL.

[0063] Example 4

[0064] Ability of 6E3-H1L1 antibody to block complement classical pathway (CP) activation

[0065] Heating was used to aggregate human IgG into HAIgG, which acts as an activator of the classical complement pathway. Standard reactive serum was used as a positive control for activating the classical complement pathway. An in vitro evaluation method for the effect of antibodies on complement activity was established using the terminal complement activation marker sC5b-9 as the detection index. After three freeze-thaw cycles, the concentration of cC5b-9 in the standard reactive serum did not change significantly, indicating the stability of the serum sample. The experimental procedure was briefly as follows: plasma from healthy individuals was rapidly thawed in a 37°C water bath and immediately placed on ice. A negative control group (containing control antibody #A7001, Beyotime Biotechnology Co., Ltd.), a positive control group (containing HAIgG), and an experimental group (containing the test antibody 6E3-H1L1, Crovalimab) were set up, with 100 μL of mixed serum added to each group. The samples were incubated in a 37°C water bath for 1 h (mixed every 10 min). After incubation, sC5b-9 in the samples was quantitatively analyzed according to the sC5b-9 detection kit.

[0066] The results show that after the addition of HAIgG to activate complement, the concentration of sC5b-9 in the negative control group did not increase, while the concentration of sC5b-9 in the positive control group increased significantly. 6E3-H1L1 and Crovalimab both inhibited the production of sC5b-9 activated by the classical pathway. Figure 2 Furthermore, 6E3-H1L1 showed better inhibitory effects than Crovalimab.

[0067] Example 5

[0068] The ability of the 6E3-H1L1 antibody to block activation of the alternative complement pathway (AP).

[0069] Zymosan has the ability to activate the complement alternative pathway in vivo and in vitro. By adding Zymosan as an activator of the complement alternative pathway, standard reaction serum is stimulated as a positive control for the activation of the complement alternative pathway. The complement terminal activation marker sC5b-9 is used as an indicator to establish an in vitro evaluation method for the activation of the complement alternative pathway by antibodies. After three freeze-thaw cycles, the cC5b-9 concentration in the serum did not change significantly, indicating the stability of the serum sample. The brief steps of the experiment are as follows: after the healthy human plasma is taken out, it is quickly thawed in a 37 °C water bath, and then immediately placed on ice. Set up a negative control group (add control antibody, #A7001, Biyun Tian Biological Company), a positive control group (add Zymosan), and an experimental group (antibody to be tested, 6E3-H1L1, Crovalimab). Add 100 μL / well of mixed serum to each group. Incubate the samples in a 37 °C water bath for 1 h (mix every 10 min). After incubation, quantitatively analyze sC5b-9 in the samples according to the method of the sC5b-9 detection kit.

[0070] As can be seen from the results, after the addition of Zymosan to activate the complement alternative pathway, the sC5b-9 concentration in the negative control group did not increase, the sC5b-9 concentration in the positive control group increased significantly, and 6E3-H1L1, Crovalimab had inhibitory effects on the activation of sC5b-9 by the classical pathway. Figure 3 ), and moreover, the inhibitory effect of 6E3-H1L1 was better than that of Crovalimab.

[0071] Example 6

[0072] C5 humanized antibody-mediated cell killing effect (CD16-NFκB-Luciferase reporter gene)

[0073] We constructed 293T-CD16 cells and then introduced the NFκB-Luciferase reporter gene vector to obtain the CD16-NFκB-Luciferase cell strain. The activation ability of humanized C5 antibodies on the 293T-CD16 cell signaling pathway was detected by Luciferase assay. In the experiment, the weaker the fluorescence intensity detected, the stronger the activation activity of the C5 humanized antibody on the signaling pathway, which also represents the stronger activity of the antibody-mediated cell killing effect (ADCC). Collect 293T-CD16 cells, and dilute them to 2.0×10 4The 96-well plate was added with 50 μL / well of the sample. The negative control (PBS), the control antibody (human IgG1 antibody, #A7001, Biyun Tian Biological Technology Co., Ltd.), the C5 humanized antibody, and the control antibody Crovalimab were added at the designed concentrations. The antibody was diluted in a gradient series of concentrations starting from an initial concentration of 15 μg / mL. The diluent was DMEM complete medium (containing 10% FBS). The corresponding wells were added with 50 μL / well of the diluent, and the blank group was added with DMEM complete medium. Each sample had two replicate wells. The 96-well plate was placed in a 37°C, 5% CO2 cell incubator for 6 h. After the incubation, the 96-well plate was removed, and 50 μL / well of luciferase detection reagent, which had been equilibrated to room temperature, was added. The plate was placed at room temperature for about 3 min. The chemiluminescence signal was detected by the luminescence mode of a multifunctional microplate reader. The data were processed by the GraphPad Prism 8.0 data processing software, and a column chart was drawn. The experimental results showed that the C5 humanized antibodies 6E7-HwLw, 6E3-H1L1, and 6E3-H2L1 and the control antibody all showed weak luminescence signals, indicating weak ADCC activity Figure 4 ). The ADCC effects of the antibodies were not significantly different.

[0074] The applicant states that the present application is illustrated by the above examples of a monoclonal antibody targeting human complement C5 and the application thereof, but the present application is not limited to the above examples, i.e., it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific modes, etc., all fall within the protection scope and disclosure scope of the present application.

[0075] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details in the above embodiments. Within the technical concept scope of the present application, various simple modifications can be made to the technical solutions of the present application, and these simple modifications all belong to the protection scope of the present application.

[0076] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined by any suitable means without contradiction. In order to avoid unnecessary repetition, the present application will not further describe various possible combination modes.

Claims

1. A monoclonal antibody targeting human complement C5, characterized in that, The monoclonal antibody includes a heavy chain variable region and a light chain variable region. The heavy chain variable region includes HCDR1, HCDR2 and HCDR3, and the light chain variable region includes LCDR1, LCDR2 and LCDR3. The amino acid sequence of HCDR1 includes the sequence shown in SEQ ID NO.1, the amino acid sequence of HCDR2 includes the sequence shown in SEQ ID NO.2, and the amino acid sequence of HCDR3 includes the sequence shown in SEQ ID NO.

3. The amino acid sequence of LCDR1 includes the sequence shown in SEQ ID NO.4, the amino acid sequence of LCDR2 includes the sequence shown in SEQ ID NO.5, and the amino acid sequence of LCDR3 includes the sequence shown in SEQ ID NO.

6.

2. A nucleic acid molecule, characterized in that, The nucleic acid molecule encodes the monoclonal antibody targeting human complement C5 as described in claim 1.

3. An expression carrier, characterized in that, The expression vector contains the nucleic acid molecule as described in claim 2.

4. A host cell, characterized in that, The host cell contains the expression vector as described in claim 3.

5. The application of the monoclonal antibody targeting human complement C5 according to claim 1, the expression vector according to claim 3, or the host cell according to claim 4 in the preparation of the detection reagent, wherein the target of the detection reagent is complement C5.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the monoclonal antibody targeting human complement C5 as described in claim 1, or the expression vector as described in claim 3, or the host cell as described in claim 4, as well as a pharmaceutically acceptable carrier and / or diluent.

7. The use of any one or a combination of at least two of the monoclonal antibody targeting human complement C5 according to claim 1, the expression vector according to claim 3, the host cell according to claim 4, or the pharmaceutical composition according to claim 6 in the preparation of a drug for the prevention, improvement, or treatment of rare diseases, autoimmune diseases, chronic kidney disease, etc., caused by C5 overactivation, or a drug for inhibiting immune rejection.

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