Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1998-08-20
2003-08-19
Wortman, Donna (Department: 1648)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S204100, C424S234100, C424S265100, C424S279100, C424S282100, C424S283100
Reexamination Certificate
active
06607732
ABSTRACT:
The present invention relates to Immunogenic complex in the form of ISCOM™ (complexes as described for example in U.S. Pat. No. 4,578,269) and/or ISCOM™ matrix (complexes as described for example in U.S. Pat. No. 5,679,354) and mucus targeting molecules for use for preparing vaccines and immune stimulating compositions for oral, nasal, urogenital and/or rectal administration.
Immunization strategies have been available for many years. However, there has been a remarkable lack of success in vaccination to control mucosal diseases. Earlier findings indicate that antigen presentation of non-replicating antigens via the mucosal surface is an inefficient means of immune response stimulation and that novel strategies are required in this route (Novel vaccination strategies for the control of mucosal infection, Alan J. Husband, Vaccine, Vol. 11, Issue 2, 107-112). Vaccination with living attenuated microorganisms has been the only possible way of protection against mucosal diseases.
It has now unexpectedly been shown that ISCOMs™ containing, and ISCOM™ matrix mixed with, mucosal targeting molecules or antigens give raise to high titers of antibodies when administered to mucosas. Moreover ISCOMs™, containing such mucosal targeting molecules together with antigens which do not readily immunize by the mucosal mode of administration (so called passenger antigens), give raise to an immune response even in several other mucosals remote from the site of administration.
The mucosal targeting molecules have the capacity to target the lymphatic system following mucosal administration. They may be antigens which assist passenger antigens in inducing immune response and often, they will also induce immune response to themselves. In a complex mixture of antigens, some may exhibit a capacity for being target molecules for passenger molecules as well as for themselves. The strategy of using a mixture of two or more components also involves the prospect of modulating the ensuing immune response to itself as well as to passenger antigens. The modulatory effect is particularly prominent in iscom formulations with targeting molecules exemplified by IgG2a enhancement, as well as the capacity for iscoms to enhance conversion of the mucosal antibody response to IgA in mucus which is best illustrated by the enhancing effect on the IgA response to CTB. ISCOM™-matrix simply added to other antigens and mixed as a separate entity has similar properties as well as but they are often less prominent.
BACKGROUND
Lipid-containing and quillaja saponin-containing structures such as ISCOMs™ (immunostimulating complexes) and ISCOM™-matrices have been reported to be effective carriers of pharmacologically and/or immunologically active substances or molecule complexes. See for example WO-A1-90/03184. In many cases, parenteral immunization of laboratory animals with structures incorporating different antigens has been demonstrated to give rise to a stronger immune response against the antigens at issue than that which is obtained after immunization with the corresponding antigen(s) in a free form.
ISCOMs™ are documented to be effective carriers in enhancing the immunogenicity of small and large molecules (antigens) using parenteral administration. It has been shown that iscoms with incorporated antigens, such as protein, according to EP 0 109 942, and ISCOMs™ that are carriers for small molecules, such as small antigens and oligopeptides, according to EP 0 180 564, effectively evoke immune response toward both large and small molecules.
It has also been shown that protein antigen, such as ovalbumin (OVA), in ISCOM™ is able to evoke immune response even after oral immunization that includes antibody formation, T-helper cells under MHC class-2 restriction and cytotoxic T-cells (CTL) (killer cells) under MHC class 1-restriction, but that several immunizations are required (and unrealistically high doses) (Morein, B., Lovgren, K., Ronnberg, B. Clin. Immunother. 3, 461-75, 1995). On the contrary, after giving large doses (hundreds or several hundreds of &mgr;g per dose of ovalbumin orally in free form, ie unincorporated in iscom), there is either no immune response or a low one. Free ovalbumin gives rise to tolerance and suppression to a subsequent parenteral immunization.
ISCOM™-matrices (and ISCOM™ have well-documented, built-in adjuvant activity that evokes antibody-mediated and cell-mediated immune response. Cell-mediated immune responses under both class 1 and class 2 MHC-restrictions are evoked by ISCOMs™.
In comparison to parenteral immunization, the immune response after oral and intranasal administration of ISCOMs™ has been low (Mowat et al, Immunology 72, 317-322 (1991); Mowat et al., Immunology, 80, 527 (1993)). Moreover, in applying intranasal and oral immunizations, certain antigens that are incorporated in ISCOM™, such as the g-protein of the rabies virus or gp 120/160 of HIV-1, have not evoked measurable immune response in the form of serum antibody response measured in ELISA. In all likelihood this is due to the fact that only a small number of the perorally or intranasally administered particles can penetrate the mucous layer, be absorbed by the intestinal epithelium barrier or M-cells of Peyers patches and there come in contact locally with the immune system.
Problems involving limited absorption and insufficient antigen presentation caused by the inability of antigens to penetrate the mucous barrier and target antigen presenting cells (APC), lymphatic tissue and/or the epithelium layer, eg Peyer's patches (PP) or Lamina propria (LP) in the intestines, or lymphatic tissues in the tonsil region in the pharynx or other mucous-coated surfaces. Mucosal immune response will generally only occur when mucosal administration is carried out locally. ISCOMs™, like other antigen-presented structures, have a limited ability to penetrate mucus, and, in varying degrees, a limited ability to bind and be absorbed by the epithelium, or to reach and be absorbed by M-cells in PP to thereafter be forwarded to antigen-presented cells (APC) and to stimulate lymphocyte populations. Even when administration is done into the nasal mucosa, the targeting and antigen uptake by APC and the induction of the immune response is insufficient when using current technology. CT and LT have been used as mucus targeting molecules but due to high toxicity those are not suitable for use in man and animals. The B-subunit of these toxins are not toxic but very much less effective and for that reason not practically suitable for prophylactic or clinical use. There is thus a need for better presentation systems for antigens that are intended for use in oral or nasal administration. An important reason why there is this need for better antigen-presenting systems that are effective in administration via mucosal membranes is that this kind of administration evokes a local immune response in the membranes. Although it is known that common lymphatic systems exist where immunization e.g. in the gut will result in immune responses in remote mucosal surfaces via gut associated lymphatic tissue (GALT) or immunization in the respiratory tract with result in immune response in other mucosal surfaces via broncho-associated lymphatic tissue (BALT) these responses are generally low and mucus targeting molecules or antigen presenting systems promoting remote mucosal targeting is not particularly defined. A number of infections occur via mucosal membranes in places like the respiratory passages, the intestinal tracts or the genital tract, and a first immune defence barrier exists in the mucosal membranes. Moreover, both oral and nasal administrations in contrast to parenteral administration by injection have the advantage of not requiring medically-trained personnel.
SUMMARY OF THE INVENTION
The invention relates to Immunogenic complex in the form of ISCOM™ and/or ISCOM™ matrix and mucus targeting molecules for use for preparing vaccines and immune stimulating compositions for oral, nasal, urogenital and/or rectal administration.
It has been shown that by using
Bengtsson Karin Lovgren
Ekstrom Jill
Morein Bror
Wortman Donna
Young & Thompson
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