USE OF ANTIBODY AGAINST TETANUS TOXIN IN THE PREVENTION OR TREATMENT OF TETANUS

Abstract

Provided is an application of an anti-tetanus toxin antibody in preventing or treating tetanus. The anti-tetanus toxin antibody is applied in a specific administration regimen, and can achieve the technical effects of being quicker to take effect and having a longer protection time than existing passive immunization agents, and can therefore effectively prevent or treat tetanus.

Description

Application of an anti-tetanus toxin antibody in preventing or treating tetanus

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the priority benefit of Chinese invention patent application No. CN202311265343.6 filed on September 27, 2023, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] 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

[0004] Tetanus is a specific infection caused by Clostridium tetani, which invades the body and reproduces in an oxygen-deficient environment, producing a toxin (tetanus toxin), which causes muscle spasms. Tetanus toxin primarily attacks motor neurons in the nervous system, resulting in clinical symptoms such as lockjaw, paroxysmal spasms, and tonic spasms. Globally, the mortality rate of tetanus is as high as 30%-50%, with the mortality rate for severe cases and newborns reaching as high as 80%. Although tetanus is less common in developed countries, it remains widespread in low- and middle-income countries and underdeveloped regions, representing a significant public health issue.

[0005] Wound treatment and the rational use of tetanus immunization preparations after injury are crucial for preventing tetanus infection. Tetanus prevention methods include active immunization (i.e., tetanus vaccine) and passive immunization (such as tetanus-specific immunoglobulin). Domestically available 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, equine tetanus antitoxin is mainly derived from horse serum, which has the problem of potential hypersensitivity reaction of the receptor and a long immunization cycle. Although equine tetanus immunoglobulin has a lower allergy rate than TAT, it still cannot overcome the application barriers that are common with animal-derived therapeutic drugs. Tetanus human immunoglobulin is a blood product and has the potential risk of infectious diseases such as AIDS and hepatitis B. In addition, due to the complexity of its industrial production and limited output, it cannot fully meet market demand. Moreover, clinical applications have found that the immune effects of these immune preparations last for a relatively 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.

[0006] Therefore, there is still a need in the art for new tetanus passive immunization preparations for preventing or treating tetanus.

[0007] Summary of the Invention

[0008] 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 available passive immunization preparations for tetanus, an effective method is to promptly inject an anti-tetanus toxin antibody that is better in efficacy (reaching antibody protection levels faster, maintaining protection for a longer time, and achieving higher antibody titers), safety, and quality controllability, and is suitable for large-scale production.

[0009] 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.

[0010] "TRN0011" is an immunoglobulin G1 (IgG1) monoclonal antibody that binds to the specific surface of the tetanus toxin protein with high affinity, neutralizing the toxin to prevent the enzymatic cleavage of the tetanus toxin, thereby protecting the body. Through in vitro and in vivo pharmacodynamic studies on animals, as well as randomized, double-blind, placebo-controlled, dose-escalation studies of TRN0011's safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects, the applicants of this application have provided a preventive or therapeutic use for tetanus, as well as corresponding preventive or therapeutic regimens, using this antibody as the active agent.

[0011] Specifically, the present invention provides the following technical solutions.

[0012] 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: 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.

[0013] 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.

[0014] More preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region.

[0015] 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 set forth in SEQ ID NO. 5; and a light chain comprising the amino acid sequence set forth in SEQ ID NO. 10.

[0016] In the context of the present invention, the term "tetanus" refers to 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. According to the 2020 edition 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, which must include at least one of the following manifestations: (1) clenched jaw or a 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. A positive result is a reflex spasm of the masseter muscle instead of normal reflex nausea. Tetanus can cause temporary functional changes in the central nervous system, manifested as tonic contraction and paroxysmal spasms 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.

[0017] 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 have not yet been 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).

[0018] The subject is a mammal, which may or may not be infected with Clostridium tetani. In the context of the present invention, the term "mammal" refers to any animal classified as a mammal, including but not limited to humans, livestock and agricultural animals, and zoo, sports or pet animals, such as sheep, dogs, horses, cats, cattle, rats, pigs, apes such as macaques, and the like. Preferably, the mammal is a primate, more preferably a human. When the subject is a human, the subject is preferably an adult over the age of 18.

[0019] Tetanus is prevented or treated by administering the drug to the subject once. Preferably, the drug is an intramuscular injection preparation for administration of the drug.

[0020] 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, the antibody dose achieved is 10 mg.

[0021] Alternatively, based on the average 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; preferably, the antibody dose achieved is 83-250 μg / kg; more preferably, the antibody dose achieved is 167 μg / kg.

[0022] Administration of the above-mentioned drug can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0023] 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 48 hours, preferably 24 hours, more preferably 12 hours, further preferably 6 hours, or even shorter after administration.

[0024] Administration of the above-mentioned drug can achieve the anti-tetanus neutralizing antibody titer in the subject's body for more than 90 days, preferably more than 105 days.

[0025] In this aspect of the present invention, the use of the antibody in the preparation of a medicament for preventing or treating tetanus can be arbitrarily selected from the above-mentioned characteristics (e.g., dosage, route of administration, frequency of administration, dosing 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 for a single intramuscular injection into the subject to achieve a 10 mg antibody dose.

[0026] In another aspect, the present invention provides an anti-tetanus toxin antibody for use as a prophylactic 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 set forth 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 set forth in SEQ ID NO. 6, SEQ ID NO. 7, and SEQ ID NO. 8, respectively.

[0027] 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.

[0028] More preferably, the anti-tetanus toxin antibody comprises all or part of the heavy chain constant region and / or the light chain constant region.

[0029] 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 set forth in SEQ ID NO. 5; and a light chain comprising the amino acid sequence set forth in SEQ ID NO. 10.

[0030] The term "tetanus" is as defined above. In particular, the symptoms of tetanus treated by the anti-tetanus toxin antibodies provided by the present invention are spasms of the muscles of facial expression, neck, back, abdomen, limbs, and diaphragm.

[0031] The anti-tetanus toxin antibodies provided by the present invention are used in a method for preventing or treating tetanus, which may include administering (e.g., injecting) the antibodies to a subject to prevent or treat tetanus. The subject is a mammal that has or has not been infected with Clostridium tetani.

[0032] The term "mammal" is as defined above. Preferably, the mammal is a primate, more preferably a human. When the subject is a human, it is preferably an adult, for example an adult over 18 years old.

[0033] Preferably, the method comprises administering a single dose 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.

[0034] 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.

[0035] Alternatively, based on the average 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.

[0036] The above method can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0037] 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.

[0038] The above method can achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

[0039] In this aspect of the present invention, the administration characteristics (e.g., dosage, route of administration, frequency of administration, and period of administration, etc.) specified for the use of the antibody as a prophylactic 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 for use as a prophylactic or therapeutic agent for tetanus, or for use in a method for the prophylaxis or treatment of tetanus, comprising administering a single intramuscular injection of 10 mg of the anti-tetanus toxin antibody to the subject.

[0040] In another aspect, the present invention provides a method for preventing or treating tetanus, comprising administering an anti-tetanus toxin antibody to a subject in need thereof. The anti-tetanus toxin antibody is as defined above.

[0041] 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.

[0042] The method for preventing or treating tetanus provided by the present invention may comprise administering (e.g., injecting) the antibody to a subject to prevent or treat tetanus. The subject is a mammal that has or has not been infected with Clostridium tetani. For example, the subject is a person who has not been fully immunized against tetanus or whose immunization history is unknown.

[0043] The term "mammal" is as defined above. Preferably, the mammal is a primate, more preferably a human. When the subject is a human, it is preferably an adult, for example an adult over 18 years old.

[0044] Preferably, the method comprises administering a single dose 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.

[0045] 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.

[0046] Alternatively, based on the average 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.

[0047] The above method can achieve an anti-tetanus neutralizing antibody titer of ≥0.01 IU / mL in the subject.

[0048] 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.

[0049] The above method can achieve the anti-tetanus neutralizing antibody titer in the subject for more than 90 days, preferably more than 105 days.

[0050] In this aspect of the present invention, the administration characteristics (e.g., dosage, route of administration, frequency of administration, and period of administration) specified 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, comprising administering a single intramuscular injection of 10 mg of the anti-tetanus toxin antibody to the subject.

[0051] The applicant of this application conducted in vitro and in vivo pharmacodynamic experiments on the immunoglobulin G1 (IgG1) monoclonal antibody previously provided by the applicant, as well as, in particular, a randomized, double-blind, placebo-controlled, dose-escalation study of 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.

[0052] Studies have shown that the tetanus monoclonal antibody TRN0011, when administered to subjects in a specific dosing regimen, can achieve a faster onset of action and longer duration of protection than tetanus human immunoglobulin (HTIG), and can therefore effectively prevent or treat tetanus.

[0053] Specifically, literature, relevant guidelines, and previous studies have shown that, regardless of whether passive or active immunization is used, as long as the anti-tetanus neutralizing antibody content in the body's serum reaches 0.01 IU / mL, immune protection can be achieved. The serum antibody level of the marketed tetanus human immunoglobulin can exceed 0.01 IU / mL three days after injection (see "Rongsheng Yipu HTIG Instructions" [Clinical Trial]). 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 rise to the minimum protective level of 0.01 IU / mL six hours after administration, or even shorter, and the increase in neutralizing antibody titer increases with the increase in the dose.

[0054] Moreover, in terms of the duration of protection, intramuscular injection of TRN0011 provided anti-tetanus protection to the majority (>90%) of the population 12 hours after administration, and continued until 105 days after administration. This means that compared with human tetanus 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 anti-tetanus neutralizing antibody titers far above the minimum protection threshold can still be detected on day 106 after administration, it can be seen that the administration of TRN0011 can provide much longer-term protection.

[0055] In addition, based on the results of various studies, it can be determined that TRN0011 causes low immunogenicity and has no impact on individual pharmacokinetic and safety results; and TRN0011 has good safety and tolerability.

[0056] 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

[0057] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

[0058] FIG1 shows 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.

[0059] FIG2 shows the Kaplan Meier curve of the duration of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) ≥ 0.01 IU / mL compared with the baseline in Example 1.

[0060] FIG3 shows a graph showing the time trend of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) compared to the baseline in Example 1.

[0061] Best Mode for Carrying Out the Invention

[0062] The present invention is described below with reference to specific examples. Those skilled in the art will appreciate 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.

[0063] 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.

[0064] 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.

[0065] The test drug in the following examples is an injection containing TRN0011; or a placebo containing the same excipients as the injection but without an antibody.

[0066] Regardless of the specific dosage, the groups that received TRN0011 were collectively referred to as "TRN0011 groups."

[0067] Anti-tetanus neutralizing antibody titers were measured in serum using enzyme-linked immunosorbent assay (ELISA).

[0068] The HTIG control used in the following examples is immunoglobulin from Hualan Biotechnology Co., Ltd.

[0069] In the following examples, "subject" and "volunteer" are interchangeable.

[0070] Example 1

[0071] 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 of TRN0011 antibody, tetanus human immune globulin (HTIG), or placebo after a single intramuscular injection.

[0072] Trial Objectives: The primary objective is to compare the anti-tetanus toxin neutralizing antibody titers of TRN0011 and tetanus human immune globulin (HTIG) after a single intramuscular (IM) injection in Chinese adult volunteers. Secondary objectives are 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.

[0073] 1. Research design

[0074] 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).

[0075] Qualified volunteers were admitted to the research center on Day -1, completed the relevant examinations and randomization required by the protocol, and received the trial drugs on Day 1. The dispensing and administration of the trial drugs were performed by unblinded researchers, and the injection time of all trial drugs was controlled within 30 (± 3) seconds.

[0076] After dosing, volunteers underwent safety assessments at the research center, including physical examinations, vital signs, 12-lead electrocardiograms (ECGs), and laboratory tests (complete blood counts, 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.

[0077] (2) Enrolled personnel

[0078] Given the serious clinical consequences of tetanus prophylaxis failure, dose exploration in trauma patients is not appropriate. Furthermore, considering that tetanus patients are generally healthy except for trauma, this study recruited healthy volunteers or those with stable chronic diseases.

[0079] The study participants were selected according to the following criteria.

[0080] Inclusion criteria:

[0081] 1) Chinese adults (aged ≥18 years old), male or female;

[0082] 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 to not pose significant risks to the volunteers.

[0083] (3) Research plan

[0084] A total of 240 Chinese adult volunteers were enrolled.

[0085] The volunteers were randomly assigned to receive TRN0011 5 mg (0.25 mL), TRN0011 10 mg (0.5 mL), TRN0011 15 mg (0.75 mL), HTIG 250 IU (2.5 mL), or placebo (0.5 mL) in a 2:2:1:2:1 ratio. All received a single intramuscular injection into the buttocks.

[0086] The TRN0011 dosage for these groups was determined based on preliminary experimental results. HTIG is the preferred passive immunization agent for tetanus prevention, recommended by current international and domestic guidelines. It has a proven protective effect against tetanus and has long been widely used clinically. A single intramuscular injection of 250 IU of HTIG is the standard dose for tetanus prevention in clinical practice. Therefore, HTIG was selected as a positive control at a dose of 250 IU. Furthermore, to fully evaluate the safety of TRN0011, a placebo control was also used.

[0087] (IV) Evaluation of research indicators

[0088] Primary endpoint:

[0089] The proportion of volunteers whose anti-tetanus toxin neutralizing antibody titer increased by ≥0.01 IU / mL compared with the baseline level (ΔTiter) at 24 hours after administration (serum anti-tetanus toxin neutralizing antibody titer is the pharmacodynamic indicator in this study)

[0090] The incubation period for tetanus ranges from 3 to 21 days after infection, with a median of 7 days. The longest onset can be 178 days after infection, and the shortest can be 1-2 days, primarily for cephalic tetanus. Therefore, products designed to prevent tetanus should provide protection within 24 hours of injury.

[0091] According to World Health Organization (WHO) guidelines and previous studies, the level of neutralizing antibodies against tetanus toxin in the body correlates with protective efficacy after active or passive immunization. In the US Food and Drug Administration's (FDA) list of surrogate endpoints for drug approval and licensing, the level of antibodies against tetanus toxin is a surrogate endpoint for tetanus vaccines.

[0092] There is evidence that anti-tetanus toxin neutralizing antibody levels exceeding 0.01 IU / mL as 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 considering that the subjects may have received active tetanus immunization (tetanus vaccine) in the past and therefore have 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 24 hours after medication.

[0093] Secondary endpoints:

[0094] Safety endpoints, including the types and incidence of adverse events and serious adverse events, as well as the results of physical examinations, vital signs, 12-lead ECGs, and laboratory tests (complete blood count, blood biochemistry, and urinalysis);

[0095] Change from baseline in anti-tetanus toxin neutralizing antibody titers at 24 hours, 48 ​​hours (day 3), and on days 7, 21, 30, and 90 after dosing;

[0096] 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 dosing;

[0097] The proportion of volunteers whose anti-tetanus toxin neutralizing antibody titers increased by ≥0.01 IU / mL compared with baseline levels at both 24 hours and 30 days after treatment;

[0098] Duration of post-dose increase in anti-tetanus toxin neutralizing antibody titer by ≥0.01 IU / mL compared to baseline;

[0099] Anti-tetanus toxin neutralizing antibody titers at 24 hours, 48 ​​hours (day 3), and 7, 21, 30, and 90 days after administration;

[0100] 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 dosing;

[0101] Pharmacokinetic parameters of TRN0011. PK parameters primarily include peak concentration (Cmax), time to peak concentration (Tmax), elimination half-life (t1 / 2), area under the plasma concentration-time curve (AUC0-t) from 0 to t, and area under the plasma concentration-time curve (AUC0-∞) from 0 to ∞; if data permit, apparent clearance (CL / F) and apparent volume of distribution (Vd / F) are also included.

[0102] The positive rate of anti-drug antibodies (ADA) in volunteers in the TRN0011 group.

[0103] (V) Statistical methods

[0104] Analysis Set

[0105] Full Analysis Set (FAS): All randomized volunteers who received at least one dose of the trial drug will serve as the full analysis set. The full analysis set will be used to analyze volunteer distribution, demographics, and baseline characteristics.

[0106] Anti-tetanus toxin neutralizing antibody titer analysis set: All randomized volunteers who received at least one dose of the investigational drug and had at least one valid post-dose serum anti-tetanus toxin neutralizing antibody titer test data were included in the anti-tetanus toxin neutralizing antibody titer analysis set for this trial. If an event occurs that affects the neutralization antibody titer or detection (such as a serious violation of the protocol inclusion criteria, use of prohibited drugs during the study, etc.), all or part of the neutralization antibody test data of the corresponding volunteer will not be included in the anti-tetanus toxin neutralizing antibody titer analysis.

[0107] Safety Analysis Set (SS): All volunteers who were randomized, received at least one dose of the investigational drug, and had at least one post-dose safety assessment were included in the SS. The SS is the safety evaluation population for this trial.

[0108] PK Concentration Analysis Set (PKCS): All randomized volunteers who received at least one dose of investigational drug and had at least one analyzable PK concentration during the trial were included in the PKCS. If an event occurred that could affect PK concentration results or measurements (e.g., a serious violation of protocol inclusion criteria, use of a prohibited drug during the study), all or part of the PK data for the corresponding volunteer would not be included in the PKCS. The PK Concentration Analysis Set will be used for pharmacokinetic concentration analyses.

[0109] PK Parameter Analysis Set (PKPS): All randomized volunteers who received at least one dose of investigational product and had at least one analyzable PK parameter during the trial. If an event occurs that could affect PK parameter results (e.g., a serious violation of protocol inclusion criteria, use of a prohibited drug during the study), all or part of the PK data for the corresponding volunteer will be excluded from the PKPS. The PK Parameter Analysis Set will be used for pharmacokinetic parameter analysis.

[0110] 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.

[0111] Basic Principles

[0112] 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.

[0113] Anti-tetanus toxin neutralizing antibody titer, PK, immunogenicity and safety analyses were all 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.

[0114] Analysis of anti-tetanus toxin neutralizing antibody titer levels

[0115] The anti-tetanus toxin neutralizing antibody titer level analysis is based on the anti-tetanus toxin neutralizing antibody titer level analysis set.

[0116] According to the dosing group, the number, percentage, 95% CI, and 90% CI (based on the Clopper-Pearson method) of volunteers with ΔTiter ≥ 0.01 IU / mL 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 by the tetanus antibody IgG rapid test results at the time of random stratification).

[0117] This study also conducted subgroup analysis of all tetanus toxin neutralizing antibody titer-related endpoints based on the volunteers' baseline tetanus toxin neutralizing antibody titer (chemiluminescence detection results of serum samples), with 0.01 IU / mL (<0.01 IU / mL and ≥0.01 IU / mL) as the cutoff value.

[0118] A sensitivity analysis was performed using the Newcombe Wilson Score to calculate the 95% CI and 90% CI of the difference in the percentage of volunteers with an increase in anti-tetanus toxin neutralizing antibody titer of ≥0.01 IU / mL compared with the baseline level between different groups.

[0119] Pharmacokinetic analysis

[0120] PK concentration analysis

[0121] The PK concentrations of the investigational drug were summarized by dosing group and planned sampling time point, including the number of volunteers, the number of volunteers below the lower limit of quantification (BLQ), the arithmetic mean, SD, median, minimum, maximum, CV (based on the arithmetic mean), and geometric mean.

[0122] Mean drug concentrations were plotted against time (linear and semi-logarithmic scales) according to the planned sampling times.

[0123] PK parameter analysis

[0124] PK parameters (Cmax, AUC0-t, AUC0-∞, Tmax, t1 / 2, Vd / F, CL / F, etc.) were calculated by non-compartmental analysis (NCA).

[0125] 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.

[0126] The individual PK parameters of all randomized volunteers are listed according to the dosing group.

[0127] Immunogenicity analysis

[0128] The number and percentage of volunteers who were ADA-positive at least once during the trial, at baseline, at least once after baseline, and at each visit after baseline were summarized according to the actual dosing group.

[0129] The immunogenicity test results at each time point are tabulated according to the dosing group.

[0130] Security Analysis

[0131] The safety data were summarized by actual administration group and dose. 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).

[0132] Adverse events were coded using the Medical Dictionary for Research and Development (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.

[0133] Analysis conducted

[0134] Primary endpoint analysis

[0135] The primary endpoint analysis was performed after all participants had data on the primary endpoint, as well as safety data from the Day 30 visit. This analysis also included data on all safety and other secondary endpoints available at that time.

[0136] Updated analyses of safety endpoints and other secondary endpoints

[0137] At the end of the trial, updated analyses of safety endpoints and other secondary endpoints were performed.

[0138] (VI) Research Results

[0139] 1. Distribution and characteristics of volunteers

[0140] This study enrolled 240 adult volunteers, including 151 in the TRN0011 group (61 in the 5 mg group, 61 in the 10 mg group, and 29 in the 15 mg group), 59 in the HTIG group, and 30 in the placebo group. Seven volunteers withdrew prematurely from the study, including three in the TRN0011 5 mg group, two in the 10 mg group, one in the 15 mg group, and one in the HTIG group. Six of these volunteers (five in the TRN0011 group and one in the HTIG group) withdrew prematurely due to loss to follow-up, and one (in the TRN0011 5 mg group) withdrew prematurely due to inability to return for follow-up.

[0141] See Table 1.

[0142] Table 1. Distribution of volunteers (all volunteers)

[0143] The percentages are calculated based on the number of volunteers randomized to each actual dosing group.

[0144] All 240 volunteers were included in the FAS and SS sets. All volunteers in the TRN0011 and HTIG groups (210 total) were included in the anti-tetanus toxin neutralizing antibody titer analysis set. All volunteers in the TRN0011 group (151 total) were included in the PKCS, PKPS, and immunogenicity analysis sets.

[0145] 2. Anti-tetanus toxin neutralizing antibody titer results

[0146] 2.1 Primary Endpoint

[0147] At 24 hours after dosing, the proportion of volunteers with anti-tetanus toxin neutralizing antibodies ΔTiter ≥ 0.01 IU / mL in the TRN0011 5mg, 100% and 100% groups, respectively, was significantly higher than that in the HTIG group (81.4%). No significant differences were observed between the TRN0011 dosing groups. The differences between the TRN0011 5mg, 10mg and 15mg 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.

[0148] 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.

[0149] See Table 2 for the results.

[0150] Table 2. Summary of the proportion of volunteers with an increase in anti-tetanus toxin neutralizing antibody titer (ΔTiter) ≥ 0.01 IU / mL compared with baseline at 24 hours after administration and comparison between groups (Anti-tetanus toxin neutralizing antibody titer level analysis set) Baseline was defined as the last measurement before the administration of the trial drug on day 1. [1]: Evaluable volunteers were defined as those with intact anti-tetanus toxin neutralizing antibody titers at baseline and 24 hours after administration. The percentages were calculated based on the number of volunteers in the analysis set for the anti-tetanus toxin neutralizing antibody titer levels in each dosing group. [2]: The percentages were calculated based on the number of evaluable volunteers in each dosing group. [3]: Based on the Clopper-Pearson method. [4]: ​​Based on the stratified Miettinen-Nurminen method, stratification was performed according to the results of the tetanus antibody IgG rapid test at the time of randomization.

[0151] Secondary End Points

[0152] The following results were obtained for the secondary endpoints.

[0153] 2.2.1 After administration, the proportion of volunteers with ΔTiter ≥ 0.01 IU / mL reached 55.7%, 80.3%, and 96.6% in the TRN0011 5mg, 10mg, and 15mg groups at 6 hours, and reached 100% at 72, 48, and 12 hours, respectively. In contrast, the proportion of volunteers in the HTIG group at 6 hours was only 20.3%, and it did not reach 100% until 7 days.

[0154] 2.2.2 At 12 hours after dosing, the proportions of patients with ΔTiter ≥ 0.01 IU / mL in the TRN0011 5mg, 10mg, and 15mg groups reached 75.4%, 91.8%, and 100%, respectively, significantly higher than the HTIG group (55.9%). The intergroup differences between the TRN0011 groups and the HTIG group were 19.5%, 35.9%, and 44.1%, respectively, with the lower limits of their 95% CIs all exceeding 0.

[0155] 2.2.3 From hour 48 to day 30, the proportion of patients with ΔTiter ≥ 0.01 IU / mL remained high (>90.0%) in all TRN0011 treatment groups and the HTIG group. Thereafter, the TRN0011 10 mg and 15 mg groups maintained high levels, remaining at 96.6% and 96.4% on day 106. However, this proportion in the HTIG group decreased significantly to 64.3% on day 60 and further to 13.8% on day 106. The results are shown in Figure 1.

[0156] 2.2.4 Analysis of the proportion of volunteers with ΔTiter ≥ 0.01 IU / mL at 24 hours and 30 days showed that the rates in the TRN0011 5mg, 100% and 100% groups were higher than those in the HTIG group (78.0%).

[0157] 2.2.5 Volunteers in the TRN0011 5mg, 10mg, and 15mg groups reached peak ΔTiter levels between days 7 and 14 after dosing, with geometric mean titers (GMTs) of 0.1362, 0.2801, and 0.4786 IU / mL, respectively. The increase in ΔTiter was generally linear with increasing dose. Similar to TRN0011, ΔTiter in the HTIG group peaked on day 7 after dosing, but the mean titer (0.0392 IU / mL) was significantly lower than in all TRN0011 groups.

[0158] 2.2.6 After administration, the GMT of ΔTiter in each TRN0011 administration group was ≥0.01 IU / mL from the 6th hour to the 106th day. In the HTIG group, the GMT of ΔTiter was ≥0.01 IU / mL from the 12th hour after administration to the 60th day.

[0159] 2.2.7 At each time point after administration, the ΔTiter GMT of the TRN0011 group was higher than that of the HTIG group.

[0160] In addition, the Kaplan Meier curve 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) is shown in Figure 2; the trend graph of the increase in the anti-tetanus toxin neutralizing antibody titer (ΔTiter) compared with the baseline after administration over time (anti-tetanus toxin neutralizing antibody titer level analysis set) is shown in Figure 3.

[0161] 3. Pharmacokinetics

[0162] 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 in drug exposure was basically linear with the dose escalation ratio.

[0163] The median time to peak serum drug concentration of TRN0011 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.

[0164] There were no significant differences in the mean distribution volume and clearance of TRN0011 5mg, 10mg, and 15mg groups, with mean Vd / F values ​​ranging from 7320 to 8570mL and mean CL / F values ​​ranging from 8.17 to 10.2mL / h.

[0165] 4. Immunogenicity

[0166] Results showed that among the 151 volunteers who received TRN0011, only 2.65% (4 / 151) experienced TRN0011-related immunogenicity, defined as a positive ADA test result. The highest ADA-positive titer was 6.14, and none showed neutralizing activity. Furthermore, immunogenicity was found to have no significant impact on individual PK and safety outcomes.

[0167] 5. Security

[0168] Key safety results are as follows:

[0169] Among all volunteers who received TRN0011, 48.3% (73 / 151) experienced at least one TEAE, a slightly lower incidence than in the HTIG group (54.2%, 32 / 59) and the placebo group (53.3%, 16 / 30). The incidence of TEAEs was similar across all TRN0011 treatment groups, with no dose-related effect observed.

[0170] 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 (10.6% vs 16.7% and 8.6% vs 6.7%, respectively).

[0171] 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 was severe and the researchers judged it to be unrelated to the trial drug.

[0172] During the trial, no volunteer died or withdrew from the study prematurely due to TEAEs.

[0173] 6. Conclusion

[0174] 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 standard treatment for passive tetanus immunization prevention in clinical practice, HTIG 250 IU, and placebo.

[0175] In this study, the mean serum anti-tetanus toxin neutralizing antibody titers (ΔTiter) reached 0.0113, 0.0342, and 0.0727 IU / mL at 6 hours after administration of TRN0011 5mg, 10mg, and 15mg, respectively, reaching the minimum protection level of 0.01 IU / mL. At these times, the proportion of subjects with ΔTiter ≥ 0.01 IU / mL was 55.7%, 80.3%, and 96.6%, respectively. At the same time point, the mean ΔTiter after administration of HTIG 250IU was 0.0050 IU / mL, and the proportion of subjects with ΔTiter ≥ 0.01 IU / mL was only 20.3%, which does not provide ideal anti-tetanus protection in the general population.

[0176] 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 less than 2 days from injury to the onset of tetanus symptoms, this study selected the 24th hour after administration as the primary endpoint for evaluating the tetanus toxin neutralizing antibody titer.

[0177] 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.

[0178] Further evaluation of relevant secondary endpoints showed that TRN0011 10mg and 15mg provided protection in a higher proportion of the study population as early as 12 hours after dosing. At this time, the mean ΔTiter values ​​for the two dosing groups were 0.0711 and 0.1476 IU / mL, respectively, and the proportion of ΔTiter ≥ 0.01 IU / mL was 91.8% and 100%, respectively. The data further showed that the protective effect provided by TRN0011 10mg and 15mg was sustained until the end of the trial. That is, at 106 days after dosing, the mean ΔTiter values ​​for the two groups were still 0.0241 and 0.0444 IU / mL, and the proportion of ΔTiter ≥ 0.01 IU / mL remained at 96.6% and 96.4%.

[0179] Comparison of TRN0011 10mg and 15mg in terms of tetanus protection showed that, except for a higher proportion of people protected at 6 hours after administration, the 15mg dose did not provide significant benefits compared to 10mg in terms of the proportion of people protected or the duration of protection at other time points. This study also found that after administration of TRN0011 5mg, 10mg, and 15mg, serum anti-tetanus toxin neutralizing antibody titers increased faster and to a greater extent than after HTIG 250IU. Compared to TRN0011 10mg, 91.8% of volunteers had a ΔTiter ≥ 0.01IU / mL 12 hours after administration, while only 55.9% of volunteers in the HTIG group achieved this level of protection at this time point, and it was not until 48 hours that a proportion comparable to TRN0011 10mg (93.2%) 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, 106 days after administration.

[0180] 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.

[0181] 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.

[0182] In terms of immunogenicity, only a very low proportion (2.65%) of volunteers in this study experienced immunogenic reactions related to TRN0011, with the highest ADA-positive sample titer reaching 6.14, and none exhibited neutralizing activity. PK parameter comparisons and AE information summaries showed that immunogenicity had no significant impact on individual PK and safety outcomes. This is consistent with the immunogenicity results of TRN0011 shown in previous studies.

[0183] In this study, the incidence of TEAEs in the TRN0011 group was similar to that in the HTIG and placebo groups, and the severity was mild to moderate. The most common TEAEs were increased blood triglycerides and increased blood uric acid, which also occurred at similar rates in the TRN0011 and placebo groups (10.6% vs 16.7% and 8.6% vs 6.7%, respectively).

[0184] 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.

[0185] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can 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 fall within the scope of the claims attached to the present invention.

Claims

1. Use of an antibody against tetanus toxin in the manufacture of a medicinal product for the prevention or treatment of tetanus; The tetanus toxin antibody comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, respectively comprising the amino acid sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; and a light chain CDR1, a light chain CDR2, and a light chain CDR3, respectively comprising the amino acid sequences set forth in SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO:

8.

2. The use according to claim 1, wherein the antibody against tetanus toxin comprises: a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO: 4; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO: 9; preferably, the anti-tetanus toxin antibody comprises all or part of a heavy chain constant region and / or a light chain constant region; more preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Even more preferably, the anti-tetanus toxin antibody comprises: a heavy chain comprising the amino acid sequence presented in SEQ ID NO: 5; and a light chain comprising the amino acid sequence presented in SEQ ID NO:

10.

3. The use according to claim 1 or 2, characterized in that the medicinal product is administered to a subject who has been infected or has not yet 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 aged 18 years or older; and / or tetanus is prevented or treated by a single administration of a drug to a subject; preferably, the drug is an intramuscular injection preparation for administering the drug.

4. The use according to any one of claims 1 to 3, characterized in that the dose of the antibody achieved upon administration of the medicinal product varies in the range from 0.6 mg to 15 mg, for example 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; preferably, the achieved dose of the antibody varies in the range from 5 mg to 15 mg; more preferably, the achieved dose of the antibody is 10 mg; and / or based on the body weight of the subject, the antibody dose achieved upon administration of the drug ranges from 10 μg / kg to 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; preferably, the achieved antibody dose ranges from 83 μg / kg to 250 μg / kg; more preferably, the achieved antibody dose is 167 μg / kg.

5. Use according to any one of paragraphs 1-4, characterized in that the medicinal product is used to achieve a titer of neutralizing antibodies against tetanus of ≥0.01 IU / ml in a subject; preferably, the titer of neutralizing antibodies against tetanus is detectable in the subject's serum; more preferably, the medicinal product is used to achieve a tetanus neutralizing antibody titer of ≥0.01 IU / ml in a subject within 48 hours, preferably 24 hours, more preferably 12 hours, even more preferably 6 hours or even less, after administration of the dose; and / or the medicinal product is used to achieve a tetanus neutralizing antibody titer that lasts for more than 90 days, preferably lasts for more than 105 days, in a subject.

6. An antibody against tetanus toxin for use in a method comprising administering the antibody to a subject in need thereof for the prevention or treatment of tetanus; the anti-tetanus toxin antibody comprises: a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3, respectively comprising the amino acid sequences set forth in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3; light chain CDR1, light chain CDR2 and light chain CDR3, respectively comprising the amino acid sequences set forth in SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO:

8.

7. The anti-tetanus toxin antibody of claim 6, wherein the anti-tetanus toxin antibody comprises: a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO: 4; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO: 9; preferably, the anti-tetanus toxin antibody comprises all or part of a heavy chain constant region and / or a light chain constant region; more preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Even more preferably, the anti-tetanus toxin antibody comprises: a heavy chain comprising the amino acid sequence presented in SEQ ID NO: 5; and a light chain comprising the amino acid sequence presented in SEQ ID NO:

10.

8. The anti-tetanus toxin antibody of claim 6 or 7, wherein the subject is a mammal infected or not yet infected with Clostridium tetani; preferably the subject is a primate, more preferably a human, such as an adult, and even more preferably an adult 18 years of age or older; and / or the method comprises administering an anti-tetanus toxin antibody to a subject in a single dose for the prevention or treatment of tetanus; preferably, the anti-tetanus toxin antibody is administered by intramuscular injection.

9. The anti-tetanus toxin antibody of any one of claims 6 to 8, wherein the antibody dose administered in the method ranges from 0.6 mg to 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 ranges from 5 mg to 15 mg; more preferably, the antibody dose is 10 mg; and / or based on the body weight of the subject, the antibody dose administered in the method ranges from 10 μg / kg to 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; preferably, the antibody dose ranges from 83 μg / kg to 250 μg / kg; more preferably, the antibody dose is 167 μg / kg.

10. The anti-tetanus toxin antibody according to any one of claims 6-9, wherein the method achieves a tetanus neutralizing antibody titer of ≥0.01 IU / ml in the subject; preferably, the titer of neutralizing antibodies against tetanus is detectable in the subject's serum; more preferably, the medicinal product is used to achieve a tetanus neutralizing antibody titer of ≥0.01 IU / ml in a subject within 48 hours, preferably 24 hours, more preferably 12 hours, even more preferably 6 hours or even less, after administration of the dose; and / or the method achieves a tetanus neutralizing antibody titer that persists for greater than 90 days, preferably that persists for greater than 105 days, in a subject.

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

8.

12. The method according to claim 11, wherein the anti-tetanus toxin antibody comprises: a heavy chain variable region comprising the amino acid sequence presented in SEQ ID NO: 4; and a light chain variable region comprising the amino acid sequence presented in SEQ ID NO: 9; preferably, the anti-tetanus toxin antibody comprises all or part of a heavy chain constant region and / or a light chain constant region; more preferably, the anti-tetanus toxin antibody is a monoclonal antibody comprising two heavy chains and two light chains; Even more preferably, the anti-tetanus toxin antibody comprises: a heavy chain comprising the amino acid sequence presented in SEQ ID NO: 5; and a light chain comprising the amino acid sequence presented in SEQ ID NO:

10.

13. The method according to claim 11 or 12, wherein the subject is a mammal, whether or not infected with Clostridium tetani; preferably the subject is a primate, more preferably a human, such as an adult, and even more preferably an adult 18 years of age or older; and / or the method comprises administering an anti-tetanus toxin antibody to a subject in a single dose for the prevention or treatment of tetanus; preferably, the anti-tetanus toxin antibody is administered by intramuscular injection.

14. The method according to any one of claims 11 to 13, characterized in that the dose of the antibody administered in the method varies in the range of 0.6 mg to 15 mg, for example 0.6 mg, 1.8 mg, 2.1 mg, 5 mg, 6 mg, 10 mg or 15 mg; preferably, the dose of the antibody varies in the range of 5 mg to 15 mg; more preferably, the dose of the antibody is 10 mg; and / or based on the body weight of the subject, the antibody dose administered in the method ranges from 10 μg / kg to 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; preferably, the antibody dose ranges from 83 μg / kg to 250 μg / kg; more preferably, the antibody dose is 167 μg / kg.

15. The method according to any one of paragraphs 11-14, characterized in that the method achieves a tetanus neutralizing antibody titer of ≥0.01 IU / ml in the subject; preferably, the titer of neutralizing antibodies against tetanus is detectable in the subject's serum; more preferably, the medicinal product is used to achieve a tetanus neutralizing antibody titer of ≥0.01 IU / ml in a subject within 48 hours, preferably 24 hours, more preferably 12 hours, even more preferably 6 hours or even less after dosing; and / or the method achieves a tetanus neutralizing antibody titer that persists for greater than 90 days, preferably that persists for greater than 105 days, in a subject.