CN111671910B - Combined antibody preparation for resisting staphylococcus infection - Google Patents
Combined antibody preparation for resisting staphylococcus infection Download PDFInfo
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- CN111671910B CN111671910B CN202010599549.2A CN202010599549A CN111671910B CN 111671910 B CN111671910 B CN 111671910B CN 202010599549 A CN202010599549 A CN 202010599549A CN 111671910 B CN111671910 B CN 111671910B
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Abstract
The invention provides a combined antibody preparation for resisting staphylococcus infection, which comprises an antibody for resisting antibacterial toxin and a chelating agent, wherein the chelating agent is a chelating agent combined with metal ions. The antibacterial toxin is a monoclonal antibody SYN100 antibody of anti-staphylococcal alpha-toxin, the heavy chain sequence of the specificity of the antibody is SEQ ID NO. 1, and the light chain sequence is SEQ ID NO. 2. The combined preparation provided by the invention can effectively inhibit the growth and reproduction of bacteria, can prevent the bacteria from damaging organism cells or tissues from multiple aspects, and has the advantages of simple preparation, small dosage during use and good application prospect.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a combined antibody preparation for resisting staphylococcus infection.
Background
With the use of intravenous injection or medical interventional instruments, the number of people or hospital cross-infections has increased in recent years, and hospital-acquired infections are one of the main causes of morbidity and mortality in people. The main types of nosocomial infections include: urinary tract infections (33% of the total infectious etiology), pneumonia (15.5%), infections at surgical sites (14.8%), and infections from blood (13%) (Emori and Gaynes, 1993).
The main pathogens causing nosocomial cross-infections are staphylococcus aureus, coagulase-negative staphylococcus (mainly staphylococcus epidermidis), enterococcus, coliform bacteria and pseudomonas aeruginosa. Although the number of pathogens is essentially on the same level, S.aureus and S.epidermidis are the most prominent pathogens if evaluated for risk and isolation of resistant strains.
Staphylococci, by secreting bacterial toxins and bacteria, invade the body and can cause a number of different diseases among humans and animals. Staphylococci, when bred by improper food storage and excreted toxins, can also cause food poisoning in humans or animals.
Staphylococcus epidermidis belongs to opportunistic pathogens, and causes wound infection through incompletely sterilized surgical instruments. Contamination of medical instruments for example: cardiac pacemakers, spinal fluid drains, continuous flow peritoneal dialysis tubing, instruments used in orthopedic surgery and heart valve repair.
Staphylococcus aureus is the major pathogen causing cross-infection in hospital hospitals and has a high morbidity and mortality rate. It is mainly responsible for osteomyelitis, endocarditis, septic arthritis, pneumonia, abscess and toxic shock syndrome. Staphylococcus aureus (Staphylococcus aureus) can live on the surface of dry objects, increasing the chance of pathogen infection. Infection with any type of staphylococcus aureus can cause staphylococcal scalded skin syndrome, mainly due to the excessive reaction of skin tissues to toxins after bacterial endotoxins enter human blood samples. Staphylococcus aureus can also cause bacteremia/septicemia, endangering human life. Wherein Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospital cross-infection.
Currently, disease infections of Staphylococcus aureus and Staphylococcus epidermidis are commonly treated with antibiotics, such as penicillin. Vancomycin replacement therapy was used for penicillin-resistant strains. However, with the increasing proportion of broad-spectrum drug-resistant staphylococcus aureus year by year, the treatment scheme of antibiotics is dangerous. Vancomycin-resistant strains have also emerged in recent years. The lack of effective antibiotics against such MRSA strains causes further spread of drug-resistant bacteria and threatens human health.
Another alternative to antibiotics for the treatment of staphylococcus aureus infections is passive immunotherapy with antibodies against staphylococcus aureus-associated antigens. For example, polyclonal sera are used for the treatment of Staphylococcus aureus infections (WO00/15238) or antibody therapy against the surface membrane teichoic acid of Staphylococcus aureus using monoclonal antibodies (WO 98/57994).
To date, there is no effective antibody drug or vaccine product in the world for the treatment or prevention of staphylococcal infections. In clinical trials, there are three therapeutic staphylococcus aureus monoclonal antibody formulations against staphylococcal alpha-toxin: AR301(Aridis Pharmaceuticals, phase III, clinics), ASN100 (arasanis Bioscience, clinics phase II) and MEDI4893 (mediimmune LLC, clinics phase II), which have a common feature of large clinical doses: the dosage of each human part of the antibody is 1.4g, 1.8g and 2-5 g. Moreover, merely neutralizing the toxins released by the bacteria does not effectively inhibit the continued growth and reproduction of the bacteria, preventing the bacteria from continuing to invade cells or tissues of the body. From the results of earlier clinical trials, the clinical efficacy of these anti- α -toxin monoclonal antibody drugs for the treatment of infections with staphylococcus aureus was not ideal using conventional antibody dosages. Therefore, the therapeutic scheme using overdose becomes the only choice for clinical trials of these antibody drugs, and even if these drugs are proved to have clinical effects, the large dosage of the drugs required by each patient will cause difficulties in the mass production and preparation of the drug products.
It has been found that the use of antibiotics in combination with chelating agents such as EDTA increases the sensitivity of bacteria to antibiotics and reduces the dosage of antibiotics, but such combinations are not effective in clinical infections caused by the growing prevalence of antibiotic-resistant Staphylococcus strains.
There is therefore still an urgent need to develop therapeutic or prophylactic methods for treating staphylococcus aureus infections.
Disclosure of Invention
In order to solve the above problems, the present invention provides a combined antibody preparation comprising a combined preparation of an anti-staphylococcal antibody and a chelator component. The combined use of the monoclonal antibody SYN100 for resisting staphylococcus alpha-toxin and the chelating agent not only can neutralize the main pathogenic factor alpha-toxin of staphylococcus, but also can capture metal ions necessary for the growth of bacteria, effectively block the synthesis of bacterial cell walls, increase the permeability of bacterial cell membranes and the sensitivity to antibodies, effectively inhibit the growth and reproduction of bacteria, and prevent the damage of bacteria to body cells or tissues from multiple aspects; meanwhile, the use of the chelating agent can greatly reduce the effective use dosage of the anti-alpha-toxin monoclonal antibody and enhance the effect of the anti-alpha-toxin antibody medicament on treating or preventing bacterial infection.
The terms:
sdrE: serine-aspartate repeat, a Serine aspartate repeat.
Bbp: bone Sialoprotein-binding Protein.
HIa: anti-staphylococcal alpha hemolysin.
MntC is manganese ion transfer protein.
MgtE is magnesium ion transporter.
CDR regions: complementary-determining region of an antibody.
EDTA: ethylene diamine tetraacetic acid.
In one aspect, the invention provides a biological agent for treating or preventing a staphylococcal infection.
Specifically, the biological agent comprises a monoclonal antibody for neutralizing the alpha-toxin of the bacterial pathogenic factor and a chelating agent for inhibiting the growth of bacteria.
Further, the monoclonal antibody for neutralizing the alpha-toxin of the bacterial pathogenic factor comprises one or more of an antibody against staphylococcus, anti-sdrE, anti-Bbp, anti-MntC, anti-MgtE or an antibody against bacterial capsular polysaccharide.
Further, the anti-staphylococcal antibody is a monoclonal antibody against staphylococcal alpha-toxin; the monoclonal antibody against staphylococcus alpha-toxin has specific CDR regions, and the binding constant between the monoclonal antibody and staphylococcus alpha-toxin is 0.1 to 20nM, 0.5 to 10nM or 1.0 to 10nM when detected by ELISA; the antibody may be a humanized antibody, a fully human antibody or a chimeric antibody.
Further, the anti-staphylococcal antibody comprises anti-staphylococcal alpha hemolysin (HIa) antibody SYN 100; the heavy chain variable region sequence of the SYN100 antibody comprises one or more of SEQ ID NO 3, SEQ ID NO 4 or SEQ ID NO 5; the variable region sequence of the SYN100 antibody light chain comprises one or more of SEQ ID NO 6, SEQ ID NO 7 or SEQ ID NO 8.
The heavy chain amino acid sequence of the monoclonal antibody SYN100 for resisting alpha-toxin is shown as SEQ ID NO. 1, and the light chain amino acid sequence is shown as SEQ ID NO. 2.
Further, the heavy chain amino acid sequence of the anti- α -toxin monoclonal antibody SYN100 at least includes 70%, 75%, 80%, 90%, 95%, or 99% of the amino acid sequence of SEQ ID No. 1, and the light chain amino acid sequence at least includes 70%, 75%, 80%, 90%, 95%, or 99% of the amino acid sequence of SEQ ID No. 2.
The chelating agent is one or more of chelating agents combined with metal ions, particularly chelating agents combined with manganese ions, magnesium ions or calcium ions, such as EDTA, EDTA disodium, EDTA calcium sodium, iminodisuccinic acid sodium salt, aminotriacetic acid, diethylene triamine pentaacetic acid and salts thereof, citric acid, tartaric acid and gluconic acid, hydroxyethyl ethylenediamine triacetic acid, dihydroxyethyl glycine, potassium sodium tartrate, sorbitol, diethylene pentahexanoate (DTPA), 3, 5-diphenyl-1, 2, 4-triazole, EDTA-tris or EDTA tetrasodium, or monoclonal antibodies specifically combined with magnesium ions, or monoclonal antibodies specifically combined with manganese ions.
Preferably, the chelating agent is EDTA or disodium EDTA salt.
Specifically, the treatment or prevention of staphylococcus aureus infections includes, but is not limited to, the treatment or prevention of staphylococcus aureus or staphylococcus epidermidis infections.
Specifically, the monoclonal antibody for resisting staphylococcus aureus alpha-toxin is combined with the alpha-toxin to prevent soluble HIa monomer from further forming insoluble heptameric complex and transmembrane pore canal to achieve the aim of prevention or treatment.
Furthermore, the monoclonal antibody against staphylococcus aureus alpha-toxin is combined with the N-terminal sequence of staphylococcus aureus HIa, and further, the monoclonal antibody against staphylococcus aureus alpha-toxin is combined with the first 50 amino acids of HIa amino acid residues of staphylococcus aureus.
Preferably, the antibody is administered to a human or animal at a dose of: 0.1mg/kg to 100 mg/kg; further preferably, the antibody is administered to a human or animal at a dose of: 0.1mg/kg to 1mg/kg, 1mg/kg to 5mg/kg, 5mg/kg to 20 mg/kg. The dosage of the chelating agent used in human body or animal body is 0.5-50mM, 50-200mM, 200mM-500mM or 500 mM-1M; preferably 1-50 mM.
The preparation also comprises complement; the complement is purified complement protein or complement protein expressed by animal cells or yeast cells.
In some embodiments, the formulation comprises EDTA and SYN100 antibodies; the final use concentration of the EDTA is 1-1.2 mM; the final concentration of SYN100 antibody was 4-5 mg/mL.
When the biological preparation is clinically used, the biological preparation is prepared and combined respectively, or the biological preparation is prepared and combined.
In clinical use, the biological preparation can be used for intramuscular injection, subcutaneous injection, intraperitoneal injection, local injection or intravenous injection. Comprises the sequential or simultaneous use of EDTA and antibody by different injection routes, or combined preparation and combined use. EDTA or antibody is also added into physiological saline or glucose solution for intravenous infusion to treat staphylococcus or assist treatment.
The invention also provides a vaccine for preventing bacteremia and hospital-acquired infection of human beings.
The vaccine comprises the combined antibody preparation.
The vaccine also comprises other pharmaceutically acceptable carriers.
In some embodiments, the vaccine comprises: 4-5mg/mL SYN100 antibody, 1-10mM EDTA.
The combined use of the monoclonal antibody SYN100 for resisting staphylococcus alpha-toxin and the chelating agent can not only neutralize the main pathogenic factor alpha-toxin of staphylococcus, but also capture metal ions necessary for the growth of bacteria, effectively block the synthesis of bacterial cell walls, increase the permeability of bacterial cell membranes and the sensitivity to antibodies, effectively inhibit the growth and reproduction of bacteria, and prevent the damage of bacteria to organism cells or tissues from multiple aspects; meanwhile, the use of the chelating agent can greatly reduce the effective dosage of the anti-alpha-toxin monoclonal antibody and enhance the curative effect of the anti-alpha-toxin antibody medicament on treating or preventing bacterial infection. The combined preparation provided by the invention is simple to prepare, has a small dosage when aiming at the infection caused by staphylococcus aureus, and has a good application prospect.
Drawings
FIG. 1 shows the results of the growth inhibition of EDTA on Staphylococcus aureus 1, Staphylococcus aureus 2, and Staphylococcus epidermidis.
FIG. 2 shows the results of the assay of the inhibition of Staphylococcus aureus growth by the interaction of the antibody SYN100 and EDTA.
FIG. 3 is a graph showing the results of detection that EDTA and magnesium chloride of different concentrations affect the growth of Staphylococcus aureus.
Detailed Description
The present invention will be further illustrated in detail with reference to the following specific examples, which are not intended to limit the present invention but are merely illustrative thereof. The experimental methods used in the following examples are not specifically described, and the materials, reagents and the like used in the following examples are generally commercially available under the usual conditions without specific descriptions.
EXAMPLE 1 inhibition of Staphylococcus growth by chelating Agents
The sources of staphylococcus aureus and staphylococcus epidermidis of the present example are:
the Staphylococcus epidermidis is deposited under the accession number BNCC 337371.
The medium used in this example was Tryptic Soy Broth (TSB) medium purchased from BD.
Selecting two staphylococcus aureus with different bacterial types and one staphylococcus epidermidis, inoculating the two staphylococcus aureus and the one staphylococcus epidermidis in a culture medium, marking the time when inoculation is finished as 0 hour, and setting a staphylococcus aureus negative control group and a staphylococcus epidermidis negative control group, wherein the bacterium selected in the staphylococcus aureus negative control group is staphylococcus aureus 1. EDTA was added to the medium of 3 experimental groups to a final concentration of 1mM after 6 hours of culture. Each group measured the OD of the medium at 0 hr, 6 hr and 24 hr, respectively600The spectrophotometric value under the condition.
As shown in FIG. 1, the test groups (Staphylococcus aureus 1, Staphylococcus aureus 2, and Staphylococcus epidermidis) added with EDTA after the bacteria were cultured for 24 hours after the disodium EDTA was added for 6 hours of growth, and the bacterial growth was significantly inhibited as compared with the test control group without EDTA. The EDTA has obvious inhibition effect on the growth of staphylococcus.
EXAMPLE 2 combination of anti-staphylococcal toxin antibody and chelating agent to achieve inhibitory effects on staphylococcal growth
The Staphylococcus aureus of this example was deposited under accession number ATCC 45921.
The culture medium selected in this example was TSB.
The inoculation time of Staphylococcus aureus was recorded as 0 hour.
Grouping:
(in the previous experiment, SYN100 was added alone, and no bacteriostatic effect was observed, so that it was not included in the group.)
Group of EDTA: inoculating staphylococcus aureus to a culture medium for 6 hours, and adding EDTA to a final concentration of 1 mM;
SYN100+ EDTA group: inoculating staphylococcus aureus to the culture medium, and culturing for 6 hours, and adding EDTA (the final concentration is 1mM) and SYN100 antibody (the final concentration is 0.1 mg/mL);
negative control group: no other reagent is added in the later period.
The OD of the culture medium was measured at 6 hours and 24 hours for each group600And (4) a spectral photometric value.
As shown in FIG. 2, after 24 hours of culture, the growth of Staphylococcus aureus was significantly inhibited as compared with the control group to which the EDTA and SYN100 antibodies were not added, while the test group to which the EDTA and SYN100 antibodies were added had a more significant inhibition of bacterial growth than the test group to which only EDTA was added.
Showing that the EDTA and the SYN100 monoclonal antibody for resisting staphylococcal toxin have obvious combined inhibition effect on the growth of bacteria.
Example 3 complement-mediated Sterilization assay
The staphylococcus aureus of this example was deposited under accession number ATCC 55804; complement type is Rabbit Complement, available from Pel Freez, cat # 31064-5.
The culture medium selected in this example was Typtic Soy Agar (TSA) and TSB (BD).
1. Adding reagents into a culture medium for just inoculating staphylococcus aureus according to the following groups:
(1) EDTA (1.2mM final concentration) + 100. mu.L of SYN100 antibody (4.25mg/mL) + 100. mu.L of complement;
(2) EDTA (1.2mM final concentration) + 100. mu.L complement.
The number of colonies in the medium after 24 hours of culture was counted, and the results were as follows:
as can be seen from the results, the killing effect of EDTA (1.2mM) in combination with the SYN100 antibody on bacteria was significantly better than that of EDTA alone (average colony count 5vs 52) in the complement-mediated bactericidal assay.
2. Adding reagents into a culture medium for just inoculating staphylococcus aureus according to the following groups:
(1) EDTA (1.0mM final concentration) + 100. mu.L of SYN100 antibody (4.25mg/mL) + 50. mu.L of complement;
(2) EDTA (1.0mM final concentration) + 50. mu.L complement.
The number of colonies in the medium after 24 hours of culture was counted, and the results were as follows:
as can be seen from the results, the killing effect of EDTA (1.0mM) in combination with the SYN100 antibody on bacteria was significantly better than that of EDTA and complement alone (average colony count 48vs 121) in the complement-mediated bactericidal assay.
Example 4EDTA Competition for Mg ions to inhibit the growth of Staphylococcus
The Staphylococcus aureus of this example was deposited under accession number ATCC 55804.
The medium used in this example was Tryptic Soy Broth (TSB) medium, source BD.
Drugs (final concentrations) were added to the culture medium of the freshly inoculated staphylococcus aureus in groups as follows:
(1)1mM EDTA；
(2)1mM EDTA +5mM magnesium chloride;
(3)1mM EDTA +10mM magnesium chloride;
(4)1mM EDTA +50mM magnesium chloride;
detecting OD of culture solution after 24-stage culture600The spectral photometric value of (d).
The results are shown in FIG. 3, and the addition of 1mM EDTA to the Staphylococcus aureus cultures significantly inhibited the growth of the bacteria. However, when 5mM, 10mM and 50mM magnesium chloride were added to the control cultures, respectively, the growth of the bacteria gradually returned to normal. The magnesium ions are required for the growth of the bacteria, and the chelating agent is combined with the magnesium ions to rob metal ions necessary for the growth of the bacteria, so that the growth of the bacteria is inhibited.
EDTA inhibits bacterial growth by competitively chelating magnesium ions required for bacterial growth.
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Claims (4)
1. A combined antibody preparation comprising an antibody against an antibacterial toxin and a chelating agent; the chelating agent is a chelating agent combined with metal ions;
the monoclonal antibody for resisting staphylococcal alpha-toxin is a SYN100 antibody; the heavy chain variable region sequence of the SYN100 antibody is one or more of SEQ ID NO 3, SEQ ID NO 4 or SEQ ID NO 5; the sequence of the variable region of the light chain of the SYN100 antibody is one or more of SEQ ID NO 6, SEQ ID NO 7 or SEQ ID NO 8;
the chelating agent is EDTA or EDTA disodium.
2. The combined antibody preparation of claim 1, wherein the heavy chain sequence specific for the SYN100 antibody is SEQ ID No. 1 and the light chain sequence is SEQ ID No. 2.
3. The combination antibody formulation of claim 2, wherein said formulation comprises EDTA and SYN100 antibodies; the final use concentration of the EDTA is 1-1.2 mM; the final concentration of SYN100 antibody was 4-5 mg/mL.
4. The combination antibody preparation of any one of claims 1-3, wherein said preparation further comprises complement; the complement is purified complement protein or complement protein expressed by animal cells or yeast cells.
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|---|---|---|---|
| CN202010599549.2A CN111671910B (en) | 2020-06-28 | 2020-06-28 | Combined antibody preparation for resisting staphylococcus infection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010599549.2A CN111671910B (en) | 2020-06-28 | 2020-06-28 | Combined antibody preparation for resisting staphylococcus infection |
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| CN111671910A CN111671910A (en) | 2020-09-18 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071585A1 (en) * | 1999-05-03 | 2000-11-30 | Medarex, Inc. | Human antibodies to staphylococcus aureus |
| CN106459187A (en) * | 2013-12-09 | 2017-02-22 | 纽约大学 | Compositions and methods for phagocyte delivery of anti-staphylococcal agents |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071585A1 (en) * | 1999-05-03 | 2000-11-30 | Medarex, Inc. | Human antibodies to staphylococcus aureus |
| CN106459187A (en) * | 2013-12-09 | 2017-02-22 | 纽约大学 | Compositions and methods for phagocyte delivery of anti-staphylococcal agents |
Non-Patent Citations (3)
| Title |
|---|
| Assessment of an Anti-Alpha-Toxin Monoclonal Antibody for Prevention and Treatment of Staphylococcus aureus-Induced Pneumonia;L. Hua et al.;《Antimicrobial Agents and Chemotherapy》;20131202;第58卷;摘要、第1109页Murine pneumonia model、图7 * |
| Identification of Anti-Alpha Toxin Monoclonal Antibodies That Reduce the Severity of Staphylococcus aureus Dermonecrosis and Exhibit a Correlation between Affinity and Potency;C. Tkaczyk et al.;《Clinical and Vaccine Immunology》;20120111;第19卷;第378页Cloning and expression of wild-type S. aureus AT and nonhemolytic H35L mutant，Expression and purification of chimeric anti-AT MAbs * |
| 细胞膜渗透性对氟喹诺酮耐药表皮葡萄球菌药物敏感性的影响;刘皈阳等;《中国药学杂志》;20010630;第36卷(第6期);第385页左栏4.4部分 * |
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