WO1992021378A1 - Vaccines with erythrocytes as antigen carriers - Google Patents
Vaccines with erythrocytes as antigen carriersInfo
- Publication number
- WO1992021378A1 WO1992021378A1 PCT/IT1992/000061 IT9200061W WO9221378A1 WO 1992021378 A1 WO1992021378 A1 WO 1992021378A1 IT 9200061 W IT9200061 W IT 9200061W WO 9221378 A1 WO9221378 A1 WO 9221378A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vaccines
- production
- specific
- neutralizing antibodies
- antibodies according
- Prior art date
Links
Classifications
-
- 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
- A61K39/385—Haptens or antigens, bound to carriers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
- A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
-
- 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
- A61K2039/515—Animal cells
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6006—Cells
Definitions
- This invention relates to vaccines employing erythrocytes as antigen carriers.
- this invention relates to vaccines obtained employing cells of the erythrocyte lineage as carriers and natural adjuvants for the production of specific and neutralizing antibodies in domestic and breeding animals and in humans.
- the US patents No. 4,327,710 and 4,389,209 disclose procedures for introducing additive compounds into the erythrocytes of mammalians.
- the European Patent EP 101342 discloses a procedure for introducing the haemoglobin allosteric effectors, in order to modulate the activity comprising the steps of incubating the erythrocytes with a hypotonic solution that favours the entrance of exogenous compounds, without damaging irremediably the cells and of performing a further successive incubation in an isotonic solution that requires erythrocytes.
- mouse erythrocytes can function like antigen carriers in order to stimulate the natural production of protective antibodies, once they have been introduced into the organism to immunize, because of their natural destination into the spleen, which is an immunopoietic organ. Accordingly, it has been possible to obtain vaccines that make use of erythrocytes not only as carriers but also as antigen natural adjuvants, so as to have the value of a good alternative with respect to other vaccination schemes, and more particularly in domestic and breeding animals, without having recourse to long and often impracticable booster shots.
- Such vaccines obtained also through the employment of recombinant antigenic peptides show to be stable, as they do not undergo extracellular proteolysis phaenomena and they make also useless the employment of adjuvants, like colloidal gels or other molecules deriving from microbiological or bacteria or biotechnological origin, which quite often cause local effects like ache, erythemas, rashes, and so on.
- an object of this invention consists in vaccines for the production of specific and neutralizing antibodies, such vaccines being characterized in that cells of the erythrocyte lineage are employed as antigen carriers; preferably, said. erythrocite lineage cells function both as antigen carriers and as adjuvants.
- said erythrocyte lineage cells are included in the bone-marrow cell, erythroblast and erythrocyte group, and preferably said cells of the erythrocyte lineage are erythrocytes; even more preferably said erythrocytes are incubated in the presence of said antigen in a hypotonic solution for giving rise to a controlled haemolysis and to the introduction of said antigens, and they are then incubated in an isotonic solution.
- said erythrocyte lineage cells are bone-marrow cells or erythroblasts in which said antigens are introduced into said bone-marrow cells or erythroblasts by means of a microinjection, or by introducing of nucleic acid segments coding for them by transfection.
- an object of this invention consists in vaccines for the production of specific and neutralizing antibodies, said vaccines being characterized in said antigens are of natural or biotechnological origin.
- said antigen is a non toxic derivative of diphtheria toxin, and preferably said non toxic deri ⁇ vative of diphtheria toxin is the substance known as
- said antigen is a non toxic derivative of tetanic toxin, preferably said non toxic derivative of tetanic toxin is tetanic anatoxin, detoxified by treatment with 0.6 % formaldehyde.
- said antigen is a non toxic derivative of whooping- cough toxin, preferably said non toxic derivative of whooping-cough toxin being the PT-9K/129G mutant.
- the non toxic mutant of the whooping-cough toxin (PT-9K/129G) which, with respect to the SI subunit sequence of the native molecule, has a lysine instead of an arginine in the position 9 and a glycine instead of a glutamic acid in the position 129 (Pizza et. al.. Science, 246, 497 (1989);- Nencioni et. al., Infect. Immun., 58_, 1308 (1990)).
- Such antigens have been introduced into mouse erythrocytes of the BDF strain, whereas in the case of whooping-cough toxin, also Balb/c strains have been employed.
- CCM197 - diphtheria toxin
- the evaluation of the specific antibodies for each one of the three antigens, at the different immunization times, has been carried out through radioimmunoassay. This has been carried out conventionally on 96-well plates, by causing the antigen to adhere, saturating with BSA and then adding in successive steps the serum to be analyzed and a commercially available antiserum of 125I labeled anti-IgG rabbit. After different washes at each one of the various steps, the radioactivity of wells was counted, then subtracting from the same the radioactivity of control samples containing non-immune serum.
- the evaluation of the antibodies that neutralized the diphtheria toxin and the tetanic toxin was performed according to the F.U. IX Ed., pg. 1440 and the following, and pg. 1446 and the following, in vivo with guinea-pigs and in rabbits, considering as neutralizing a concentration less than or equal to 0.01 I.U. (International Units) / ml.
- the values obtained were less than or equal to 1.0 I.U./ml; for tetanic toxin the values were less than or equal to 2.0 I.U./ml.
- the estimation of the antibodies neutralizing the whooping-cough toxin was carried out by the CHO (Chinese Hamster Ovary) cells test (Gillenius et. al., J.Biol. Stand., 13, 61 (1985)).
- the neutralizing titre is expressed as the inverse of the dilution of the serum capable of neutralizing toxic effect induced on the CHO cells by 120 pg of nonmutated toxin, and it turned out to be 1/160.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Zoology (AREA)
- Botany (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
This invention discloses vaccines obtained employing as the antigen carriers as well as the adjuvants cells of the erythrocyte lineage, in particular erythrocytes which induce, if injected into the organism to immunize through intravenous route, the production of specific and neutralizing antibodies. More particularly, vaccines against whooping-cough, diphtheria and tetanic infection are disclosed.
Description
VACCINES WITH ERYTHROCYTES AS ANTIGEN CARRIERS
This invention relates to vaccines employing erythrocytes as antigen carriers.
More particularly, this invention relates to vaccines obtained employing cells of the erythrocyte lineage as carriers and natural adjuvants for the production of specific and neutralizing antibodies in domestic and breeding animals and in humans.
Procedures are already known from the prior art for introducing exogenous compounds into human and animal erythrocytes.
Among such procedures, the US patents No. 4,327,710 and 4,389,209 disclose procedures for introducing additive compounds into the erythrocytes of mammalians. The European Patent EP 101342 discloses a procedure for introducing the haemoglobin allosteric effectors, in order to modulate the activity comprising the steps of incubating the erythrocytes with a hypotonic solution that favours the entrance of exogenous compounds, without damaging irremediably the cells and of performing a further successive incubation in an isotonic solution that requires erythrocytes.
Even from the technical literature not belonging to patents some similar procedures are known (De Loach, J.R. , and Ihler, G.M. (1977) Biochim. Biophys. Acta 496, 136-145; De Loach, J.R., and Prandel, U. Editors (1985). Red Blood Cells as Carries for Drugs pp. 1-162.
Bibliotheca Haematologica, Karger, Basel; De Flora, A. (1985). The impact of biotechnology on diagnostics (Albertini et. al. Editors), pp. 223-236. Elsevier Science Publisher, Amsterdam; De Loach, J.R., Andrews, K. , Sheffield, C.C., and Koths, K. (1987) Advances In the Biosciences Vol. 67, pp. 183-190 Perga on Press, Oxford) , which generally have the scope of constructing natural carriers of drugs or bioregulators for improving the pharmacokinetic properties thereof. The traditional immunization schemes as regards to antigens in experimental animals provide the use of adjuvants of various kinds. Such adjuvants (as for instance Freund's adjuvants, the complete and the incomplete one) cannot be employed for vaccinations in humans, which instead make use of colloidal gels (as for instance aluminum salts) , in order to obtain the transient formation of granulomas in deep intramuscular sites, leading to a slow release of the antigen.
The study of new adjuvants for vaccine of antigens is a very fecund field also because of the introduction of many peptides, which have been produced through recombinant DNA technologies. This is true both for human vaccinations and for vaccinations to be performed in domestic and breeding animals. More particularly, in case of the latter, the need is increasingly felt for the realisation of vaccines capable of conferring permanent immunization, so as to avoid the need for having recourse to costly operations
for giving booster shots which are also difficult to carry out on a large scale.
The authors of this invention have found that mouse erythrocytes can function like antigen carriers in order to stimulate the natural production of protective antibodies, once they have been introduced into the organism to immunize, because of their natural destination into the spleen, which is an immunopoietic organ. Accordingly, it has been possible to obtain vaccines that make use of erythrocytes not only as carriers but also as antigen natural adjuvants, so as to have the value of a good alternative with respect to other vaccination schemes, and more particularly in domestic and breeding animals, without having recourse to long and often impracticable booster shots.
Such vaccines obtained also through the employment of recombinant antigenic peptides, show to be stable, as they do not undergo extracellular proteolysis phaenomena and they make also useless the employment of adjuvants, like colloidal gels or other molecules deriving from microbiological or bacteria or biotechnological origin, which quite often cause local effects like ache, erythemas, rashes, and so on.
Accordingly, an object of this invention consists in vaccines for the production of specific and neutralizing antibodies, such vaccines being characterized in that cells of the erythrocyte lineage are employed as antigen carriers; preferably, said.
erythrocite lineage cells function both as antigen carriers and as adjuvants.
Again according to this invention said erythrocyte lineage cells are included in the bone-marrow cell, erythroblast and erythrocyte group, and preferably said cells of the erythrocyte lineage are erythrocytes; even more preferably said erythrocytes are incubated in the presence of said antigen in a hypotonic solution for giving rise to a controlled haemolysis and to the introduction of said antigens, and they are then incubated in an isotonic solution. Alternatively said erythrocyte lineage cells are bone-marrow cells or erythroblasts in which said antigens are introduced into said bone-marrow cells or erythroblasts by means of a microinjection, or by introducing of nucleic acid segments coding for them by transfection.
Again an object of this invention consists in vaccines for the production of specific and neutralizing antibodies, said vaccines being characterized in said antigens are of natural or biotechnological origin.
According to a preferred embodiment of this invention, said antigen is a non toxic derivative of diphtheria toxin, and preferably said non toxic deri≡ vative of diphtheria toxin is the substance known as
CRM197.
According to another kind of embodiment, said antigen is a non toxic derivative of tetanic toxin, preferably said non toxic derivative of tetanic toxin is tetanic anatoxin, detoxified by treatment with 0.6 % formaldehyde.
According to a third embodiment of the invention, said antigen is a non toxic derivative of whooping- cough toxin, preferably said non toxic derivative of whooping-cough toxin being the PT-9K/129G mutant.
This invention will be disclosed in the following working examples of the same.
Example 1 Introduction of antigens into mouse erythrocytes
According to the method disclosed in the European Patent EP 101341 which, briefly stated, provides a hypotonic control haemolysis of erythrocytes, in the presence of the compound to be trapped, and the suc≡ cessive incubation in an isotonic solution, the fol≡ lowing compounds have been separately introduced into mouse erythrocytes:
- CRM 197 (cross practing material) a non toxic mutagenized protein that differs from diphtheria toxin in the position 52, where glycine has been substituted with glutamic acid (Uchida et. al.. Science, 175, 901
(1972); Giannini et. al. , Nucleic Acid Res., 12, 4063 (1984));
- tetanic anatoxin, obtained through treatment of tetanic toxin, produced by a Clostridium tetani strain, and detoxified with 0.6 % (vol/vol) formaldehyde, according to the recommendations of the Organizzazione Mondiale della Sanita (O.M.S.);
- the non toxic mutant of the whooping-cough toxin (PT-9K/129G) which, with respect to the SI subunit sequence of the native molecule, has a lysine instead of an arginine in the position 9 and a glycine instead of a glutamic acid in the position 129 (Pizza et. al.. Science, 246, 497 (1989);- Nencioni et. al., Infect. Immun., 58_, 1308 (1990)). Such antigens have been introduced into mouse erythrocytes of the BDF strain, whereas in the case of whooping-cough toxin, also Balb/c strains have been employed.
Animals of the corresponding strain (15 for each group) have been treated by intravenous injection with the erythrocytes containing the antigens disclosed according to the following schemes:
- diphtheria toxin (CRM197);
- through intravenous route of 20 Aig of antigen trapped within erythrocytes, followed by two more administrations, respectively of 25 Aig (on the day 15) and of 22 Λig (on the day 30) ;
- tetanic anatoxin: 42 Λig on the day 0; 17 /ug on the day 1; 57 ug on the day 28 and 31 ug on the day 38;
- the mutant PT-9K/128G of the whooping-cough toxin: 10 ig on the day 0; 10 Λig on the day 30 and 10 ug on the day 60.
The evaluation of the specific antibodies for each one of the three antigens, at the different immunization times, has been carried out through radioimmunoassay. This has been carried out conventionally on 96-well plates, by causing the antigen to adhere, saturating with BSA and then adding in successive steps the serum to be analyzed and a commercially available antiserum of 125I labeled anti-IgG rabbit. After different washes at each one of the various steps, the radioactivity of wells was counted, then subtracting from the same the radioactivity of control samples containing non-immune serum.
The evaluation of the antibodies that neutralized the diphtheria toxin and the tetanic toxin was performed according to the F.U. IX Ed., pg. 1440 and the following, and pg. 1446 and the following, in vivo with guinea-pigs and in rabbits, considering as neutralizing a concentration less than or equal to 0.01 I.U. (International Units) / ml. In the case of diphtheria toxin, the values obtained were less than or equal to 1.0 I.U./ml; for tetanic toxin the values were less than or equal to 2.0 I.U./ml.
The estimation of the antibodies neutralizing the whooping-cough toxin was carried out by the CHO (Chinese Hamster Ovary) cells test (Gillenius et. al., J.Biol. Stand., 13, 61 (1985)). The neutralizing titre is expressed as the inverse of the dilution of the serum capable of neutralizing toxic effect induced on the CHO cells by 120 pg of nonmutated toxin, and it turned out to be 1/160.
The results so obtained show that all three antigens, trapped within red cells and administered through intravenous route, are capable of inducing significative levels of specific and neutralizing antibodies.
Claims
1. Vaccines for the production of specific and neutralizing antibodies, said vaccines being character rized in that cells of the erythrocyte lineage are employed as antigen carriers.
2. Vaccines for the production of specific and neutralizing antibodies according to claim 1, said vaccines being characterized in that said erythrocyte lineage cells operate both as antigen carriers and as adjuvants.
3. Vaccines for the production of specific and neutralizing antibodies according to any one of the preceding claims, said vaccines being characterized in that said erythrocyte lineage cells are comprised in the group of bone-marrow cells, erythroblasts and erythrocytes.
4. Vaccines for the production of specific and neutralizing antibodies according to claim 3, said vac≡ cines being characterized in that said erythrocyte lineage cells are erythrocytes.
5. Vaccines for the production of specific and neutralizing antibodies according to claim 4, said vac≡ cines being characterized in that said erythrocytes are incubated in the presence of said antigen in a hypoto≡ nic solution for giving rise to a controlled haemolysis and to the introduction of said antigens, and then they are incubated in an isotonic solution.
6. Vaccines for the production of specific and neutralizing antibodies according to claim 3, said vac≡ cines being characterized in that said erythrocyte lineage cells are bone-marrow cells or erythroblasts.
7. Vaccines for the production of specific and neutralizing antibodies according to claim 6, characte≡ rized in that said antigens are introduced into said bone-marrow cells or erythroblasts by means of a microinjection, or by introducing of nucleic acid segments coding for the same through transfection.
8. Vaccines for the production of specific and neutralizing antibodies according to any one of the preceding claims, said vaccines being characterized in that said antigens are of natural or biotechnological origin.
9. Vaccines for the production of specific and neutralizing antibodies according to claim 8, said vac≡ cines being characterized in that said antigen is a non-toxic derivative of diphtheria toxin.
10. Vaccines for the production of specific and neutralizing antobodies according to claim 9, charac≡ terized in that said non-toxic derivative of diphtheria toxin is the compound known as CRM197.
11. Vaccines for the production of specific and neutralizing antibodies according to claim 8, said vac≡ cines being characterized in that said antigen is a non-toxic derivative of tetanic toxin.
12. Vaccines for the production of specific and neutralizing antibodies according to claim 11, said vaccines being characterized in that said nontoxic derivative of tetanic toxin is tetanic anatoxin which has been detoxified through treatment with 0.6 % formaldehyde.
13. Vaccines for the production of specific and neutralizing antibodies according to claim 8, charac≡ terized in that said antigen is a known toxin deriva≡ tive of whooping-cough toxin.
14. Vaccines for the production of specific and neutralizing antibodies according to claim 13, said vaccines being characterized in that said nontoxic derivative of whooping-cough toxin is the mutant PT-9K/129G.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM91A000385 | 1991-06-03 | ||
| ITRM910385A IT1245867B (en) | 1991-06-03 | 1991-06-03 | VACCINES USING ERYTHROCYTES AS ANTIGEN VEHICLES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992021378A1 true WO1992021378A1 (en) | 1992-12-10 |
Family
ID=11400177
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IT1992/000061 WO1992021378A1 (en) | 1991-06-03 | 1992-06-02 | Vaccines with erythrocytes as antigen carriers |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2151092A (en) |
| IT (1) | IT1245867B (en) |
| WO (1) | WO1992021378A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002007752A2 (en) * | 2000-07-24 | 2002-01-31 | Gendel Limited | Red blood cell as vehicle for agent-membrane translocation sequence conjugate |
| WO2013040547A2 (en) * | 2011-09-15 | 2013-03-21 | The Research Foundation Of State University Of New York | Compounds and methods of immunization with tumor antigens |
| CN114432261A (en) * | 2022-02-24 | 2022-05-06 | 深圳市众循精准医学研究院 | Preparation method of targeted delivery vaccine and erythrocyte vaccine |
| WO2022206160A1 (en) * | 2021-03-29 | 2022-10-06 | 华中科技大学 | Immune preparation, composition comprising immune preparation and use thereof, and preparation method |
| US11554141B2 (en) | 2014-04-01 | 2023-01-17 | Rubius Therapeutics, Inc. | Methods and compositions for immunomodulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4144131A (en) * | 1974-05-23 | 1979-03-13 | Wisconsin Alumni Research Foundation | Immobilization of enzymes on human tissue or erythrocytes |
| EP0101341A1 (en) * | 1982-07-05 | 1984-02-22 | Etablissement Public dit: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) | Process and device for the encapsulation in erythrocytes of at least one biologically active substance, in particular hemoglobin allosteric effectors, and erythrocytes so obtained |
| EP0362758A2 (en) * | 1988-10-05 | 1990-04-11 | HAPGOOD, C.V., a Netherlands Antilles Limited Partnership | Electro-insertion of proteins into animal cell membranes |
-
1991
- 1991-06-03 IT ITRM910385A patent/IT1245867B/en active IP Right Grant
-
1992
- 1992-06-02 AU AU21510/92A patent/AU2151092A/en not_active Abandoned
- 1992-06-02 WO PCT/IT1992/000061 patent/WO1992021378A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4144131A (en) * | 1974-05-23 | 1979-03-13 | Wisconsin Alumni Research Foundation | Immobilization of enzymes on human tissue or erythrocytes |
| EP0101341A1 (en) * | 1982-07-05 | 1984-02-22 | Etablissement Public dit: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) | Process and device for the encapsulation in erythrocytes of at least one biologically active substance, in particular hemoglobin allosteric effectors, and erythrocytes so obtained |
| EP0362758A2 (en) * | 1988-10-05 | 1990-04-11 | HAPGOOD, C.V., a Netherlands Antilles Limited Partnership | Electro-insertion of proteins into animal cell membranes |
Non-Patent Citations (1)
| Title |
|---|
| BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY vol. 14, 1991, pages 347 - 356 CAROLINA POLVANI ET AL. 'MURINE RED BLOOD CELLS AS EFFICIENT CARRIERS OF THREE BACTERIAL ANTIGENS FOR THE PRODUCTION OF SPECIFIC AND NEUTRALIZING ANTIBODIES' * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002007752A2 (en) * | 2000-07-24 | 2002-01-31 | Gendel Limited | Red blood cell as vehicle for agent-membrane translocation sequence conjugate |
| WO2002007752A3 (en) * | 2000-07-24 | 2003-08-28 | Gendel Ltd | Red blood cell as vehicle for agent-membrane translocation sequence conjugate |
| WO2013040547A2 (en) * | 2011-09-15 | 2013-03-21 | The Research Foundation Of State University Of New York | Compounds and methods of immunization with tumor antigens |
| WO2013040547A3 (en) * | 2011-09-15 | 2014-05-08 | The Research Foundation Of State University Of New York | Compounds and methods of immunization with tumor antigens |
| US11554141B2 (en) | 2014-04-01 | 2023-01-17 | Rubius Therapeutics, Inc. | Methods and compositions for immunomodulation |
| US11576934B2 (en) | 2014-04-01 | 2023-02-14 | Rubius Therapeutics, Inc. | Methods and compositions for immunomodulation |
| WO2022206160A1 (en) * | 2021-03-29 | 2022-10-06 | 华中科技大学 | Immune preparation, composition comprising immune preparation and use thereof, and preparation method |
| CN114432261A (en) * | 2022-02-24 | 2022-05-06 | 深圳市众循精准医学研究院 | Preparation method of targeted delivery vaccine and erythrocyte vaccine |
| CN114432261B (en) * | 2022-02-24 | 2023-11-28 | 初源汇企业管理(深圳)合伙企业(有限合伙) | Preparation method of targeted delivery vaccine and erythrocyte vaccine |
Also Published As
| Publication number | Publication date |
|---|---|
| ITRM910385A0 (en) | 1991-06-03 |
| ITRM910385A1 (en) | 1992-12-03 |
| IT1245867B (en) | 1994-10-25 |
| AU2151092A (en) | 1993-01-08 |
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