Application of anti-tetanus toxin antibody in prevention or treatment of tetanus

Abstract

The invention provides an application of an anti-tetanus toxin antibody in prevention or treatment of tetanus. The anti-tetanus toxin antibody is applied according to a specific administration scheme, and the technical effects that the anti-tetanus toxin antibody takes effect more quickly and the protection time is longer than that of an existing passive immune preparation can be achieved, so that tetanus can be effectively prevented or treated.

Description

Technical Field

[0001] The present invention relates to the field of antibody drugs, and in particular to the use of an anti-tetanus toxin antibody in preventing or treating tetanus. Background Art

[0002] Tetanus is a specific infection caused by Clostridium tetani invading the human body and growing and multiplying in an oxygen-deficient environment to produce toxins (tetanus toxin) that cause muscle spasms. Tetanus toxin mainly attacks motor neurons in the nervous system, so the disease is characterized by clenched jaws, paroxysmal spasms, and tonic spasms. Globally, the mortality rate of tetanus is as high as 30%-50%, among which the mortality rate of severe patients and newborns is as high as 80%. Although the incidence of tetanus is low in developed countries, it is still common in low- and middle-income countries and underdeveloped areas, and is an important public health issue.

[0003] Wound care after injury and the rational use of tetanus immunization preparations are crucial to prevent tetanus infection. Tetanus prevention methods include active immunization (i.e. tetanus vaccine) and passive immunization (such as tetanus-specific immunoglobulin). The current domestic passive tetanus immunization preparations include human tetanus immunoglobulin (HTIG), equine tetanus antitoxin (TAT) and equine tetanus immunoglobulin F (ab') 2 . However, these preparations all have certain defects. For example, horse tetanus antitoxin is mainly derived from horse serum, which has the problem of potential hypersensitivity reaction of receptors and a long immunization cycle. Although horse tetanus immunoglobulin has a lower allergy rate than TAT, it still cannot overcome the application barriers commonly seen in animal-derived therapeutic drugs. Tetanus human immunoglobulin is a blood product, which has the potential risk of infectious diseases such as AIDS and hepatitis B. In addition, due to its complex industrial production and limited production, it cannot fully meet the needs of the market. In addition, it has been found in clinical applications that the immune effects of these immune preparations last for a short time. Generally, horse tetanus antitoxin only lasts for 9 days, horse tetanus immunoglobulin generally lasts for 10 days, and tetanus human immunoglobulin (half-life 25 days) can only last for 2-3 weeks.

[0004] Therefore, there is still a need in the art for new tetanus passive immunization preparations for preventing or treating tetanus. Summary of the invention

[0005] Tetanus toxin is highly toxic, acts quickly, and has a high mortality rate. When a patient is diagnosed with tetani, a large amount of bacteria and toxins are generally present in the body. In view of the various defects of the currently used passive tetanus immunization preparations, an effective way is to timely inject anti-tetanus toxin antibodies that are better in efficacy (reaching antibody protection level faster, maintaining protection for a longer time, and having higher antibody titers), safety, and quality controllability and are suitable for large-scale production.

[0006] The applicant of the present application previously proposed a recombinant natural fully human monoclonal antibody against tetanus toxin, which is referred to as “TRN0011” in the present invention. The amino acid sequence of TRN0011 is as follows.

[0007]

[0008]

[0009] "TRN0011" is an immunoglobulin G1 (IgG1) monoclonal antibody that can bind to the specific surface of tetanus toxin protein with high affinity, and prevent the enzymatic activity of tetanus toxin by neutralizing the toxin, thereby protecting the body. Through animal in vitro and in vivo pharmacodynamics experiments on TRN0011 and randomized, double-blind, placebo-controlled, dose-escalation studies of safety, tolerability, pharmacokinetics and pharmacodynamics in healthy subjects, the applicant of this application uses the antibody as an active agent and provides its preventive or therapeutic use in tetanus and corresponding preventive or therapeutic schemes.

[0010] Specifically, the present invention provides the following technical solutions.

[0011] In one aspect, the present invention provides a use of an anti-tetanus toxin antibody in the preparation of a medicament for preventing or treating tetanus; the anti-tetanus toxin antibody comprises:

[0012] A heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3, respectively; and

[0013] The light chain CDR1, light chain CDR2 and light chain CDR3 respectively contain the amino acid sequences shown in SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.8.

[0014] Preferably, the anti-tetanus toxin antibody comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO.4; and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO.9.

[0015] More preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region.

[0016] According to a specific embodiment of the present invention, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains. Preferably, the anti-tetanus toxin antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO.5; and a light chain comprising the amino acid sequence shown in SEQ ID NO.10.

[0017] In the context of the present invention, the term "tetanus" refers to a specific infection in which Clostridium tetani invades the human body and grows and reproduces in an oxygen-deficient environment to produce toxins (tetanus toxin) and cause muscle spasms. According to the 2020 version of the "Non-neonatal Tetanus Diagnosis and Treatment Guidelines" issued by the National Health Commission, the diagnosis of non-neonatal tetanus is mainly based on typical clinical manifestations, and at least one of the following manifestations is required: (1) clenched teeth or wry smile; (2) painful muscle spasms. For patients with doubtful diagnosis, a tongue depressor test can be used. The method is to use a tongue depressor to gently touch the back of the patient's pharynx. The occurrence of masseter reflex spasm instead of normal reflex nausea is positive. Tetanus can cause temporary functional changes in the central nervous system, manifested as tonic contraction and paroxysmal spasm of skeletal muscles throughout the body. In particular, the symptoms of tetanus are spasms of facial expression muscles, neck, back, abdomen, limb muscles, and diaphragm muscles.

[0018] According to the present invention, the anti-tetanus toxin antibody is used to prepare a drug capable of preventing or treating tetanus, and the drug can be administered (e.g., injected) to a subject to prevent or treat tetanus. The drug is used for subjects who have been infected or not yet infected with Clostridium tetani. Theoretically, as long as a wound or break is caused, the subject may be infected with tetanus and needs to be prevented. Common causes include: (1) a history of trauma or damage to the skin or mucous membranes (such as animal injuries, injection of drugs such as drugs, childbirth or miscarriage); (2) a history of bacterial infection of the skin, mucous membranes, and soft tissues (such as chronic otitis media, chronic sinusitis, periodontal infection, etc.); (3) a history of digestive tract damage (such as a history of digestive tract surgery).

[0019] The subject is a mammal. In the context of the present invention, the term "mammal" refers to any animal classified as a mammal, including but not limited to humans, domestic and agricultural animals, and zoo, sports or pet animals, such as sheep, dogs, horses, cats, cows, rats, pigs, apes such as macaques, etc. Preferably, the mammal is a primate, more preferably a human. In the case where the subject is a human, an adult over 18 years old is preferred.

[0020] Tetanus is prevented or treated by a single administration of the medicament to the subject.

[0021] Preferably, the drug is in the form of an intramuscular injection formulation for administration of the drug.

[0022] The administration of the drug achieves an antibody dose of 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg;

[0023] Preferably, the antibody dose achieved is 5-15 mg;

[0024] More preferably, a dose of 10 mg of antibody is achieved.

[0025] Alternatively, based on the average body weight of the subject of 60 kg, the administration of the drug achieves an antibody dose of 10-250 μg / kg, such as 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg;

[0026] Preferably, the antibody dose achieved is 83-250 μg / kg;

[0027] More preferably, an antibody dose of 167 μg / kg is achieved.

[0028] Administration of the above-mentioned drug can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0029] Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; more preferably, the drug is used to achieve an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject's body within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration.

[0030] Administration of the above-mentioned drug can achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

[0031] In this aspect of the present invention, the use of the antibody in the preparation of a medicament for preventing or treating tetanus can arbitrarily select the above-mentioned characteristics (such as dosage, route of administration, frequency of administration, administration cycle, etc.) for combination use. For example, according to a specific embodiment of the present invention, the present invention provides the use of the anti-tetanus toxin antibody in the preparation of a medicament for preventing or treating tetanus, wherein the medicament is used for a single intramuscular injection to the subject to achieve an antibody dose of 10 mg.

[0032] In another aspect, the present invention provides an anti-tetanus toxin antibody for use as a preventive or therapeutic agent for tetanus, and thus for use in a method for preventing or treating tetanus comprising administering the antibody to a subject in need thereof. The anti-tetanus toxin antibody comprises: a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3, respectively; and a light chain CDR1, a light chain CDR2 and a light chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.8, respectively.

[0033] Preferably, the anti-tetanus toxin antibody provided by the present invention comprises: a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO.4; and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO.9.

[0034] More preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region.

[0035] According to a specific embodiment of the present invention, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains. Preferably, the anti-tetanus toxin antibody comprises: a heavy chain comprising the amino acid sequence shown in SEQ ID NO.5; and a light chain comprising the amino acid sequence shown in SEQ ID NO.10.

[0036] The term "tetanus" is as defined above. In particular, the symptoms of tetanus treated by the anti-tetanus toxin antibody provided by the present invention are spasms of the muscles of facial expression, neck, back, abdomen, limbs, and diaphragm.

[0037] The anti-tetanus toxin antibody provided by the present invention is used in a method for preventing or treating tetanus, which may include administering (e.g., injecting) the antibody to a subject to prevent or treat tetanus. Wherein, the subject is a mammal that has been infected or has not been infected with Clostridium tetani.

[0038] The term "mammal" is as defined above. Preferably, the mammal is a primate, more preferably a human. In the case where the subject is a human, preferably an adult, such as an adult over 18 years old.

[0039] Preferably, the method comprises a single administration of the anti-tetanus toxin antibody to the subject to prevent or treat tetanus; preferably, the administration of the anti-tetanus toxin antibody is performed by intramuscular injection.

[0040] The antibody dose administered in the method is 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; preferably, the antibody dose is 5-15 mg; more preferably, the antibody dose is 10 mg.

[0041] Alternatively, based on the average body weight of the subject of 60 kg, the antibody dose administered in the method can be 10-250 μg / kg, for example 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg; preferably, the antibody dose is 83-250 μg / kg; more preferably, the antibody dose is 167 μg / kg.

[0042] The above method can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0043] Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; more preferably, the method comprises achieving an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration of the antibody.

[0044] The above method can achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

[0045] In this aspect of the present invention, the administration characteristics (such as dosage, administration route, administration frequency, administration cycle, etc.) defined when the antibody is used as a preventive or therapeutic agent for tetanus can be arbitrarily selected and used in combination. For example, according to a specific embodiment of the present invention, the present invention provides the antibody, which is used as a preventive or therapeutic agent for tetanus, or in a method for preventing or treating tetanus, comprising a single intramuscular injection of 10 mg of the anti-tetanus toxin antibody to the subject.

[0046] In another aspect, the present invention provides a method for preventing or treating tetanus, the method comprising administering an anti-tetanus toxin antibody to a subject in need thereof. The anti-tetanus toxin antibody is as defined above.

[0047] The term "tetanus" is as defined above. In particular, the symptoms of tetanus are spasms of the muscles of facial expression, neck, back, abdomen, limbs, and diaphragm.

[0048] The method for preventing or treating tetanus provided by the present invention may include administering (e.g., injecting) the antibody to a subject to prevent or treat tetanus. Wherein, the subject is a mammal that has been infected or has not been infected with Clostridium tetani. For example, the subject belongs to a group of people who are not fully immunized against tetanus or whose immunization history is unknown.

[0049] The term "mammal" is as defined above. Preferably, the mammal is a primate, more preferably a human. In the case where the subject is a human, preferably an adult, such as an adult over 18 years old.

[0050] Preferably, the method comprises a single administration of the anti-tetanus toxin antibody to the subject to prevent or treat tetanus; preferably, the administration of the anti-tetanus toxin antibody is performed by intramuscular injection.

[0051] The antibody dose administered in the method is 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; preferably, the antibody dose is 5-15 mg; more preferably, the antibody dose is 10 mg.

[0052] Alternatively, based on the average body weight of the subject of 60 kg, the antibody dose administered in the method can be 10-250 μg / kg, for example 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg; preferably, the antibody dose is 83-250 μg / kg; more preferably, the antibody dose is 167 μg / kg.

[0053] The above method can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0054] Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; more preferably, the method comprises achieving an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration of the antibody.

[0055] The above method can achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

[0056] In this aspect of the present invention, the administration characteristics (e.g., dosage, administration route, administration frequency, administration cycle, etc.) defined for the method of using the antibody to prevent or treat tetanus can be arbitrarily selected and used in combination. For example, according to a specific embodiment of the present invention, the present invention provides a method for preventing or treating tetanus, the method comprising a single intramuscular injection of 10 mg of the anti-tetanus toxin antibody to the subject.

[0057] The applicant of the present application conducted in vitro and in vivo animal pharmacodynamics experiments on the immunoglobulin G1 (IgG1) monoclonal antibody previously provided, as well as randomized, double-blind, placebo-controlled, dose-escalation studies on safety, tolerability, pharmacokinetics and pharmacodynamics in healthy subjects, and determined an optimal antibody application scheme suitable for the prevention or treatment of tetanus in humans.

[0058] Studies have shown that the tetanus monoclonal antibody TRN0011, when administered to subjects in a specific dosing regimen, can achieve a more rapid onset of action and longer duration of protection than tetanus human immunoglobulin (HTIG), and can therefore effectively prevent or treat tetanus.

[0059] Specifically, literature, relevant guidelines and previous studies have shown that whether passive or active immunization is used, as long as the anti-tetanus neutralizing antibody content in the body's serum reaches 0.01IU / mL, immune protection can be obtained. The serum antibody of the tetanus human immunoglobulin that has been on the market can exceed 0.01IU / mL 3 days after injection (see "Rongsheng Yipu HTIG Instructions" [Clinical Trials]). In contrast, based on the results of various studies, it can be determined that after intramuscular injection of TRN0011, the serum anti-tetanus toxin neutralizing antibody titer can be increased to the minimum protection level of 0.01IU / mL within 6 hours after administration, or even shorter, and the increase in neutralizing antibody titer increases with the increase in the dosage.

[0060] Moreover, in terms of the duration of the protection level, intramuscular injection of TRN0011 can provide anti-tetanus protection to most (>90%) of the people who received the drug 12 hours after administration, and last until the 105th day after administration, that is, compared with tetanus human immunoglobulin, it can provide anti-tetanus protection earlier and for a longer period of time, and the antibody titer level is higher. In addition, considering that the anti-tetanus neutralizing antibody titer far above the minimum protection threshold can still be detected on the 106th day after administration, it can be seen that the administration of TRN0011 can provide much longer protection.

[0061] In addition, based on the results of various studies, it can be determined that TRN0011 causes low immunogenicity and has no effect on individual pharmacokinetic and safety results; and TRN0011 has good safety and tolerability.

[0062] Therefore, without being bound by any theory, it is expected that the anti-tetanus toxin antibody can achieve a better effect of preventing or treating tetanus. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] The embodiments of the present invention are described in detail below with reference to the accompanying drawings, wherein:

[0064] Figure 1 The proportion of subjects in Example 1 whose anti-tetanus toxin neutralizing antibody titer increased (ΔTiter) by ≥ 0.01 IU / mL compared with the baseline is shown.

[0065] Figure 2 The Kaplan Meier curve of Example 1 showing the duration of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) ≥ 0.01 IU / mL compared with the baseline.

[0066] Figure 3 The graph shows the trend of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) over the baseline in Example 1 over time. DETAILED DESCRIPTION

[0067] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0068] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0069] The antibody used in the following examples is the recombinant natural fully human monoclonal antibody TRN0011 against tetanus toxin (referred to as "antibody" or "previously proposed antibody" in the context of the present invention), and the amino acid sequence and other characteristics of the antibody are as defined above.

[0070] The test drug in the following examples is an injection containing TRN0011; or a placebo, which contains the same excipients as the injection but does not contain antibodies.

[0071] Regardless of the specific dosage, the groups to which TRN0011 was administered are collectively referred to as "TRN0011 groups".

[0072] Anti-tetanus neutralizing antibody titers were measured in serum using enzyme-linked immunosorbent assay (ELISA).

[0073] The HTIG control used in the following examples is immunoglobulin from Hualan Biotechnology Co., Ltd.

[0074] In the following examples, "subject" and "volunteer" are interchangeable.

[0075] Example 1

[0076] A multicenter, randomized, double-blind, parallel-controlled, dose-finding study was conducted in Chinese adult volunteers to compare the anti-tetanus toxin neutralizing antibody titer levels and safety after a single intramuscular injection of TRN0011 antibody with tetanus human immune globulin (HTIG) or placebo.

[0077] Purpose of the trial: The primary purpose is to compare the anti-tetanus toxin neutralizing antibody titer levels after a single intramuscular injection (IM) of TRN0011 and tetanus human immune globulin (HTIG) in Chinese adult volunteers. The secondary purpose is to compare the safety and tolerability of TRN0011, HTIG and placebo after a single intramuscular injection in Chinese adult volunteers; to evaluate the pharmacokinetic (PK) characteristics of TRN0011 in Chinese adult volunteers; and to evaluate the immunogenicity of TRN0011 injection in Chinese adult volunteers.

[0078] 1. Research design

[0079] The study included a screening period (day -28 to day -2), a hospitalization period (day -1 to day 4), and a follow-up period (day 5 to day 106).

[0080] Qualified volunteers were admitted to the research center on day -1, completed the relevant examinations and random grouping required by the protocol, and received the trial drugs on day 1. The preparation and administration of the trial drugs were performed by non-blind researchers, and the injection time of all trial drugs was controlled within 30 (± 3) seconds.

[0081] After administration, volunteers received safety assessments at the research center, including physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and laboratory tests (blood routine, blood biochemistry, and urine routine). At the same time, researchers collected serum samples as planned for anti-tetanus toxin neutralizing antibody titers, PK, and immunogenicity analyses.

[0082] (II) Group members

[0083] Considering the serious clinical consequences of tetanus prevention failure, it is not suitable to conduct dose exploration in trauma population. At the same time, considering that the population with tetanus indication is mostly in a healthy state except for trauma, this study recruited healthy volunteers or volunteers with chronic diseases but in a stable state to participate in the study.

[0084] The study participants were selected according to the following criteria.

[0085] Inclusion criteria:

[0086] 1) Chinese adults (aged ≥18 years old), male or female;

[0087] 2) Healthy volunteers or patients with stable chronic diseases whose physical examination, vital signs and clinical laboratory test results are normal or abnormal with no clinical significance during the screening period, and whose participation in the clinical study is judged by the researchers not to pose significant risks to the volunteers.

[0088] (III) Research plan

[0089] A total of 240 Chinese adult volunteers were enrolled.

[0090] The volunteers were randomly assigned to the TRN0011 5mg group (0.25mL), TRN001110mg group (0.5mL), TRN0011 15mg group (0.75mL), HTIG 250IU group (2.5mL) and placebo group (0.5mL) in a ratio of 2:2:1:2:1. All received a single intramuscular injection in the buttocks.

[0091] In the above grouping, the dose of TRN0011 was determined based on the results of previous experiments. HTIG is the preferred passive immunization agent for tetanus prevention recommended by current domestic and international guidelines. It has a definite protective effect on tetanus and has been widely used in clinical practice for a long time. A single intramuscular injection of HTIG 250IU is the conventional dose for tetanus prevention in clinical practice. Therefore, HTIG was selected as the positive control with a dose of 250IU. At the same time, in order to fully evaluate the safety of TRN0011, a placebo was selected as the control drug.

[0092] 4. Evaluation of research indicators

[0093] Primary endpoint:

[0094] The proportion of volunteers whose anti-tetanus toxin neutralizing antibody titer increased (ΔTiter) ≥ 0.01 IU / mL compared with the baseline level at 24 hours after medication (serum anti-tetanus toxin neutralizing antibody titer is a pharmacodynamic indicator in this trial)

[0095] The incubation period of tetanus is mostly between 3-21 days after infection, with a median of 7 days. The longest period can be 178 days after infection, and the shortest period may be 1-2 days, the latter mainly for head tetanus. Therefore, as a product to prevent tetanus, it should provide protection within 24 hours after trauma.

[0096] According to the relevant guidelines of the World Health Organization (WHO) and previous studies, the level of neutralizing antibodies against tetanus toxin in the body is related to the protective efficacy after the administration of active or passive immunization agents. In the list of surrogate endpoints recommended by the U.S. Food and Drug Administration (FDA) for drug approval and licensing, the immune surrogate endpoint of tetanus vaccine is the level of antibodies against tetanus toxin.

[0097] There is evidence that anti-tetanus toxin neutralizing antibody levels exceeding 0.01 IU / mL detected by in vivo neutralization tests or modified enzyme-linked immunosorbent assay (ELISA) are generally considered protective. Combined with the disease course after tetanus infection and taking into account that the subjects may have received active tetanus immunization (tetanus vaccine) in the past and therefore had pre-existing antibodies in the body, the primary endpoint of this study was determined to be the proportion of volunteers whose anti-tetanus toxin neutralizing antibody titer increased by ≥0.01 IU / mL compared with the baseline level at 24 hours after medication.

[0098] Secondary endpoints:

[0099] Safety endpoints, including: the types and incidence of adverse events and serious adverse events, and the results of physical examination, vital signs, 12-lead ECG, and laboratory tests (complete blood count, blood biochemistry, and urinalysis);

[0100] Changes from baseline in anti-tetanus toxin neutralizing antibody titers at 24 hours, 48 ​​hours (day 3), and 7, 21, 30, and 90 days after dosing;

[0101] The proportion of volunteers with an increase in anti-tetanus toxin neutralizing antibody titer of ≥0.01 IU / mL compared with baseline levels at 48 hours (day 3) and on days 7, 21, 30, and 90 after treatment;

[0102] The proportion of volunteers whose anti-tetanus toxin neutralizing antibody titers increased by ≥0.01 IU / mL compared with the baseline level at 24 hours and 30 days after treatment;

[0103] Duration of time after treatment when the anti-tetanus toxin neutralizing antibody titer increases by ≥0.01 IU / mL compared with the baseline level;

[0104] Anti-tetanus toxin neutralizing antibody titers at 24 hours, 48 ​​hours (day 3), and 7, 21, 30, and 90 days after administration;

[0105] The proportion of volunteers with anti-tetanus toxin neutralizing antibody titers ≥ 0.01 IU / mL at 24 hours, 48 ​​hours (day 3), and 7, 21, 30, and 90 days after administration;

[0106] · Pharmacokinetic parameters of TRN0011. PK parameters mainly include peak concentration (Cmax), time to peak (Tmax), elimination half-life (t1 / 2), area under the blood concentration-time curve at 0-t time (AUC0-t), area under the blood concentration-time curve at 0-∞ time (AUC0-∞); if data permit, also include apparent clearance (CL / F) and apparent distribution volume (Vd / F);

[0107] The positive rate of anti-drug antibodies (ADA) in volunteers in the TRN0011 group.

[0108] 5. Statistical methods

[0109] Analysis Set

[0110] Full Analysis Set (FAS): All volunteers who are randomized and receive at least one dose of the trial drug will serve as the full analysis set. The full analysis set will be used to analyze the distribution, demographics, and baseline characteristics of the volunteers.

[0111] Anti-tetanus toxin neutralizing antibody titer level analysis set: All volunteers who are randomized, receive at least one dose of the trial drug, and have at least one effective serum anti-tetanus toxin neutralizing antibody titer test data after administration are included in the anti-tetanus toxin neutralizing antibody titer level analysis set of this trial. If an event occurs that affects the neutralizing antibody titer level or detection (such as serious violation of the protocol inclusion criteria, use of prohibited drugs during the study, etc.), all or part of the neutralizing antibody test data of the corresponding volunteers will not be included in the anti-tetanus toxin neutralizing antibody titer level analysis.

[0112] Safety Analysis Set (SS): All volunteers who were randomized, received at least one dose of the trial drug, and had at least one safety evaluation after administration were included in the SS. The SS is the safety evaluation population of this trial.

[0113] PK Concentration Analysis Set (PKCS): All volunteers who are randomized, receive at least one dose of the trial drug, and have at least one analyzable PK concentration point during the trial are included in the PKCS of this study. If an event occurs that affects the PK concentration results or detection (such as serious violation of the protocol inclusion criteria, use of prohibited drugs during the study, etc.), all or part of the PK data of the corresponding volunteers will not be included in the PKCS. The PK concentration analysis set will be used for the analysis of pharmacokinetic concentrations.

[0114] PK parameter analysis set (PKPS): All volunteers who are randomized, receive at least one dose of the trial drug, and have at least one analyzable PK parameter during the trial. If an event occurs that affects the PK parameter results (such as serious violation of the protocol inclusion criteria, use of prohibited drugs during the study, etc.), all or part of the PK data of the corresponding volunteers will not be included in the PKPS. The PK parameter analysis set will be used for the analysis of pharmacokinetic parameters.

[0115] Immunogenicity analysis set: All volunteers who were randomized, received at least one dose of TRN0011 and had at least one post-dose immunogenicity data were included in the immunogenicity analysis set.

[0116] Basic principles

[0117] PK parameters were calculated using Phoenix WinNonlin version 8.3.1, and all other statistical analyses were performed using the Statistical Analysis System (SAS) version 9.4.

[0118] Anti-tetanus toxin neutralizing antibody titer, PK, immunogenicity and safety analyses were based on the actual dosing received by the volunteers. The remaining analyses were based on the randomized dosing groups of the volunteers unless otherwise specified.

[0119] Analysis of anti-tetanus toxin neutralizing antibody titer levels

[0120] The anti-tetanus toxin neutralizing antibody titer level analysis is based on the anti-tetanus toxin neutralizing antibody titer level analysis set.

[0121] According to the dosing group, the number, percentage, 95% CI, 90% CI (based on the Clopper-Pearson method) of volunteers with ΔTiter ≥ 0.01 IU / mL at 24 hours after medication were calculated, and the difference in the percentage of volunteers with ΔTiter ≥ 0.01 IU / mL between different groups and the 95% CI and 90% CI of the difference were provided (based on the stratified Miettinen-Nurminen method, stratified according to the results of tetanus antibody IgG rapid test during random stratification).

[0122] This study also conducted a subgroup analysis of all tetanus toxin neutralizing antibody titer-related endpoints based on the volunteers' baseline tetanus toxin neutralizing antibody titer (chemiluminescence test results of serum samples), with 0.01 IU / mL (<0.01 IU / mL and ≥0.01 IU / mL) as the cutoff value.

[0123] A sensitivity analysis was performed using the Newcombe Wilson Score to calculate the 95% CI and 90% CI for the difference in the percentage of volunteers with an increase in anti-tetanus toxin neutralizing antibody titer of ≥0.01 IU / mL from baseline between the different groups.

[0124] Pharmacokinetic analysis

[0125] PK concentration analysis

[0126] The PK concentrations of investigational drugs were summarized by dosing group and planned sampling time point, including the number of volunteers, the number of volunteers below the lower limit of quantitation (BLQ), the arithmetic mean, SD, median, minimum, maximum, CV (based on the arithmetic mean) and geometric mean.

[0127] Mean drug concentrations were plotted versus time (linear and semi-logarithmic scales) according to the planned sampling times.

[0128] PK parameter analysis

[0129] PK parameters (Cmax, AUC0-t, AUC0-∞, Tmax, t1 / 2, Vd / F, CL / F, etc.) were calculated by non-compartmental analysis (NCA).

[0130] PK parameters were summarized by dosing group, including the number of volunteers, arithmetic mean, SD, median, minimum and maximum values. For PK parameters other than Tmax, CV (based on arithmetic mean), geometric mean, geometric standard deviation and geometric coefficient of variation were also calculated.

[0131] The individual PK parameters of all randomized volunteers are listed according to the dosing group.

[0132] Immunogenicity analysis

[0133] The number and percentage of volunteers with at least one ADA-positive test during the trial, at least one ADA-positive test at baseline and after baseline, and ADA-positive test at each visit after baseline were summarized according to the actual dosing group.

[0134] The immunogenicity test results at each time point are tabulated according to the dosing group.

[0135] Security Analysis

[0136] The actual administration group and dose were summarized. Safety analysis included descriptive statistics and individual tabulations of all safety data (adverse events, physical examination, vital signs, 12-lead ECG, clinical laboratory tests, and injection site assessment).

[0137] Adverse events were coded using the Medical Dictionary for Research Assessment (MedDRA) version 25.1. Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) that occurred after administration of the investigational drug or exacerbated a pre-existing medical condition.

[0138] Analysis conducted

[0139] Primary endpoint analysis

[0140] The primary endpoint analysis was performed after the primary endpoint data were available for all volunteers, as well as safety data from the Day 30 visit. This analysis also included all safety and other secondary endpoint data available at the time of the analysis.

[0141] Updated analysis of safety endpoints and other secondary endpoints

[0142] At the end of the entire trial, updated analyses of safety endpoints and other secondary endpoints were performed.

[0143] (VI) Research Results

[0144] 1. Distribution and characteristics of volunteers

[0145] This study included 240 adult volunteers, including 151 in the TRN0011 group (including 61 in the 5mg group, 61 in the 10mg group, and 29 in the 15mg group), 59 in the HTIG group, and 30 in the placebo group. A total of 7 volunteers withdrew from the study early, including 3 in the TRN0011 5mg group, 2 in the 10mg group, 1 in the 15mg group, and 1 in the HTIG group; among them, 6 (5 in the TRN0011 group and 1 in the HTIG group) withdrew from the study early due to loss to follow-up, and 1 (TRN0011 5mg group) withdrew from the study early due to failure to return for follow-up.

[0146] See Table 1.

[0147] Table 1. Distribution of volunteers (all volunteers)

[0148]

[0149] The percentages are calculated based on the number of all randomized volunteers in each actual dosing group.

[0150] All 240 volunteers were included in the FAS set and the SS set. All volunteers in the TRN0011 group and the HTIG group (a total of 210 cases) were included in the anti-tetanus toxin neutralizing antibody titer level analysis set. All volunteers in the TRN0011 group (a total of 151 cases) were included in the PKCS set, the PKPS set, and the immunogenicity analysis set.

[0151] 2. Anti-tetanus toxin neutralizing antibody titer level results

[0152] 2.1 Primary End Point

[0153] At 24 hours after administration, the proportion of volunteers with anti-tetanus toxin neutralizing antibody ΔTiter ≥ 0.01 IU / mL in the TRN0011 5 mg, 100% and 100% groups were higher than that in the HTIG group (81.4%). No significant difference was found among the TRN0011 administration groups. The inter-group differences between the TRN0011 5 mg, 10 mg and 15 mg administration groups and the HTIG group were 10.4% (95% CI: -1.2, 24.3), 18.6% (95% CI: 10.1, 31.0) and 18.6% (95% CI: 1.7, 30.0), respectively.

[0154] The 95% CI lower limits of the percentage differences between the TRN0011 10 mg and 15 mg groups and the HTIG group were all >0, and the 90% CI lower limits of the percentage differences between all TRN0011 dosing groups and the HTIG group were all >0.

[0155] See Table 2 for the results.

[0156] Table 2. Summary of the proportion of volunteers whose anti-tetanus toxin neutralizing antibody titer increased (ΔTiter) ≥ 0.01 IU / mL compared with the baseline at 24 hours after administration and comparison between groups (anti-tetanus toxin neutralizing antibody titer level analysis set)

[0157]

[0158] Baseline was defined as the last measurement before administration of study drug on Day 1.

[0159] [1]: Evaluable volunteers were defined as those whose anti-tetanus toxin neutralizing antibody titers were not lost at baseline and 24 hours after dosing. The percentage was calculated based on the number of volunteers in the analysis set with anti-tetanus toxin neutralizing antibody titer levels in each dosing group.

[0160] [2]: Percentages are calculated based on the number of evaluable volunteers in each dosing group.

[0161] [3]: Based on the Clopper-Pearson method.

[0162] [4]: Based on the stratified Miettinen-Numinen method, stratification was performed according to the results of tetanus antibody IgG rapid test during randomization.

[0163] 2.2 Secondary End Points

[0164] For the secondary endpoints, the following results were obtained.

[0165] 2.2.1 After administration, the proportion of volunteers with ΔTiter ≥ 0.01 IU / mL in the TRN001 15 mg, 10 mg and 15 mg groups reached 55.7%, 80.3% and 96.6% at the 6th hour, and reached 100% at the 72nd, 48th and 12th hours, respectively. In contrast, the proportion of volunteers in the HTIG group was only 20.3% at the 6th hour, and it was not until the 7th day that it reached 100%.

[0166] 2.2.2 At 12 hours after administration, the proportion of ΔTiter ≥ 0.01 IU / mL in the TRN0011 5mg, 10mg and 15mg groups reached 75.4%, 91.8% and 100%, all higher than the HTIG group (55.9%). The inter-group differences between the TRN0011 administration groups and the HTIG group were 19.5%, 35.9% and 44.1%, respectively, and the lower limits of their 95% CI were all higher than 0.

[0167] 2.2.3 From the 48th hour to the 30th day, the proportion of ΔTiter ≥ 0.01 IU / mL in each TRN0011 administration group and the HTIG group remained at a high level (>90.0%). Thereafter, the TRN0011 10mg and 15mg groups continued to maintain a high level, and on the 106th day, the proportions of the two groups remained at 96.6% and 96.4%. However, the proportion of the HTIG group dropped significantly to 64.3% on the 60th day, and further dropped to 13.8% on the 106th day. The results are shown in Figure 1 .

[0168] 2.2.4 Analysis of the proportion of volunteers with ΔTiter ≥ 0.01 IU / mL at 24 hours and 30 days showed that the proportions of volunteers in the TRN001 15 mg, 100% and 100% groups were higher than that in the HTIG group (78.0%).

[0169] 2.2.5 Volunteers in the TRN0011 5mg, 10mg and 15mg groups reached a peak value of ΔTiter on the 7th to 14th day after administration, with geometric mean titers (GMT) of 0.1362, 0.2801 and 0.4786 IU / mL, respectively. The increase in ΔTiter was basically linear with the increase in the dosage. Similar to TRN0011, ΔTiter in the HTIG group reached a peak on the 7th day after administration, but the average titer level (0.0392 IU / mL) was significantly lower than that of each TRN0011 administration group.

[0170] 2.2.6 After administration, the GMT of ΔTiter in each TRN0011 administration group was ≥0.01IU / mL from the 6th hour to the 106th day, and the time when ΔTiter GMT in the HTIG group was ≥0.01IU / mL was from the 12th hour after administration to the 60th day.

[0171] 2.2.7 At each time point after administration, the ΔTiter GMT of the TRN0011 group was higher than that of the HTIG group.

[0172] In addition, the Kaplan Meier curves of the duration of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) ≥ 0.01 IU / mL compared with the baseline in each treatment group (anti-tetanus toxin neutralizing antibody titer level analysis set) are shown in Figure 2 ; The trend of the anti-tetanus toxin neutralizing antibody titer (ΔTiter) after administration compared with the baseline over time (anti-tetanus toxin neutralizing antibody titer level analysis set) is shown in Figure 3 .

[0173] 3. Pharmacokinetics

[0174] The results showed that after a single intramuscular injection of TRN0011, within the dose range of 5-15 mg, serum drug exposure (AUC0-t, AUC0-∞ and Cmax) increased with increasing dose, and the increase ratio of drug exposure was basically linear with the dose escalation ratio.

[0175] The median peak time of TRN0011 serum drug concentration is 6.0-13.0 days. After reaching the peak, the blood concentration decreases over time, and the average terminal elimination phase half-life is 25.1-26.8 days.

[0176] There was no significant difference in the mean distribution volume and clearance of TRN0011 5mg, 10mg and 15mg groups, with mean Vd / F values ​​ranging from 7320-8570mL and mean CL / F values ​​ranging from 8.17-10.2mL / h.

[0177] 4. Immunogenicity

[0178] The results showed that among the 151 volunteers who received TRN0011, only 2.65% (4 / 151) of the volunteers had immunogenic reactions related to TRN0011, that is, the ADA test results were positive, and the highest titer of ADA positive samples was 6.14, and none of them had neutralizing activity. It was also found that immunogenicity had no significant effect on individual PK and safety results.

[0179] 5. Security

[0180] Key safety results are as follows:

[0181] Among all volunteers who received TRN0011, 48.3% (73 / 151) of the volunteers experienced at least one TEAE, which was slightly lower than that in the HTIG group (54.2%, 32 / 59) and the placebo group (53.3%, 16 / 30). The incidence of TEAEs in each TRN0011 administration group was similar, and no dose-related relationship was observed.

[0182] Almost all TEAEs were mild or moderate in severity. The most common TEAEs were increased blood triglycerides and increased blood uric acid, which occurred at similar rates in the TRN0011 and placebo groups, at 10.6% vs 16.7% and 8.6% vs 6.7%, respectively.

[0183] During the trial, no serious adverse events (SAEs) were reported in volunteers who received TRN0011 and placebo. One SAE (subdural hemorrhage) was reported in a volunteer who received HTIG. The severity of the SAE was severe and the researchers judged it to be unrelated to the trial drug.

[0184] During the trial, no volunteer died or withdrew from the study prematurely due to TEAE.

[0185] 6. Conclusion

[0186] In the current trial, this study selected three fixed doses of TRN0011, 5 mg, 10 mg, and 15 mg, and compared them with the current clinical standard treatment for passive tetanus immunization prevention, HTIG 250 IU, and placebo.

[0187] In this study, the mean serum anti-tetanus toxin neutralizing antibody titer ΔTiter of TRN0011 5mg, 10mg and 15mg reached 0.0113, 0.0342 and 0.0727IU / mL at 6 hours after administration, which means the minimum protection level of 0.01IUmL has been reached. At this time, the proportion of ΔTiter ≥ 0.01IU / mL in the test population was 55.7%, 80.3% and 96.6%, respectively. At the same time point, the mean ΔTiter after administration of HTIG 250IU was 0.0050IU / mL, and the proportion of ΔTiter ≥ 0.01IU / mL in the test population was only 20.3%, which cannot provide ideal anti-tetanus protection in the population.

[0188] Considering that the incubation period of tetanus is mostly 3-21 days after trauma, and clinical reports show that only about 10% of trauma patients have tetanus symptoms within 2 days from injury, this study selected the 24th hour after administration as the primary endpoint for evaluating tetanus toxin neutralizing antibody titers.

[0189] At the primary endpoint, 24 hours after administration, the mean neutralizing antibody titers ΔTiter of the TRN0011 5mg, 10mg and 15mg groups increased to 0.0450, 0.1095 and 0.2094 IU / mL, and the proportion of ΔTiter ≥ 0.01 IU / mL also further increased to 91.8%, 100% and 100%, respectively. That is, the three doses selected in this study can provide anti-tetanus protection in a wide range of people 24 hours after administration.

[0190] Further evaluation of relevant secondary endpoints showed that TRN0011 10mg and 15mg provided protection in a higher proportion of the subjects at 12 hours after administration. At this time, the mean ΔTiter values ​​of the two dosing groups were 0.0711 and 0.1476IU / mL, respectively, and the proportions of ΔTiter ≥ 0.01IU / mL were 91.8% and 100%, respectively. The data further showed that the protection provided by TRN0011 10mg and 15mg could last until the end of the trial, that is, on the 106th day after administration, the mean ΔTiter values ​​of the two groups were still 0.0241 and 0.0444IU / mL, and the proportions of ΔTiter ≥ 0.01IU / mL remained at 96.6% and 96.4%.

[0191] Comparison of the data on the protection provided by TRN0011 10mg and 15mg against tetanus showed that the 15mg dose provided protection in a higher proportion of the population at 6 hours after administration, but did not provide more significant benefits than 10mg in terms of the proportion of protected population and duration of protection at other time points. This study also found that after administration of TRN0011 5mg, 10mg and 15mg, the titer of serum anti-tetanus toxin neutralizing antibodies in the body increased faster and to a higher extent than HTIG 250IU. Compared with TRN0011 10mg, 91.8% of volunteers had ΔTiter ≥ 0.01IU / mL 12 hours after administration, only 55.9% of volunteers in the HTIG group reached this level of protection at this time point, and it was not until the 48th hour that the proportion (93.2%) comparable to TRN0011 10mg was reached. In addition, at day 60 after administration of HTIG 250 IU, ΔTiter ≥ 0.01 IU / mL was maintained in only 64.3% of the volunteers, while the anti-tetanus protection of TRN0011 10 mg and 15 mg lasted until the end of the trial, that is, day 106 after administration.

[0192] Judging from the neutralizing antibody titer levels at each time point after administration, the TRN0011 5mg, 10mg and 15mg groups were also higher than the HTIG 250IU group.

[0193] The PK parameters of TRN0011 observed in this study were basically consistent with those observed in completed trials. The serum drug concentration increased with increasing dose, showing a basically linear characteristic. The peak time of serum drug concentration was between 6.0-13.0 days, and the half-life was 25.1-26.8 days.

[0194] In terms of immunogenicity, only a very low proportion (2.65%) of volunteers were observed to have immunogenic reactions related to TRN0011 in this study, and the highest ADA positive sample titer was 6.14, and none of them had neutralizing activity. PK parameter comparison and AE information summary showed that immunogenicity had no significant effect on individual PK and safety results. This is also consistent with the TRN0011 immunogenicity results shown in previous studies.

[0195] In this study, the incidence of TEAEs in the TRN0011 group was similar to that in the HTIG group and the placebo group, and the severity was mild and moderate. The most common TEAEs were increased blood triglycerides and increased blood uric acid, and the incidence of these two types of TEAEs was also similar in the TRN0011 group and the placebo group, 10.6% vs 16.7% and 8.6% vs 6.7%, respectively.

[0196] In summary, this study continues to show that TRN0011 has good safety and tolerability. Based on the analysis of anti-tetanus toxin neutralizing antibody titer data, TRN0011 can provide better anti-tetanus protection than HTIG.

[0197] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of the claims attached to the present invention.

Claims

1. Use of an anti-tetanus toxin antibody in the preparation of a medicament for preventing or treating tetanus; the anti-tetanus toxin antibody comprises: A heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3, respectively; and The light chain CDR1, light chain CDR2 and light chain CDR3 respectively contain the amino acid sequences shown in SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.

8.

2. The use according to claim 1, characterized in that The anti-tetanus toxin antibody comprises: A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO.4; and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO.9; Preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region; More preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Further preferably, the anti-tetanus toxin antibody comprises: A heavy chain comprising the amino acid sequence shown in SEQ ID NO.5; and A light chain comprising the amino acid sequence shown in SEQ ID NO.

10.

3. The use according to claim 1 or 2, characterized in that The drug is used for a subject who has been infected or has not been infected with Clostridium tetani, and the subject is a mammal; Preferably, the subject is a primate, more preferably a human, such as an adult, and even more preferably an adult over 18 years old.

4. The use according to any one of claims 1 to 3, characterized in that preventing or treating tetanus by administering a single dose of the medicament to the subject; Preferably, the drug is in the form of an intramuscular injection formulation for administration of the drug.

5. The use according to any one of claims 1 to 4, characterized in that The administration of the drug achieves an antibody dose of 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; Preferably, the antibody dose achieved is 5-15 mg; More preferably, a dose of 10 mg of antibody is achieved.

6. The use according to any one of claims 1 to 4, characterized in that The administration of the drug achieves an antibody dose of 10-250 μg / kg, such as 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg, based on the subject's body weight; Preferably, the antibody dose achieved is 83-250 μg / kg; More preferably, an antibody dose of 167 μg / kg is achieved.

7. The use according to any one of claims 1 to 6, characterized in that The drug is used to achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject; Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; More preferably, the drug is used to achieve an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration.

8. The use according to any one of claims 1 to 7, characterized in that The medicament is used to achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

9. An anti-tetanus toxin antibody for use in a method for preventing or treating tetanus comprising administering the antibody to a subject in need thereof; the anti-tetanus toxin antibody comprising: A heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3, respectively; and The light chain CDR1, light chain CDR2 and light chain CDR3 respectively contain the amino acid sequences shown in SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.

8.

10. The anti-tetanus toxin antibody according to claim 9, characterized in that The anti-tetanus toxin antibody comprises: A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO.4; and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO.9; Preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region; More preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Further preferably, the anti-tetanus toxin antibody comprises: A heavy chain comprising the amino acid sequence shown in SEQ ID NO.5; and A light chain comprising the amino acid sequence shown in SEQ ID NO.

10.

11. The anti-tetanus toxin antibody according to claim 9 or 10, characterized in that The subject is a mammal that has been infected or has not been infected with Clostridium tetani; Preferably, the subject is a primate, more preferably a human, such as an adult, and even more preferably an adult over 18 years old.

12. The anti-tetanus toxin antibody according to any one of claims 9 to 11, characterized in that The method comprises a single administration of the anti-tetanus toxin antibody to the subject to prevent or treat tetanus; Preferably, the anti-tetanus toxin antibody is administered by intramuscular injection.

13. The anti-tetanus toxin antibody according to any one of claims 9 to 12, characterized in that The dosage of the antibody administered in the method is 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; Preferably, the antibody dosage is 5-15 mg; More preferably, the antibody dose is 10 mg.

14. The anti-tetanus toxin antibody according to any one of claims 9 to 12, characterized in that The dosage of the antibody administered in the method is 10-250 μg / kg, such as 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg, based on the body weight of the subject; Preferably, the antibody dosage is 83-250 μg / kg; More preferably, the antibody dose is 167 μg / kg.

15. The anti-tetanus toxin antibody according to any one of claims 9 to 14, characterized in that The method achieves an anti-tetanus neutralizing antibody titer of ≥ 0.01 IU / mL in the subject; Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; More preferably, the drug is used to achieve an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration.

16. The use according to any one of claims 9 to 15, characterized in that The method achieves the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

17. A method for preventing or treating tetanus, the method comprising administering an anti-tetanus toxin antibody to a subject in need thereof; the anti-tetanus toxin antibody comprising: A heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 comprising the amino acid sequences shown in SEQ ID NO.1, SEQ ID NO.2 and SEQ ID NO.3, respectively; and The light chain CDR1, light chain CDR2 and light chain CDR3 respectively contain the amino acid sequences shown in SEQ ID NO.6, SEQ ID NO.7 and SEQ ID NO.

8.

18. The method according to claim 17, characterized in that The anti-tetanus toxin antibody comprises: A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO.4; and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO.9; Preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region; More preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Further preferably, the anti-tetanus toxin antibody comprises: A heavy chain comprising the amino acid sequence shown in SEQ ID NO.5; and A light chain comprising the amino acid sequence shown in SEQ ID NO.

10.

19. The method according to claim 17 or 18, characterized in that The subject is a mammal that has been infected or has not been infected with Clostridium tetani; Preferably, the subject is a primate, more preferably a human, such as an adult, and even more preferably an adult over 18 years old.

20. The method according to any one of claims 17 to 19, characterized in that The method comprises a single administration of the anti-tetanus toxin antibody to the subject to prevent or treat tetanus; Preferably, the anti-tetanus toxin antibody is administered by intramuscular injection.

21. The method according to any one of claims 17 to 20, characterized in that The dosage of the antibody administered in the method is 0.6-15 mg, such as 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; Preferably, the antibody dosage is 5-15 mg; More preferably, the antibody dose is 10 mg.

22. The method according to any one of claims 17 to 20, characterized in that The dosage of the antibody administered in the method is 10-250 μg / kg, such as 10 μg / kg, 30 μg / kg, 35 μg / kg, 83 μg / kg, 100 μg / kg, 167 μg / kg or 250 μg / kg, based on the body weight of the subject; Preferably, the antibody dosage is 83-250 μg / kg; More preferably, the antibody dose is 167 μg / kg.

23. The method according to any one of claims 17 to 22, characterized in that The method achieves an anti-tetanus neutralizing antibody titer of ≥ 0.01 IU / mL in the subject; Preferably, the anti-tetanus neutralizing antibody titer is detectable in the serum of the subject; More preferably, the drug is used to achieve an anti-tetanus neutralizing antibody titer ≥ 0.01 IU / mL in the subject within 48 h, preferably 24 h, more preferably 12 h, further preferably 6 h, or even shorter time after administration.

24. The method according to any one of claims 17 to 23, characterized in that The method achieves the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

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