Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-01-06
2002-03-12
Salimi, Ali R. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C514S054000, C514S885000, C424S278100
Reexamination Certificate
active
06355414
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is related to the field of medicine, particularly to the development of new formulations for immunological potentiation allowing the increase of the amount and quality of the immune response to vaccine antigens.
The technical aim of the invention is the development of formulations that are capable of increasing the levels of the immune response of the body to vaccine antigens.
The adjuvants are substances that increase or optimize the immune response to antigens inoculated through the mucosal or systemic routes. The adjuvants or their formulations are combined with the antigen to generate or potentiate the type of response desired, decrease the number of inoculations and reduce the amount of antigen needed to obtain and maintain protection (McElrath, M. C. 1995 Seminars in Cancer Biology 6: 375-385).
Adjuvants have been developed as a necessity due to the advancements of modern biotechnology with the production of pure soluble recombinant and synthetic antigens. In general, these antigens are safe, but generally shows a decreased immunogenicity compared to those of the original organism. An important function of adjuvants or their formulations, is to increase the complexity of the antigen facing the immune system, in a safe way, thus increasing its immunogenicity (Alving, R. C. 1992 AIDS Res. Hum. Retroviruses 8 (8): 1427-1430).
At present, the search for new adjuvants and immunological stimulators, as well as the development of new ways of delivering antigens and pharmaceuticals, is one of the lines of world research in the pharmaceutical field, especially in vaccines. The development of the adjuvants for mucosal use is a present need in the vaccine field (Report of the Expert Panel VI: Concerted efforts in the field of mucosal immunology 1996 Vaccine 14: 644-664). They may be classified as mucosal and systemic adjuvants, considering that the physiological characteristics on receiving and processing the antigen in both inoculation routes generate different adjuvation procedures. The mucosal route, according to the characteristics of the antigen, require binding or coating procedures with specific ligands that send the antigens to the M cells. The adjuvant activity for mucosal antigens is obtained through strategies that help the antigen to cross the borders imposed by the route. The physical characteristics of the antigen may favor its phagocytosis. Once the antigen has been assimilated, the adjuvant may influence the response by any of the known mechanisms: antigen adsorption, depot effect, cytokine induction, complement activation, recruiting of different cell populations of the immunological system, antigen delivery to different antigen presenting cells, regulation of the expression through class I or class II and the stimulation to produce different antibody subtypes (McElrath M. C. 1995 Seminars in Cancer Biology 6: 375-385).
Some of the immunological stimulators known, as muramyldipeptides (MDP), monophosphoryl-lipid A (MPL), the lipoid amine Avridine and those known as toxins:
V. cholerae
(CT) and of
E. coli
(HLT) toxins, are recognized adjuvants for antigens administered through the mucous route (Walker, R. I. 1994 Vaccine 12 (5): 387-400).
The MDP and MPL have been studied in liposomal formulations for therapeutic and prophylactic use, however, the toxins and their sub-units (specially the CT and CTB) are the most common mucosal adjuvants.
The ability of CT to act as an oral adjuvant has been confirmed by a large number of researchers (McGhee, J. R. et al. 1992 Vaccine 10 (2): 75-88). The Cholera Toxin does not fulfill the classical definition of an adjuvant because it stimulates an immune response against itself and its adjuvant activity depends on its immunogenicity (Elson, C. O. 1987 Fed. Proc. 46: 1778). The immunomodulating effects of the CT and HLT explaining their strong adjuvant activity, include the increase in antigen presentation by several types of B cells, the increase in B cells differentiation to the IgA isotype, the interaction with T cells and the induction of cytokine production (Lintermans, P. 1995 Advanced Drug Delivery Reviews 18: 73-89).
From the practical point of view, the use of the holotoxin in man is not possible due to its toxicity. A better strategy is the detoxification of the CT, by separating the CTA subunit or through mutations of the gene codifying it. CT as well as the CTB (less toxic subunit of CT) may potentiate the immune response to several antigens bound covalently through specific interactions with M cells (Holmgren, J. et al. 1993 Vaccine 11: 1179-1184).
The antigen delivery systems have reached a sufficiently high degree of development as to have an impact on immunization. It is expected that the solid particulated systems for parenteral or non-parenteral administration should be among the first licensed products (Li Wan Po et al. 1995 Advanced Drug Delivery Reviews 18: 101-109).
Through the possibilities offered by the antigen delivery systems in the particulation of soluble antigens, and taking advantage of the physiological characteristics of the mucosal route, these systems have been tested and have shown adjuvant activity. In the literature they have been classified as:
a) synthetic/inactivated and b) alive (Report of the Expert Panel VII: Vaccine Delivery Systems 1996 Vaccine 14: 644-664). Enclosed in the first group, according to their non-living characteristic, there are two different groups. In respect to the first group, the artificial polymeric particles have been studied with different results comprising: the co-polymeric microspheres of lactic and glycolic acids, also alternative polymers as polyphosphacenes, cellulose acetate polymers, iminocarbonates, ethylenvinyl acetate polymers, proteinoid microspheres, dextran polyanhydrid and nanospheres; the particles produced from natural materials: alginates, gelatins and seeds of plants and also the liposomes and their variants: proteoliposomes, virosomes and ISCOMs (Li Wan Po et al. 1995 Advanced Drug Delivery Reviews 18: 101-109).
The size of the particles is within the group of important factors for antigen sending. In the case of the mucosal immunization route it has been reported that particles of a diameter greater than 10 &mgr;m are not absorbed (Eldridge J. H. 1990 J. Control. Release 11:205-214). In experiments with rats it was observed that after oral administration, only particles of 5 &mgr;m deeply penetrated the Peyer Patches and those of 1 &mgr;m of diameter, penetrated the lymphonodes and went into the bloodstream (Jani, P. et al 1990 J. Pharm. Pharmacol. 42:821-826)(Alpar, H. O. et al. 1989 J. Pharm. Pharmacol 41:194-196).
The extrapolation of these results in man is not yet defined and sometimes the adsorption by the gastrointestinal tract is not a requirement for adjuvant activity although it has been proven that with the adsorption of the diphtheria toxoid in plant seed of up to 2 mm diameter, the immune response was potentiated (Mirchamski, H. et al. 1994 Vaccine 12:1167-1172).
The determination of the optimum size of the controlled release systems through the oral, rectal or vaginal routes is under study (Li Wan Po et al. 1995 Advanced Drug Delivery Reviews 18:101-109).
Another factor affecting the particles is the hydrophobic-hydrophilic balance, which may be modified to obtain a modulation of the immune response (Jani, P. et al 1990 J. Pharm. Pharmacol. 42:821-826).
Recently, the use of vaccines of protein cochleates described in 1975 (Papahadjopoulos D. et al 1975 Biochem. Biophys. Acta 394: 483), has been patented. The cochleates are complexes of liposomes and divalent cations (mainly calcium) that, through the calcium-phospholipid interaction, enable the formation of a liposome structure coiled on itself, allowing the immunization through different routes (Gould Foguerite, S. WO 95/09648). With this structure, the immune response of antibodies, as well as the cell mediated responses are stimulated (Gould Foguerite, S. 1994 AIDS Res. Hum. Retroviruses 10 (Supl. 2): S99-S103).
The absorptio
Aguilar Rubido Julio César
Carmenate Portilla Tania
Cruz Ricondo Luis Javier
Diaz Martinez Maylin
Guillen Nieto Gerardo Enrique
Centro de Ingenieria Genetica y Biotechnologia
Hoffmann & Baron , LLP
Salimi Ali R.
LandOfFree
Immunopotentiating formulations for vaccinal use does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Immunopotentiating formulations for vaccinal use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Immunopotentiating formulations for vaccinal use will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2837358