AU700104B2 - Prolactin as a vaccine adjuvant - Google Patents
Prolactin as a vaccine adjuvant Download PDFInfo
- Publication number
- AU700104B2 AU700104B2 AU18765/95A AU1876595A AU700104B2 AU 700104 B2 AU700104 B2 AU 700104B2 AU 18765/95 A AU18765/95 A AU 18765/95A AU 1876595 A AU1876595 A AU 1876595A AU 700104 B2 AU700104 B2 AU 700104B2
- Authority
- AU
- Australia
- Prior art keywords
- prolactin
- vaccine
- glu
- leu
- immune response
- 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.)
- Ceased
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Description
WO 95/21625 PCT/US95/01866 PROLACTIN AS A VACCINE ADJUVANT Background of the Invention The use of vaccines to prevent diseases in humans, farm livestock, sports animals and household pets is a common practice, and considerable effort has been, and is being, made to extend this practice to cover a more extensive array of diseases to which these patients are subject. For example, the use of rabies vaccine in animals is by now commonplace, and efforts are being made to obtain suitable vaccines to immunize animals against other diseases.
One problem that frequently is encountered in the course of active immunization is that 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. Another problem is that the vaccine may be deficient in inducing cell-mediated immunity which is a primary immune defense against bacterial and viral infection.
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. The most commonly used 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.
In addition, with the advent of gene therapy it has been reported that some success has been accomplished with using genes or "naked DNA" as vaccines. However, as with some of the conventional vaccines, the immune response obtained was insufficient to afford immunization.
15-10-9,8;14:52 5/ 12 l':\OPEp\MRO\I 87SS5.S9E 15i/1O/9 -2- Accordingly, there is a need for additional effective adjuvant preparations which are suitable for potentiating vaccines for animals in general, and particularly in humans.
Summary of the Invention 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. Preferably, 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. Human prolactin cDNA is preferred.
.0 15 In another aspect, the invention relates to a method of enhancing the immune response of a subject animal to an infectious disease vaccine comprising coadministering an effective amount of prolactin or prolactin cDNA along with a vaccine.
:g Detailed Description of the Invention 20 Definitions As used herein, "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. The amino acid sequence of a recombinant hPRL is shown below as SEQ ID NO:1. The recombinant PRL (r-PRL) is preferred herein.
The term "recombinant prolactin", designated as r-PRL preferably human prolactin, refers to prolactin having comparable biological activity to native prolactin prepared by recombinant DNA techniques known by those of skill in the art. In general, the P:\OPER\MRO\18765-95.308 4111/98 -3gene 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.
As used herein, the term "adjuvant" has its conventional meaning, the ability to enhance the immune response to a particular antigen. Such ability is manifested by a significant increase in immune-mediated protection. Furthermore, 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 below as SEQ ID NO:2.
As used herein, the term "vaccine" refer to a composition of matter that comprises an antigen and at least capable of conferring an immune response, cell-mediated immunity against said antigen or a protective immune response to said antigen when **administered to a human or animal subject.
The term "infectious disease vaccine" shall be taken to mean a vaccine as hereinbefore defined wherein the antigen component thereof comprises a live or killed infectious disease agent of the human or animal subject, such as a bacterial or viral pathogen or alternatively, an antigenic component of said infectious disease agent and wherein the immune response, protective immune response or cell-mediated immunity confers protection against said infectious disease agent. Accordingly, persons skilled in the art will be aware than an infectious disease vaccine is distinct from other vaccines which may confer immunity against any antigen.
General Method Formulations containing prolactin for adjuvant purposes are most conveniently administered by intramuscular or subcutaneous injections or intraperitoneal although other methods of administration are possible.
WO 95/21625 PCT/US95/01866 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.
Sustained and continuous release formulations are of considerable variety and could be used in the method of the present invention, as is understood by those skilled in the art.
Prolactin can be administered separately from the vaccine or in combination with the vaccine. When prolactin is combined 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" provide diminished protection in terms of level, extent, and/or duration). Examples of such 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,transmissible gastroenteritis vaccine, pseudorabies vaccine, and rabies vaccine.
WO 95/21625 PCT/US95/01866 In addition, because we have demonstrated in vitro and in vivo data that indicate that prolactin can enhance the immune response to an immunogen and thereby function as a vaccine adjuvant, it is believed that the 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 plasmid vectors, liposomes, viral vectors). This could be accomplished as described by Pellegrini et al., Molec. Endocrinolgy, 6, 1023 (1992), Maniatis et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press (1989) and Felger et al., Proc. Natl.
Acad. Sci., 84, 7413, (1991). The "genetic adjuvant" is then administered along with either cDNA encoding the immunogen in an appropriate delivery vehicle or "naked" solely the cDNA). In addition, the "genetic adjuvant" could be administered along with the immunogen itself. The injection sequence would be optimized per immunogen, 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.
EXAMPLE 1 Co-mitogenicity of recombinant human prolactin (r-hPRL) Peripheral blood lymphocytes (PBL) 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 15-10- 8;114:52 7/ 12 P:\OPER\MR\OU176S-p,SP IS/10I98 -6- 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. 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 2x106/ml in serum-free AIM-V medium from Gibco and added to the wells of round bottom 96 well microtiter plates in a 100 volume (2x10 5 PBL/well).
A suboptimal dose of the T cell mitogen concanavalin A (Con A: 0.2 /g/ml) was added in a 50 p1 volume together with 50 pl of varying concentrations of r-hPRL (0-1000 ng/ml final). Cultures were done in triplicate. The cells were incubated at 37°C/5% CO, for 72 hours and the amount of proliferation measured by tritiated thymidine incorporation. Tritiated thymidine Cilwell) 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.
15 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.
20 Table 1 Co-mitogenic activity of recombinant human prolactin (cpm SEM) Con A r-hPRL (no/ml) Donor 1 Donor 2 Donor 3 No prolactin 22323±4585 35942±810 16549±1618 0.1 22949±2003 34040±1446 170831 895 1 35882+3665 45839±2137 27590±3151 32832±1972 37658±150 22991+2358 100 25963±4855 35009±2105 22674±1662 1000 23990+1534 35921±1690 26646±2574 WO 95/21625 PCT/US95/01866 EXAMPLE 2 Enhancement of antigen-specific proliferation by 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 il PBL (2x10 5 /well), 50 pl streptokinase (25 pg/ml final) and gl 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%CO2.
The results, shown in Table 2 below, indicated that rhPRL, at a concentration of 1 ng/ml, significantly enhanced streptokinase-induced proliferation.
Table 2 Effect of recombinant human prolactin on streptokinase-specific proliferation Streptokinase r-hPRL (ng/ml) Proliferation (cpm SEM) No prolactin 31807±4235 0.1 30220±5448 1 50964±6469 35620±11318 100 36713±2230 1000 33494±7990 WO 95/21625 PCT/US95/01866 EXAMPLE 3 Effect of prolactin in enhancing the immune response to an immunogen Twenty-four 150 gram male Sprague-Dawley rats were divided into 4 groups. The control group received an intraperitoneal injection of 10 lig BSA mixed with alum. The other 3 groups received intraperitoneal injections of 10 g BSA mixed with alum along with either 180 ig prolactin, 375 j.g prolactin or 750 gg prolactin. Tail vein bleeds were taken weekly for 4 weeks and the serum evaluated for antibody to BSA by a Radioimmunosorbent Assay (RIA). The animals were boosted after the 4th bleed with 10pg 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 To measure the effect of r-hPRL on the cellular response of rats immunized with BSA, blood was collected from individual animals sacrificed 101 days after boosting. To isolate peripheral blood lymphocytes (PBL), blood samples were diluted 4 fold in the phosphate-buffered saline (PBS) and centrifuged at 2000 rpm for 20 minutes. The buffy coat was collected and contaminating red blood cells were removed by the addition of Tris-ammonium chloride lysis buffer followed by a 10 minute incubation at 37°C. PBL were then washed twice in PBS and resuspended at 5x10 6 /ml in RPMI-1640 medium supplemented with 100 u/ml penicillin, 100 gg/ml streptomycin, 20 mM Hepes buffer, 2 mM L-glutamine, 5x10 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 jl volume (5x10 5 cells/well) and cultured in the presence of medium alone (background control) or 1000 p-g/ml BSA added in a 100 il volume. Cultures were done in C-88;14: 52 8/ 12 S/ 12 P:\OPERMROUM7 6 WAM 15O10M -9triplicate. Proliferation was measured by tritiated thymidine incorporation after 5 days of culture at 37' C/5% C02.
The results indicated that, overall, PBL rats immunized with BSA 180 jisg rhPRL displayed higher levels of BSA-specific proliferation than PBIL from rats immunized with antigen alone. This observation suggests that r-hPRL may act to enhance the cellular component of the immune response to an immunizing antigen. Results are compiled in Table 3 below.
Table 3 BSA-specific proliferation of rat PB.L (cpm SEM) *9 9 9 9 99 9 9 9 9 9999 9*9 .9 9 9 9 9 99 999999 99 9 9 9 99 *999 9 99 999* 9 99 0 9 99 9 9 9 9 *9*e*9 9 Group BSA alone 15 Rat 1 Rat 2 Rat 3 Rat 4 20 BSA +180 uO PRIL Rat 1 Rat 2 Rat 3 Rat 4 101 days after boosting Background 918 35 559 169 614 51 242 ±L 21 426 ±99 269 18 723 185 676 29 BSA-specific response 1236 100 1392 185 930 265 2122 ±257 2552 756 37 4328 77 2023 397 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
WO 95/21625 PCT/US95/01866 SEQUENCE LISTING GENERAL INFORMATION: APPLICANT: Richards, Susan Kaplan, Johanne Moscicki, Richard (ii) TITLE OF INVENTION: PROLACTIN AS ADJUVANT (iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: William G. Gosz STREET: One Kendall Square CITY: Cambridge STATE: MA COUNTRY: U.S.A.
ZIP: 02139 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: Patentln Release Version #1.25 (vi) CURRENT APPLICATION DATA: APPLICATION NUMBER: FILING DATE:
CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION: NAME: Gosz, William G REGISTRATION NUMBER: 27,787 REFERENCE/DOCKET NUMBER: GEN 4-2.0 WO 95/21625 PCT/US95/01866 (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: 5088722583 TELEFAX: 6173747225 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 351 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iv) ANTI-SENSE: NO FRAGMENT TYPE: N-terminal (vi) ORIGINAL SOURCE: ORGANISM: human prolactin (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Thr lie Gly Phe His Met Pro Arg Leu Cys His Glu Cys Lys Phe Arg 1 5 10 Met Thr Thr Arg Ala Asn Ser Leu Ala Thr Glu Phe His Met Pro Arg 20 25 Leu Ser Glu Gin Cys His Glu Cys Lys Phe Arg Met Thr Gly Glu Asn 40 Glu Arg Ala Thr Glu Asp Ser Tyr Met Asx Leu Ser Thr His Met Pro 55 -11- WO 95/21625 PCT/US95/01866 Arg Leu Leu Cys Ser His Met Pro Arg Leu Asx Pro Met Arg Asn Ala 70 75 Glu Asn Thr Glu Arg Glu Asp Asp Glu Phe lie Asn lie Thr lie Asn 90 His Met Ala Asn Pro Arg Glu Pro Arg Leu Ala Cys Thr lie Asn Pro 100 105 110 Arg Leu Met Arg Asn Ala Ala Cys Cys Glu Ser Ser lie Asn His Met 115 120 125 Pro Arg Leu Pro Glu Pro Leu Glu Asn Gly Thr His Leu Tyr Cys His 130 135 140 Glu Cys Lys His Met Pro Arg Leu Leu Pro lie Cys Pro Gly Gly Ala 145 150 155 160 Ala Arg Cys Gin Val Thr Leu Arg Asp Leu Phe Asp Arg Ala Val Val 165 170 175 Leu Ser His Tyr lie His Asn Leu Ser Ser Glu Met Phe Ser Glu Phe 180 185 190 Asp Lys Arg Tyr Thr His Gly Arg Gly Phe lie Thr Lys Ala lie Asn 195 200 205 Ser Cys His Thr Ser Ser Leu Ala Thr Pro Glu Asp Lys Glu Gin Ala 210 215 220 Gin Gin Met Asn Gin Lys Asp Phe Leu Ser Leu lie Val Ser lie Leu 225 230 235 240 Arg Ser Trp Asn Glu Pro Leu Tyr His Leu Val Thr Glu Val Arg Gly 245 250 255 -12- WO 95/21625 PCT/US95/01866 Met Gin Glu Ala Pro Glu Ala lie Leu Ser Lys Ala Val Glu lie Glu 260 265 270 Glu Gin Thr Lys Arg Leu Leu Glu Gly Met Glu Leu lie Val Ser Gin 275 280 285 Val His Pro Glu Thr Lys Glu Asn Glu lie Tyr Pro Val Trp Ser Gly 290 295 300 Leu Pro Ser Leu Gin Met Ala Asp Glu Glu Ser Arg Leu Ser Ala Tyr 305 310 315 320 Tyr Asn Leu Leu His Cys Leu Arg Arg Asp Ser His Lys lie Asp Asn 325 330 335 Tyr Leu Lys Leu Leu Lys Cys Arg lie lie His Asn Asn Asn Cys 340 345 350 INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 1100 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA -13- WO 95/21625 PCTJUS95/01866 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: TGCCTCATTA ACTAACCACT CACATTAAAA GAAATATAAC ATATATATTA AAAATAATCA TATCCTATAA TAATTAACTC ATCTAAAATA CAACCTACTG TACCATATAC TAACTGAATA 120 AGACTAGCAT TATTATTCAG GATAACTAAG TCCATAAGAT ATGTACCATA TTATACACAT 180 TTATAGCACG GATATTACTT ACTGGATATA CTTTGATCTA TCTTGATATT TATTATTCAA 240 AATACTACGT GATATATCGC ATGTCCCAAA CATGAACATC AAAGGATCGC CATGGAkAGG 300 GTCCCTCCTG CTGCTGCTGG TGTCAAACCT GCTGCTGTGC CAGAGCGTGG CCCCCTTGCC 360 CATCTGTCCC GGCGGGGCTG CCCGATGCCA GGTGACCCTT CGAGACCTGT TTGACCGCGC 420 CGTCGTCCTG TCCCACTACA TCCATAACCT CTCCTCAGMA ATGTTCAGCG AATTCGATAA 480 ACGGTATACC CATGGCCGGG GGTTCATTAC CAAGGCCATC AACAGCTGCC ACACTTCTTC 540 CCTTGCCACC CCCGAAGACA AGGAGCAAGC CCAACAGATG AATCAAAAAG ACTTTCTGAG 600 CCTGATAGTC AGCATATTGC GATCCTGGAA TGAGCCTCTG TATCATCTGG TCACGGAAGT 660 ACGTGGTATG CAAGAAGCCC CGGAGGCTAT CCTATCCAAA GCTGTAGAGA TTGAGGAGCA 720 AACCAAACGG CTTCTAGAGG GCATGGAGCT GATAGTCAGC CAGGTTCATC CTGAAACCAA 780 AGAAAATGAG ATCTACCCTG TCTGGTCGGG ACTTCCATCC CTGCAGATGG CTGATGAAGA 840 GTCTCGCCTT TCTGCTTATT ATAACCTGCT CCACTGCCTA CGCAGGGATT CACATAAAAT 900 CGACAATTAT CTCAAGCTCC TGAAGTGCCG AATCATCCAC AACAACAACT GCTAAGCCCA 960 CATCCATTTC ATCTATTTCT GAGAAGGTCC TTAATGATCC GTTCCATTGC AAGCTTCTTT 1020 -14- WO 95/21625 PCTJUS95/01866 TAGTTGTATC TCTTTTGAAT CCATGCTTGG GTGTAACAGG TCTCCTCTTA AAAAATAAAA 1080 ACTGACTCGT TAGAGACATC 1100
Claims (1)
15-10-98;14:52 9/ 12 -9SsM- 15/5s -16- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A composition that enhances the immune response of an animal to an infectious disease vaccine, wherein the composition comprises prolactin and the infectious disease vaccine. 2. The composition of claim 1 wherein the prolactin is human prolactin. 3. The composition of claims 1 or 2 wherein the animal is a human. 4. The composition according to any one of claims 1 to 3 wherein the prolactin comprises an amino acid sequence selected from all or a portion of the amino acid sequence of SEQ ID NO:1. 5. A method of enhancing the immune response of a subject animal to an infectious disease vaccine comprising co-administering an effective amount of prolactin along with a vaccine. 6 The method of claim 5 wherein the prolactin is human prolactin. 0 o 7. A method for enhancing the immune response in accordance with claim wherein the animal is a human. 8. The method of claim 5 wherein the prolactin comprises an amino acid sequence selected from all or a portion of the amino acid sequence of SEQ ID NO:1. 9. The composition according to any one of claims 1 to 4 when used to enhance the immune response of an animal to an infectious disease vaccine. The composition according to any one of claims 1 to 4 or claim 9 substantially as hereinbefore described with reference to the Examples. 15-10-98;14!52 10/ 12 p:\OprEKR0\i~d-5,,0.~ 17 1. The method according to any one of claims 5 to 8 substantially as hereinbefore described with reference to the Examples. DATED this FIFTEENTH day of OCTOBER., 1998 GIENZYME CORP~ORATION by DAVIES COLLISON CAVE Patent Attorneys for the Applicants a S S S S S S CS.. S. a a. S S a S*SSb S *5 a S a S. S. 59 a a ~0 S. a a a *SS*a. S S a a 5 0 *55*55 a
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JP2000510112A (en) * | 1996-04-30 | 2000-08-08 | ジェンザイム コーポレーション | Use of prolactin as a TGF-β antagonist |
AU6028298A (en) * | 1997-01-21 | 1998-08-07 | Genzyme Corporation | Enhancement of hematopoietic cells |
JP3511023B2 (en) | 1999-08-25 | 2004-03-29 | アキュプレックス,リミティド ライアビリティーカンパニー | Diagnostic assays of secreted biological fluids for detection of infectious and inflammatory conditions |
JP2003512839A (en) | 1999-10-22 | 2003-04-08 | ザ ボード オブ リージェンツ オブ ザ ユニバーシティ オブ ネブラスカ | Colostrum-derived serum amyloid A isoform |
US20050107315A1 (en) * | 2001-11-21 | 2005-05-19 | Board Of Regents Of The University Of Nebraska | Mammary-associated serum amuloid a3 promoter sequences and used 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 |
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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 |
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- 1995-02-14 WO PCT/US1995/001866 patent/WO1995021625A1/en not_active Application Discontinuation
- 1995-02-14 JP JP7521414A patent/JPH09509415A/en active Pending
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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 |
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THE JOURNAL OF EXPERIMENTAL MEDICINE VOL 178 JULY 93 P 231-6 * |
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