EP0952846A1 - Prolactin als impfstoffadjuvans - Google Patents

Prolactin als impfstoffadjuvans

Info

Publication number
EP0952846A1
EP0952846A1 EP95910999A EP95910999A EP0952846A1 EP 0952846 A1 EP0952846 A1 EP 0952846A1 EP 95910999 A EP95910999 A EP 95910999A EP 95910999 A EP95910999 A EP 95910999A EP 0952846 A1 EP0952846 A1 EP 0952846A1
Authority
EP
European Patent Office
Prior art keywords
prolactin
composition
vaccine
human
cdna
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Withdrawn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
EP95910999A
Other languages
English (en)
French (fr)
Other versions
EP0952846A4 (de
Inventor
Susan Richards
Johanne Kaplan
Richard Moscicki
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.)
Genzyme Corp
Original Assignee
Genzyme Corp
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 Genzyme Corp filed Critical Genzyme Corp
Publication of EP0952846A1 publication Critical patent/EP0952846A1/de
Publication of EP0952846A4 publication Critical patent/EP0952846A4/xx
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57554—Prolactin
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • 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

Definitions

  • the antigens used in the vaccine are not sufficiently immunogenic to raise the antibody titer to sufficient levels to provide protection against subsequent challenge or to maintain the potential for mounting these levels over extended time periods.
  • the vaccine may be deficient in inducing cell-mediated immunity which is a primary immune defense against bacterial and viral infection.
  • the vaccine In order to obtain a stronger humoral and/or cellular response, it is common to administer the vaccine in a formulation containing an adjuvant, a material which enhances the immune response of the patient to the vaccine.
  • adjuvants for vaccines are oil preparations and alum. The mechanisms by which such adjuvants function are not understood, and whether or not a particular adjuvant preparation will be sufficiently effective in a given instance is not predictable.
  • the present invention relates to a composition for enhancing the immune response of an animal to an infectious disease vaccine wherein the composition comprises prolactin.
  • the composition is human prolactin and the animal to be vaccinated is, as well, human.
  • the present invention further relates to a composition for enhancing the immune response of an animal to an infectious disease vaccine wherein the composition comprises prolactin cDNA.
  • the composition comprises prolactin cDNA.
  • Human prolactin cDNA is preferred.
  • the invention relates to a method of enhancing the immune response of a subject animal to an infectious disease vaccine comprising co-administering an effective amount of prolactin or prolactin cDNA along with a vaccine.
  • Figure 1 shows the amino acid sequence for the prolactin protein.
  • Figure 2 shows the nucleic acid sequence for the prolactin cDNA.
  • FIG. 3 is a graph illustrating the Bovine serum albumin (BSA)-specific antibody response of rats immunized with BSA alone or BSA + prolactin.
  • BSA Bovine serum albumin
  • Figure 4 is a graph illustrating a comparison of the BSA- specific proliferative response of rat PBL, at 101 day time point, between four rats receiving BSA alone versus BSA + prolactin.
  • prolactin refers to a polypeptide obtained from tissue cultures or by recombinant techniques and other techniques known to those of skill in the art, exhibiting the spectrum of activities characterizing this protein.
  • the word includes not only human prolactin (hPRL), but also other mammalian prolactin such as, e.g., mouse, rat, rabbit, primate, pig and bovine prolactin.
  • hPRL human prolactin
  • r-PRL The recombinant PRL (r-PRL) is preferred herein.
  • prolactin refers to prolactin having comparable biological activity to native prolactin prepared by recombinant DNA techniques known by those of skill in the art.
  • the gene coding for prolactin is excised from its native plasmid and inserted into a cloning vector to be cloned and then inserted into an expression vector, which is used to transform a host organism. The host organism expresses the foreign gene to produce prolactin under expression conditions.
  • the term "adjuvant” has its conventional meaning, i.e., the ability to enhance the immune response to a particular antigen. Such ability is manifested by a significant increase in immune-mediated protection.
  • the term “genetic adjuvant” refers to prolactin cDNA which comprises the complement to the DNA sequence encoding the prolactin protein as defined above. The sequence for prolactin cDNA is shown in Figure 2.
  • Formulations containing prolactin for adjuvant purposes are most conveniently administered by intramuscular or subcutaneous injections or intraperitoneal although other methods of administration are possible.
  • Standard formulations are either liquid injectables or solids which can be taken up in suitable liquids as suspensions or solutions for injection.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, and so forth.
  • Nontoxic auxiliary substances, such as wetting agents, buffers, or emulsifiers may also be added.
  • Prolactin can be administered separately from the vaccine or in combination with the vaccine.
  • the composition administered contains an immunogen that is effective in eliciting a specific response to a given pathogen or antigen, a pharmaceutically acceptable vaccine carrier and an immunopotentiating amount of prolactin.
  • the vaccine will normally be administered per manufacturer's instructions.
  • Other adjuvants may be administered either with the vaccine or together with the prolactin.
  • Prolactin will typically be used to enhance the protection afforded by animal or human vaccines that are considered "weak” (i.e., provide diminished protection in terms of level, extent, and/or duration).
  • vaccines are bacterins such as Pseudomonas Staphylococcal, Enterotoxin Streptococci, cytomegalovirus, HIV, Bordetella bacterin, Escherichia coli bacterins, Haemophilus bacterins, Leptospirosis vaccines, Moraxella bovis bacterin, Pasteurella bacterin and Vibrio fetus bacterin and attenuated live or killed virus products such as bovine respiratory disease vaccine (infectious bovine rhinotracheitis, parainfluenza-3, respiratory syncytial virus), bovine virus diarrhea vaccine, equine influenza vaccine, feline leukemia vaccine, feline respiratory disease vaccine (rhinotracheitis-calicipneumonitis viruses), canine parvovirus vaccine, transmiss
  • prolactin can enhance the immune response to an immunogen and thereby function as a vaccine adjuvant
  • exogenous administration of the prolactin gene would result in the expression of prolactin in vivo which would be available to function as an adjuvant to any immunogen whether administered through conventional means or via gene inoculation.
  • the "genetic adjuvant” could be produced by inserting prolactin cDNA into a DNA delivery vehicle (e.g., plasmid vectors, liposomes, viral vectors). This could be accomplished as described by Pellegrini I., et al., Molec.
  • the injection sequence would be optimized per immunogen, i.e., the prolactin cDNA could be co-administered with the immunogen or immunogen cDNA, or administered in advance or subsequent to their administration. It is believed that the prolactin cDNA could be inserted into the same DNA delivery vehicle. Various routes of administration could be used.
  • Peripheral blood lymphocytes were isolated from the blood of normal human volunteers by density gradient centrifugation on Ficoll Paque (Pharmacia). Heparinized blood was diluted 3 fold in phosphate-buffered saline (PBS) and centrifuged at 2000 rpm for 20 minutes. The buffy coat, located on the surface of the red blood cell pellet and consisting of white blood cells, was collected and diluted with an equal volume of PBS. The diluted buffy coat was layered on Ficoll Paque (6 mis of buffy coat on 4 mis of Ficoll Paque in a 15 ml tube) and centrifuged for 30 minutes at 1400 rpm.
  • PBS phosphate-buffered saline
  • PBL The PBL layer, found at the Ficoll-plasma interface, was collected and the cells were washed three times in PBS. PBL were then resuspended at 2x10 6 /ml in serum-free AIM-V medium from Gibco and added to the wells of round bottom 96 well microtiter plates in a 100 ⁇ l volume (2x10 5 PBL/well).
  • T cell mitogen concanavalin A (Con A; 0.2 ⁇ g/ml) was added in a 50 ⁇ l volume together with 50 ⁇ l of varying concentrations of r-hPRL (0-1000 ng/ml final). Cultures were done in triplicate. The cells were incubated at 37 ° C/5% CO2 for 72 hours and the amount of proliferation measured by tritiated thymidine incorporation.
  • Tritiated thymidine (0.5 ⁇ Ci/well) was added for the last 18 hours of incubation and cell-associated radioactivity was measured by scintillation counting after harvesting the cells onto glass fiber filters using a Skatron 96 well cell harvester.
  • Results obtained with cells from different individuals, shown in Table 1 below, indicated that r-hPRL was able to enhance the proliferative response of T lymphocytes to a suboptimal concentration of Con A. This co-mitogenic activity was best observed with r-hPRL concentrations of 1 -10 ng/ml, illustrated in Figure 3.
  • r-hPRL To test the ability of r-hPRL to enhance the proliferative response of human T cells to a specific antigen, PBL were incubated with various concentrations of r-hPRL and streptokinase, a common antigen to which most individuals are exposed. Cultures were performed in triplicate in the wells of 96 well round bottom microtiter plates and consisted of 100 ⁇ l PBL (2x10 5 /well), 50 ⁇ l streptokinase (25 ⁇ g/ml final) and 50 ⁇ l of r-hPRL at varying concentrations (0-1000 ng/ml final). Proliferation was measured by tritiated thymidine incorporation after 6 days of culture at 37 ° C/5%C02-
  • Twenty-four 150 gram male Sprague-Dawley rats were divided into 4 groups.
  • the control group received an intraperitoneal injection of 10 ⁇ g BSA mixed with alum.
  • the other 3 groups received intraperitoneal injections of 10 ⁇ g BSA mixed with alum along with either 180 ⁇ g prolactin, 375 ⁇ g prolactin or 750 ⁇ g prolactin.
  • Tail vein bleeds were taken weekly for 4 weeks and the serum evaluated for antibody to BSA by a Radioimmunosorbent Assay (RIA).
  • RIA Radioimmunosorbent Assay
  • the animals were boosted after the 4th bleed with 10 ⁇ g BSA mixed with alum.
  • Tail vein bleeds were taken over a 7 week period to obtain serum which was evaluated for the development of antibody to BSA by RIA.
  • Bovine serum albumin BSA-specific proliferation of peripheral blood lymphocytes from rats immunized with BSA +/- r-hPRL
  • BSA Bovine serum albumin
  • PBL were then washed twice in PBS and resuspended at 5x10 6 /ml in RPMI-1640 medium supplemented with 100 u/ml penicillin, 100 ⁇ g/ml streptomycin, 20 mM Hepes buffer, 2 mM L-glutamine, 5x10" 5 M 2-mercaptoethanol and 5% heat-inactivated fetal calf serum.
  • PBL were added to the wells of flat bottom 96 well microtiter plates in a 100 ⁇ l volume (5x10 ⁇ cells/well) and cultured in the presence of medium alone (background control) or 1000 ⁇ g/ml BSA added in a 100 ⁇ l volume. Cultures were done in triplicate. Proliferation was measured by tritiated thymidine incorporation after 5 days of culture at 37 ° C/5% C ⁇ 2-

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Microbiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP95910999A 1994-02-14 1995-02-14 Prolactin als impfstoffadjuvans Withdrawn EP0952846A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19635094A 1994-02-14 1994-02-14
US196350 1994-02-14
PCT/US1995/001866 WO1995021625A1 (en) 1994-02-14 1995-02-14 Prolactin as a vaccine adjuvant

Publications (2)

Publication Number Publication Date
EP0952846A1 true EP0952846A1 (de) 1999-11-03
EP0952846A4 EP0952846A4 (de) 1999-11-03

Family

ID=22725034

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95910999A Withdrawn EP0952846A1 (de) 1994-02-14 1995-02-14 Prolactin als impfstoffadjuvans

Country Status (5)

Country Link
EP (1) EP0952846A1 (de)
JP (1) JPH09509415A (de)
AU (1) AU700104B2 (de)
CA (1) CA2183260A1 (de)
WO (1) WO1995021625A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2749697A (en) * 1996-04-30 1997-11-19 Genzyme Corporation Use of prolactin as a tgf-beta antagonist
WO1998031385A1 (en) * 1997-01-21 1998-07-23 Genzyme Corporation Enhancement of hematopoietic cells
AU770994B2 (en) 1999-08-25 2004-03-11 Accuplex, L.L.C. Diagnostic assays of secreted biological fluids for detection of infection and inflammatory conditions
NZ518319A (en) 1999-10-22 2004-04-30 Univ Nebraska Nucleic acid molecules encoding serum amyloid A isoforms from mammalian colostrum used to treat and prevent enteric infections
AU2002364507A1 (en) * 2001-11-21 2003-06-10 Board Of Regents Of The University Of Nebraska Mammary-associated serum amyloid a3 promoter sequences and uses for same
US7368546B2 (en) 2003-01-21 2008-05-06 The Board Of Regents Of The University Of Nebraska Human SAA3 nucleic acid molecule, protein, and methods of use for same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002559A1 (en) * 1988-09-15 1990-03-22 Public Health Laboratory Service Board Pharmaceutical compositions for eliciting an immunostimulant effect

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725549A (en) * 1980-09-22 1988-02-16 The Regents Of The University Of California Human and rat prolactin and preprolactin cloned genes
US5028591A (en) * 1987-09-14 1991-07-02 Pitman-Moore, Inc. Method for stimulating the immune system

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002559A1 (en) * 1988-09-15 1990-03-22 Public Health Laboratory Service Board Pharmaceutical compositions for eliciting an immunostimulant effect

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9521625A1 *

Also Published As

Publication number Publication date
AU1876595A (en) 1995-08-29
JPH09509415A (ja) 1997-09-22
EP0952846A4 (de) 1999-11-03
CA2183260A1 (en) 1995-08-17
AU700104B2 (en) 1998-12-24
WO1995021625A1 (en) 1995-08-17

Similar Documents

Publication Publication Date Title
CZ168296A3 (en) Spermatic antigen corresponding to auto-antigenic epitope of spermatic bond protein
AU5153098A (en) Vaccines
EP1368477A1 (de) Impfstoffzusammensetzung
AU2002233560A1 (en) Vaccine
AU702162B2 (en) Vaccine against mycobacterial infections
KR101300905B1 (ko) 백신으로서의 생물학적 활성제와 재조합 마이코박테리움의 조합물
US20020111323A1 (en) Introduction of naked DNA or RNA encoding non-human vertebrate peptide hormones or cytokines into a non-human vertebrate
US20060127418A1 (en) Composition containing Leishmania Lip2a
AU700104B2 (en) Prolactin as a vaccine adjuvant
KR100773390B1 (ko) 단순 포진 바이러스 백신 키트
Yoon et al. Comparison of responses elicited by immunization with a Legionella species common lipoprotein delivered as naked DNA or recombinant protein
EA006233B1 (ru) Комбинированные адъювантные композиции для усиления иммунного ответа у позвоночного животного
EP0638092A1 (de) Synthetische Peptide Impfstoffe für Zahnkaries
CA2131709C (en) Immune-enhancing agent for therapeutic use in immunocompromised hosts
US7011833B1 (en) Enhancing immune responses with B7-1 or B7-2 in the absence of a crosslinking agent
CN107249628A (zh) 针对猪流行性腹泻病毒的优化的合成共有dna疫苗的免疫原性
KR100568193B1 (ko) 전염성 에프 낭병의 예방을 위한 전염성 에프 낭병바이러스 항원결정부위를 포함한 ｄｎａ 백신
Kim et al. Determination of T cell epitopes on the S1 subunit of pertussis toxin.
AU2003200723B2 (en) Encapsulated immunomodulators useful as vaccine adjuvants
CA2307541A1 (en) Encapsulated immunomodulators useful as vaccine adjuvants
KR20010103577A (ko) ＩＬ-12 활성을 증가시키는 ＩＬ-12ｐ40 소단위체돌연변이 유전자 및 이를 ＤＮＡ 백신 면역증강제로이용하는 용도
CN114591401A (zh) SARS-CoV-2编码蛋白来源的T细胞表位多肽HLVDFQVTI及其应用
Hu Adjuvanticity of chicken interleukin-2 in DNA vaccines and protein vaccines delivered via microspheres
Miyagi et al. The Timing of GM-CSF Expression Plasmid
BERGER et al. o. 3 Vaccination strategy to treat persistent viral infections

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19960807

A4 Supplementary search report drawn up and despatched

Effective date: 19980826

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20000413

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20000824