EP1194187A1 - Traitement a base d'anticorps destine a une infection par streptococcus pneumoniae - Google Patents

Traitement a base d'anticorps destine a une infection par streptococcus pneumoniae

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Publication number
EP1194187A1
EP1194187A1 EP00939927A EP00939927A EP1194187A1 EP 1194187 A1 EP1194187 A1 EP 1194187A1 EP 00939927 A EP00939927 A EP 00939927A EP 00939927 A EP00939927 A EP 00939927A EP 1194187 A1 EP1194187 A1 EP 1194187A1
Authority
EP
European Patent Office
Prior art keywords
pspa
antibody
pneumoniae
antibodies
mice
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00939927A
Other languages
German (de)
English (en)
Inventor
Gary S. Nabors
David Briles
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Pasteur SA
UAB Research Foundation
Sanofi Pasteur Inc
Original Assignee
Aventis Pasteur SA
UAB Research Foundation
Aventis Pasteur Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pasteur SA, UAB Research Foundation, Aventis Pasteur Inc filed Critical Aventis Pasteur SA
Publication of EP1194187A1 publication Critical patent/EP1194187A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1275—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Streptococcus (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to the therapeutic use of PspA antibodies for the treatment of Streptococcus pneumoniae infection in mammals, particularly in a human.
  • Streptococcus pneumoniae is an important cause of otitis media, meningitis, bacteremia and pneumonia, and a leading cause of fatal infections in the elderly and persons with underlying medical conditions, such as pulmonary disease, liver disease, alcoholism, sickle cell, cerebrospinal fluid leaks, acquired immune deficiency syndrome (AIDS), and patients undergoing immunosuppressive therapy. It is also a leading cause of morbidity in young children.
  • Pneumococcal infections i.e. infections caused by Streptococcus pneumoniae
  • the most severe pneumococcal infections involve invasive meningitis and bacteremia infections, of which there are 3,000 and 50,000 cases annually, respectively.
  • pneumococcal infections Despite the use of antibiotics and vaccines, the prevalence of pneumococcal infections has declined little over the last twenty-five years; the case-fatality rate for bacteremia is reported to be 15-20% in the general population, 30-40% in the elderly, and 36% in inner-city African Americans.
  • Less severe forms of pneumococcal disease are pneumonia, of which there are 500,000 cases annually in the U.S., and otitis media in children, of which there are an estimated 7,000,000 cases annually in the U.S. caused by pneumococci.
  • Strains of drug- resistant S. pneumoniae are becoming ever more common in the U.S. and worldwide. In some areas, as many as 30% of pneumococcal isolates are resistant to penicillin.
  • the increase in antimicrobial resistant pneumococci further emphasizes the need for either preventing pneumococcal infections or developing a therapeutic regimen to cure those already infected.
  • antisera prepared in animals to the pneumococcal capsule was used therapeutically to treat bacteremic/septic pneumonia. Since virtually all fatal pneumonia is due to bacteremic/septic pneumonia, the procedure was of an significant medical value especially in the pre-antibiotic era. Treatment with antisera in combination with good nursing care served to decrease the death rate among patients infected with Streptococcus pneumoniae. At that time antibodies were prepared in rabbits or horses to whole killed bacteria of each capsular type. Different capsular polysaccharide types differentially facilitate virulence in humans and other species.
  • the capsular type of the infecting patient was determined by the Banlung reaction or a mouse protection test and then an antiserum to the appropriate capsular polysaccharide type was given to the patient parenterally.
  • These treatments were published prior to the wide spread use of antibiotics (White, B. 1938. The Biology of Pneumococcus. The Commonwealth Fund, New York; Heffron, R. 1939. Pneumonia. The Commonwealth Fund, New York).
  • capsular type specific Different polysaccharide types differentially facilitate virulence in humans and other species. In total, there are at least 90 different capsular polysaccharide types of S. pneumoniae that cause disease in man (Heinrichsen, J. Six newly recognized types of Streptococcus pneumoniae J. Clin. Micro. 33: 2759-62 (1995)). The 23 most common capsular types represent about 90% of the pneumococcal disease in adults. These 23 polysaccharide types have been used in a licensed pneumococcal vaccine since 1983 (D.S. Fedson, M. Musher, Vaccines, S.A. Plotkin and J.E.A.
  • McDaniel et al. described in 1984 an immunogenic, species-common protein from S. pneumoniae, designated pneumococcal surface protein A (McDaniel LS, G Scott, JF Kearney, DE Briles. Monoclonal antibodies against protease sensitive pneumococcal antigens can protect mice from fatal infection with Streptococcus pneumoniae. J. Exp. Med. 160:386-397, 1984).
  • the term "PspA" was first used in a title of a paper published in 1987 (McDaniel LS, J Yother, L Vijayakumar, M McGarry, WR Guild, DE Briles.
  • PspA from S. pneumoniae contains choline-binding repeats that are responsible for the attachment of the PspA to the surface of the pneumococcus. PspA molecules interfere with complement activation, slow clearance of pneumococci from the blood of infected mice and elicit protection against pneumococcal sepsis, otitis media, and nasal carriage. Although variable, antibody responses raised to PspA are cross-reactive to heterologous PspA proteins and immunization with one PspA can protect against pneumococci that contain a heterologous PspA and capsule type (Crain et al.
  • Pneumococcal surface protein A is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae Infect. Immun. 58: 3293-99 (1990)).
  • Such cross-protective immunity has been shown using truncated PspA proteins of various lengths (McDaniel et al. , Location of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260; Microb. Pathogen 17: 323-37 (1994)).
  • PspA family 1 is composed of clades 1 and 2
  • family 2 is composed of clades 3-5
  • family 3 includes only clade 6.
  • Clade 6 is most dissimilar from all other clades. Over 97% of the PspA molecules typed to date have been found to be members of families 1 and 2. Furthermore, PspA shows cross-reactivity with the related S. pneumoniae antigen, PspC.
  • the present invention comprises a method of treating a mammal infected with Streptococcus pneumoniae, which method comprises administering to the mammal a therapeutically effective amount of one or more PspA antibodies.
  • the mammal is a human.
  • the present invention comprises the use of PspA antibodies in the manufacture of a medicament for the treatment of Streptococcus pneumoniae infection in a mammal (preferably a human).
  • the method of the invention is independent of the specific polysaccharide type of the infectious S. pneumoniae strain. Therefore, unlike the prior art, the present invention obviates the need both to type the S. pneumoniae as well as the need to use tens of different antigens from various S. pneumoniae strains to produce antibodies that cover the spectrum of different infectious S. pneumoniae strains.
  • the method of the present invention provides a less complex approach to treatment and leads to reduced delay in patient treatment.
  • the present invention comprises the use of PspA antibody as a therapeutic against S. pneumoniae infection in a mammal (preferably human).
  • the antibodies for use in the present invention can be generated by immunizing humans or animals with one or more PspA molecules.
  • Immunoglobulin for therapeutic use could be purified from plasma using the standard Cohn-Oncley method (Cohn EJ, Strong LE, Hughes WI Jr, et al. Preparation and properties of serum and plasma proteins. IV: A system for the separation into fractions of protein and lipoprotein components of biological tissues and fluids. J Am Chem Soc 1946;68:459-75. Oncley JL, Melin M, Richert DA, Cameron JW, Gross PM Jr.
  • PspA proteins from clades 2, 3, and 4 are used to generate PspA antibodies.
  • PspA proteins from clades 1 , 2, 3, 4 and 6 are used to generate PspA antibodies.
  • PspA proteins containing truncated forms of PspA proteins from clades 1, 2, 3, 4 and 6 are used to generate PspA antibodies.
  • antibodies raised against PspA (or one or more of its fragments) from one or more different strains and/or clades are administered to a subject (preferably human) infected with S. pneumoniae.
  • the antibody preparation is made from the serum of non-immunized individuals with naturally high titers of anti-PspA antibody.
  • PspA refers to pneumococcal surface protein A and fragments thereof including but not limited to PspNRxl.
  • PspA includes but is not limited to mutant proteins of naturally occurring PspA that retain at least one epitope of the naturally occurring PspA, such as PspNRxlMI.
  • PspNRxlMI A number of U.S. patents disclose various PspA fragments.
  • PspNRxl refers to a protein that is ⁇ -terminal region (aal-314) of the naturally occurring PspA polypeptide of Rxl (GenBank Accession No. M74122 and WO 92/14488).
  • the S. pneumoniae strain Rxl has been deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852 under accession no. 55834.
  • PspNRxlMI refers to a protein that is the ⁇ -terminal region (aal-314) of the naturally occurring PspA polypeptide of Rxl in which amino acid 96 has been changed from a methionine to an isoleucine.
  • PspA antibody and “anti-PspA antibody” refer to any antibody or group of antibodies to PspA, PspNRxl, or PspNRxlMI, as defined above.
  • PspA antibodies include but are not limited to polyclonal antibodies to PspA, monoclonal antibodies to PspA, monospecific polyclonal antibodies to PspA, and mixtures thereof.
  • therapeutically effective amount means an amount of PspA antibody sufficient to eliminate (preferably) an S. pneumoniae infection in the treated mammal, or halt or reduce the rate of growth of bacterial burden in the infected mammal.
  • the PspA antibodies for use in the present invention can be delivered in the form of an antiserum, an IgG fraction from an antiserum, or as a pooled
  • IgG + IgM fraction from an antiserum IgG + IgM fraction from an antiserum.
  • the PspA antibodies of the present invention could be purified from antiserum by purification techniques, many of which are well known in the art, such as immunoaffinity columns.
  • administration of PspA antibody is combined with administration of antibiotics or other antibodies to S. pneumoniae antigens.
  • PspA antibodies Such therapeutic use of the PspA antibodies is anticipated to improve the recovery time of the patient, or his/her likelihood of survival. It is envisioned that therapy with the invention would be unlikely to inhibit the activity of antibiotics when both agents are co-administered.
  • the present invention has a distinct advantage over other conceivable similar substances, such as a polyvalent anti-pneumococcal polysaccharide serum, because of the high level of cross-reactivity in the anti-PspA humoral response. Due to the cross-reactive nature of anti-PspA antibodies, the specific polysaccharide or PspA type of the infectious S. pneumoniae strain would not limit the usefulness of the invention. Therefore, unlike the prior art, in the present invention there is no need to type the S. pneumoniae, and, thus, methods of the present invention are less complex and lead to reduced delay in patient treatment.
  • the amount of PspA antibody to be administered to a mammal infected with Streptococcus pneumoniae and the regime of administration can be determined in accordance with standard techniques well known to those of ordinary skill in the pharmaceutical and veterinary arts taking into consideration such factors as the particular antigen, the adjuvant (if present), the age, sex, weight, species and condition of the particular animal or patient, and the route of administration.
  • the amount of specific antibody administered to provide an efficacious therapeutic dose for treatment of S. pneumoniae can be from between about 0.02 mg to about 5 mg per kg body weight.
  • the dosage is between about 0.1 mg to 3 mg per kg of body weight. The optimal dosage will depend upon the post-infection time of administration.
  • an efficacious dosage will require less antibody if the post-infection time elapsed is less since there is less time for the bacteria to proliferate. In like manner an efficacious dosage will depend on the bacterial load at the time of diagnosis. Multiple injections administered over a period of days could be considered for therapeutic usage.
  • compositions of the invention include liquid preparations for orifice, e.g., oral, nasal, anal, vaginal, peroral, intragastric, mucosal (e.g., perlingual, alveolar, gingival, olfactory or respiratory mucosa) etc., administration such as suspensions, syrups or elixirs; and, preparations for parenteral, subcutaneous, intradermal, intramuscular, intraperitoneal or intravenous administration (e.g., injectable administration), such as sterile suspensions or emulsions. Intravenous and parenteral administration are preferred.
  • compositions may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose or the like.
  • a suitable carrier diluent, or excipient
  • the compositions can also be lyophilized.
  • the compositions can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts, such as "REMINGTON'S PHARMACEUTICAL SCIENCE", 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
  • compositions of the invention are conveniently provided as liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions or viscous compositions that may be buffered to a selected pH. If digestive tract absorption is preferred, compositions of the invention can be in the "solid" form of pills, tablets, capsules, caplets and the like, including “solid” preparations which are time-released or which have a liquid filling, e.g., gelatin covered liquid, whereby the gelatin is dissolved in the stomach for delivery to the gut. If nasal or respiratory (mucosal) administration is desired, compositions may be in a form and dispensed by a squeeze spray dispenser, pump dispenser or aerosol dispenser. Aerosols are usually under pressure by means of a hydrocarbon. Pump dispensers can preferably dispense a metered dose or a dose having a particular particle size.
  • Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection or orally, to animals, children, particularly small children, and others who may have difficulty swallowing a pill, tablet, capsule or the like, or in multi-dose situations. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with mucosa, such as the lining of the stomach or nasal mucosa. Obviously, the choice of suitable carriers and other additives will depend on the exact route of administration and the nature of the particular dosage form, e.g., liquid dosage form
  • composition e.g., whether the composition is to be formulated into a solution, a suspension, gel or another liquid form
  • solid dosage form e.g., whether the composition is to be formulated into a pill, tablet, capsule, caplet, time release form or liquid-filled form
  • Solutions, suspensions and gels normally contain a major amount of water (preferably purified water) in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents, jelling agents, (e.g., methylcellulose), colors and/or flavors may also be present.
  • pH adjusters e.g., a base such as NaOH
  • emulsifiers or dispersing agents e.g., a base such as NaOH
  • buffering agents e.g., preservatives
  • wetting agents e.g., methylcellulose
  • jelling agents e.g., methylcellulose
  • colors and/or flavors may also be present.
  • the compositions can be isotonic, i.e., it can have the same osmotic pressure as blood and lacrimal fluid.
  • compositions of this invention may be accomplished using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • sodium chloride is preferred particularly for buffers containing sodium ions.
  • Viscosity of the compositions may be maintained at the selected level using a pharmaceutically acceptable thickening agent.
  • Methylcellulose is preferred because it is readily and economically available and is easy to work with.
  • suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickener will depend upon the agent selected. The important point is to use an amount that will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
  • a pharmaceutically acceptable preservative can be employed to increase the shelf-life of the compositions.
  • Benzyl alcohol may be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed.
  • a suitable concentration of the preservative will be from 0.02% to 2% based on the total weight although there may be appreciable variation depending upon the agent selected.
  • the components of the compositions must be selected to be chemically inert with respect to the PspA antibodies.
  • PspA/Rxl The production of PspA/Rxl is described in Nabors et al, Vaccine 18: 1743-1754 (2000). See, also, WO 99/14333 for the production of PspNRXlMI.
  • cells transformed with a plasmid containing the D ⁇ A encoding the first 314 amino acids of PspA from Rxl were grown to mid-exponential phase and induced with 0.5 mM mM IPTG (Sigma,
  • the supernatant was decanted and adjusted to 70% ammonium sulfate (J.T. Baker) to precipitate proteins. This solution was centrifuged and the supernatant was discarded. The pellet was resuspended in 30% ammonium sulfate and centrifuged. The supernatant was extensively dialyzed with a buffer consisting of 100 mM sodium acetate, 10 mM ⁇ aCl, pH 4.5. The dialysate was centrifuged and the supernatant was applied to a Q Sepharose Fast Flow (Pharmacia Biotech) column.
  • the column flow through and wash were collected and dialyzed against 50 mM Tris, 2 mM EDTA, 10 mM ⁇ aCl, pH 7.5.
  • the dialysate was centrifuged and the supernatant was applied to a Q Sepharose Fast Flow column.
  • the column was washed with 50 mM Tris, 2 mM EDTA, 100 mM ⁇ aCl, pH 7.5, then RxlMIwas eluted with 50 mM Tris, 2 mM EDTA, 200 mM ⁇ aCl, pH 7.5.
  • This eluate was analyzed by SDS- PAGE; proteins were visualized by Coomassie Blue staining and PspA products were identified by Western immunoblot analysis with monoclonal anti-PspA.
  • mice After 35 days all mice were bleed via the brachial artery. 100 ⁇ l of blood from each mouse in groups 12-17 were pooled and sterile filtered (0.45 ⁇ m). The filtrate was separated into 24 - 0.5 ml aliquots each containing 433.7 ⁇ g/ml of PspA antibody as measured by ELISA.
  • mice were then bled 24 h after the first bleed (30 h for group 1 and 36 h for groups 2 and 3).
  • a second dose of PspA antibody (1.302 ⁇ g) was administered i.p. 48 hours after the first administration, 54 and 60 h for groups 1 and 2, respectively.
  • the results of the study are listed below: Table 2
  • mice CBA/N mice from Jackson Labs
  • mice were divided into four groups of 20 each.
  • the mice in each group were infected i.v. with S. pneumoniae as follows:
  • mice were further divided into four subgroups of five mice each as follows:
  • mice receiving passive antibody before infection and no further treatment 2. Mice receiving passive NMS (normal mouse serum, 1/10 dilution) before infection and no further treatment;
  • mice infected and treated at 6, 12, and 30 hours with antibody mice infected and treated at 6, 12, and 30 hours with antibody
  • mice mice infected and treated at 6, 12, and 30 hours with NMS. All mice were bled for CFU counts at 6 hours after infection. The mice to receive antibody or NMS post-infection were treated with 100 ⁇ l of 1/10 dilution of serum in Ringer's lactate. This process was repeated at 12 and 30 hours post-infection. The results are summarized in Table 4:
  • mice in groups 1, 2, and 4 treated with PspA antibody did not manifest increased life span or reduced bacterial burden.
  • groups 1, 2, and 4 were examples in which the amount or specificity of anti-PspA delivered to the infected animals was insufficient for the bacterial burden delivered and, thus, did not constitute a therapeutically effective dose of PspA antibody.
  • mice All mice were be bled for CFU counts prior to each treatment. All treated mice received 0.1 ml of a 1/100 dilution of the immune serum described in Example 2. The data are give in Tables 5 and 6.
  • strain A66.1 (capsule type 3, PspA clade 2) and BG7322 (capsule type 6B, PspA clade 2) were used to establish infections prior to administration of antiserum. It was of note that significant survivorship or extension of life occurred in antibody-treated mice previously infected with strain A66.1. While it was possible to demonstrate a curative effect of the anti-PspA serum for strain A66.1 in Example 6, no benefit of treatment with specific anti-PspA antibody was observed for stain BG7322. However, as in the case of Example 5, this would be an example in which the amount or specificity of anti-PspA delivered to the infected animals was insufficient for the infectious dose administered. In this case, the infectious dose of BG7322 was 2216 CFU, almost 20-fold higher than that which was used in Example 5.

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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention comprend une méthode de traitement d'un mammifère infecté par Streptococcus pneumoniae, cette méthode consistant à administrer au mammifère une quantité thérapeutiquement efficace d'un ou de plusieurs anticorps PspA. Le mammifère est de préférence un humain.
EP00939927A 1999-06-16 2000-06-16 Traitement a base d'anticorps destine a une infection par streptococcus pneumoniae Withdrawn EP1194187A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13952499P 1999-06-16 1999-06-16
US139524P 1999-06-16
PCT/US2000/016581 WO2000076587A1 (fr) 1999-06-16 2000-06-16 Traitement a base d'anticorps destine a une infection par streptococcus pneumoniae

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EP1194187A1 true EP1194187A1 (fr) 2002-04-10

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JP (1) JP2003525208A (fr)
AU (1) AU5493500A (fr)
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GB0306782D0 (en) * 2003-03-25 2003-04-30 Neutec Pharma Plc Treatment of infection due to clostridium difficile
JP5854537B2 (ja) * 2012-09-19 2016-02-09 国立大学法人大阪大学 肺炎球菌表面タンパク質ａを含む肺炎球菌ワクチン

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5679768A (en) * 1991-02-15 1997-10-21 Uab Research Foundation Epitopic regions of pneumococcal surface protein A

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Publication number Priority date Publication date Assignee Title
CA2304128A1 (fr) * 1997-09-18 1999-03-25 Robert Becker Procede de production amelioree de proteines de surface pneumococciques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5679768A (en) * 1991-02-15 1997-10-21 Uab Research Foundation Epitopic regions of pneumococcal surface protein A

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0076587A1 *

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JP2003525208A (ja) 2003-08-26
AU5493500A (en) 2001-01-02
WO2000076587A1 (fr) 2000-12-21

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