WO1995021625A1 - Prolactine servant d'adjuvant pour vaccin - Google Patents

Prolactine servant d'adjuvant pour vaccin Download PDF

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Publication number
WO1995021625A1
WO1995021625A1 PCT/US1995/001866 US9501866W WO9521625A1 WO 1995021625 A1 WO1995021625 A1 WO 1995021625A1 US 9501866 W US9501866 W US 9501866W WO 9521625 A1 WO9521625 A1 WO 9521625A1
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WO
WIPO (PCT)
Prior art keywords
prolactin
composition
vaccine
human
cdna
Prior art date
Application number
PCT/US1995/001866
Other languages
English (en)
Inventor
Susan Richards
Johanne Kaplan
Richard Moscicki
Original Assignee
Genzyme Corporation
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 Corporation filed Critical Genzyme Corporation
Priority to EP95910999A priority Critical patent/EP0952846A1/fr
Priority to JP7521414A priority patent/JPH09509415A/ja
Priority to AU18765/95A priority patent/AU700104B2/en
Publication of WO1995021625A1 publication Critical patent/WO1995021625A1/fr

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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-

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

Abstract

Cette invention se rapporte à une composition destinée à accroître la réponse immunitaire d'un animal à un vaccin de maladie infectieuse, ladite composition comprenant de la prolactine. Cette composition est de préférence de la prolactine humaine et l'animal à vacciner est également de préférence l'homme. Cette invention serapporte en outre à une composition destinée à accroître la réponse immunitaire d'un animal à un vaccin de maladie infectieuse, cette composition comprenant de l'ADNc de prolactine. De l'ADNc de prolactine humaine est préféré.
PCT/US1995/001866 1994-02-14 1995-02-14 Prolactine servant d'adjuvant pour vaccin WO1995021625A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95910999A EP0952846A1 (fr) 1994-02-14 1995-02-14 Prolactine servant d'adjuvant pour vaccin
JP7521414A JPH09509415A (ja) 1994-02-14 1995-02-14 ワクチンアジュバントとしてのプロラクチン
AU18765/95A AU700104B2 (en) 1994-02-14 1995-02-14 Prolactin as a vaccine adjuvant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19635094A 1994-02-14 1994-02-14
US08/196,350 1994-02-14

Publications (1)

Publication Number Publication Date
WO1995021625A1 true WO1995021625A1 (fr) 1995-08-17

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PCT/US1995/001866 WO1995021625A1 (fr) 1994-02-14 1995-02-14 Prolactine servant d'adjuvant pour vaccin

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EP (1) EP0952846A1 (fr)
JP (1) JPH09509415A (fr)
AU (1) AU700104B2 (fr)
CA (1) CA2183260A1 (fr)
WO (1) WO1995021625A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031385A1 (fr) * 1997-01-21 1998-07-23 Genzyme Corporation Stimulation de cellules hematopoietiques
EP0921809A1 (fr) * 1996-04-30 1999-06-16 Genzyme Corporation Utilisation de la prolactine comme un antagoniste de tgf-beta
WO2003044174A2 (fr) * 2001-11-21 2003-05-30 Board Of Regents Of The University Of Nebraska Sequences de promoteurs a3 amyloides seriques associees a des mammiferes et leurs utilisations
US7214512B2 (en) 1999-10-22 2007-05-08 The Board Of Regents Of The University Of Nebraska Genomic mammary Amyloid a sequence
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
US7569338B1 (en) 1999-08-25 2009-08-04 Accuplex, Llc. Diagnostic assays of secreted biological fluids for detection of infection and inflammatory conditions

Citations (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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8821656D0 (en) * 1988-09-15 1988-10-12 Health Lab Service Board Pharmaceutical compositions for eliciting immunostimulant effect

Patent Citations (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

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
IMMUNOPHARMACOLOGY, Volume 24, issued 1987, B. SPANGELO et al., "Stimulation in Vivo Antibody Production and Concanavalin-A-Induced Mouse Spleen Cell Mitogenesis by Prolactin", pages 11-20. *
MOLECULAR ENDOCRINOLOGY, Volume 6, issued 1992, I. PELLEGRINI et al., "Expression of Prolactin and its Receptor in Human Lymphoid Cells", pages 1023-1031. *
See also references of EP0952846A4 *
THE JOURNAL OF EXPERIMENTAL MEDICINE, Volume 178, issued July 1993, W. MURPHY et al., "Differential Effects of Growth Hormone and Prolactin on Murine T Cell Development and Function", pages 231-236. *
THE JOURNAL OF INFECTIOUS DISEASES, Volume 164, issued 1991, J. STEPHENSON et al., "Adjuvant Effect of Human Growth Hormone with an Inactivated Flavivirus Vaccine", pages 188-191. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0921809A1 (fr) * 1996-04-30 1999-06-16 Genzyme Corporation Utilisation de la prolactine comme un antagoniste de tgf-beta
EP0921809A4 (fr) * 1996-04-30 2001-10-24 Genzyme Corp Utilisation de la prolactine comme un antagoniste de tgf-beta
WO1998031385A1 (fr) * 1997-01-21 1998-07-23 Genzyme Corporation Stimulation de cellules hematopoietiques
US7569338B1 (en) 1999-08-25 2009-08-04 Accuplex, Llc. Diagnostic assays of secreted biological fluids for detection of infection and inflammatory conditions
US7214512B2 (en) 1999-10-22 2007-05-08 The Board Of Regents Of The University Of Nebraska Genomic mammary Amyloid a sequence
WO2003044174A2 (fr) * 2001-11-21 2003-05-30 Board Of Regents Of The University Of Nebraska Sequences de promoteurs a3 amyloides seriques associees a des mammiferes et leurs utilisations
WO2003044174A3 (fr) * 2001-11-21 2004-07-22 Univ Nebraska Sequences de promoteurs a3 amyloides seriques associees a des mammiferes et leurs utilisations
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

Also Published As

Publication number Publication date
AU1876595A (en) 1995-08-29
AU700104B2 (en) 1998-12-24
CA2183260A1 (fr) 1995-08-17
EP0952846A1 (fr) 1999-11-03
JPH09509415A (ja) 1997-09-22
EP0952846A4 (fr) 1999-11-03

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