Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1994-12-28
1996-12-03
Kim, Kay K. A.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
4241931, 4242781, 424DIG16, 424450, 42419611, 4241941, 530345, 530403, A61K 3939, A61K 39385, A61K 9127, A61K 3902
Patent
active
055805639
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates generally to the field of immunology, and particularly to the preparation and administration of vaccines for prevention and treatment disease states such as HIV infection.
Highly specific and immunogenic antigens are preferred as vaccines. While the immunogenicity of an antigen can be increased by coupling a protein carrier to the antigen, this approach has several drawbacks. First, if the carrier is large, significant humoral immune response can be directed against the carrier rather than the antigen. Second, a large carrier can suppress humoral response to the antigen. Finally, the coupling of an antigen to a protein carrier can alter the immunogenic determinants of the antigen.
Multiple antigen peptide systems (MAPS) are designed to overcome the problems observed with conventional protein careers. Most MAPS are composed of several peptide antigens covalently linked to a branching, dendritic core composed of bifunctional units (e.g., lysines). Thus, a cluster of antigenic epitopes form the surface of a MAPS and a small matrix forms its core. As a result, the core is not immunogenic. MAPS have been used to prepare experimental vaccines against hepatitis (Tam et at., Proc. Natl. Acad. Sci. USA 86: 9084, 1989), malaria (Tam et at., J. Exp. Med. 171: 299, 1990), and foot-and-mouth disease. A further advantage of MAPS is that they are chemically unambiguous. This allows different epitopes, such as B cell and T cell epitopes, to be arranged in a particular arrangement and stoichiometry.
Specific MAPS have been and are in development for use in immunization against HIV. For example, European Patent Publication No. 0 339 695 published 11 Feb. 1989 describes a process for preparing MAPS by reacting a branched structure based on an amino acid such as lysine or ornithine with a separately synthesized antigenic compound.
European Patent Publication No. 0 328 403, published 16 Aug. 1989 describes particular peptides that are specifically immunoreactive with antibodies to HIV and suggests that MAPS which include these peptides can be used for immunization to prevent HIV infection.
Hart et al. (J. Immunol., 145: 2677, 1990) report that a synthetic peptide construct which includes amino acids 428-443 and 303-321 of HIV-I-III, envelope protein gp120, when used as a carrier-free immunogen in primates, can induce a high titer of neutralizing anti-HIV antibodies and can induce T cell proliferative response against native HIV-1 gp120.
Palker et al. (Immunology 142: 3612, 1989) describes the use of a 16 amino acid T cell epitope from HIV-1-IIIB fused to a synthetic peptide which includes a type-specific neutralizing determinant of a particular HIV-1 strain (III. 1 MN or RF) to immunize goats. Both T cells and B cells responded to epitopes within the type-specific neutralizing determinant.
PCT Application Publication No. WO 90/11778 published 18 Oct. 1990 discloses multiple antigen peptide systems in which a large number of each of T cell and B cell malarial antigens are bound to the functional groups of a dendritic core molecule.
In Copending U.S. application Ser. No. 07/744,281, now abandoned, by Tam et al., a particular multiple antigen peptide is prepared for use as a vaccine for the treatment of HIV infection that incorporates particular peptides derived from the HIV-1 III.sub.B envelope protein as well as the V3 loop of the gp120 protein of HIV 1-MN. This peptide system demonstrates the capability of generating a humoral response and the development of antibodies, and seeks to elicit a T cell response by the inclusion of a T cell epitope. The in vivo administration of this peptide requires the inclusion of an adjuvant as a means of enhancing the humoral response.
More generally, most vaccine strategy developed today particularly against human immunodeficiency virus (HIV) infection has been directed toward the humoral response of generating neutralizing antibodies. Recent advances in mapping antigens involved in immune responses have allowed detailed characterizat
REFERENCES:
Defoort et al (1992) in Peptides Chemistry and Biology Proceedings of the Twelfth American Peptide Symposium Jun. 16-21, 1991, Cambridge, Massachussets, USA, ed by J. A. Smith et al, ESCOM, Leiden, pp. 845-846.
Huang et al (1992) Ibid pp. 847-848.
Nardelli et al (1992) Innovation and Perspectives in Solid Phase Synthesis, Epton ed, Collected papers, Second International Symposium, 27th-31st. Aug., 1991, Canterbury, England, Intercept-Limited, Andrew, pp. 241-249.
Chem. Abstract. 118(13) 29 Mar. 1993 #125070j on p. 869 of Nardelli et al. (1992) Innovation and Perspectives in Solid Phase Synthesis, Epton ed. Collected pprs. 2nd Int. Symp. Aug. 27-31/1991, Canterbury, Engl; Intercept Limited, Andover pp. 241-249.
Defoort et al (1992) Proc. Natl. Acad. Sci. USA 89(9): 3879-83.
Defoort et al (1992) International J. Peptide and Protein Res. 80 (3/4) pp. 214-221.
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