Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1998-10-20
2001-04-03
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S277100
Reexamination Certificate
active
06210672
ABSTRACT:
BACKGROUND OF THE INVENTION
The body's first line of defense against pathogens is the skin. The outermost layer, the stratum corneum, is a broad zone of 20 to 30 cell layers thick. The dead cell remnants which comprise the stratum corneum are almost completely filled with keratin fibrils and surrounded by highly ordered lipid bilayers. As long as the epidermis is unbroken, the heavily keratinized stratum corneum presents a formidable physical barrier to entry for most foreign substances. The mucous membranes which line the digestive, respiratory, urinary and reproductive tracts, provide a similar, but less formidable physical barrier, lacking the thick stratum corneum.
The epithelium of both skin and mucous membranes is richly populated with immature dendritic cells, called Langerhans cells. These phagocytic leukocytes are poised for capture of antigens which may enter the epidermis through physical breaches in the stratum corneum. After physical trauma to the skin, signals are generated that induce Langerhans cells to leave the epidermis and migrate into the dermis and through afferent lymphatics to lymph nodes, carrying with them any antigens which had penetrated the protective stratum corneum (i.e. viral, bacterial, parasitic, allergic). Very small, lipophilic molecules, and some highly reactive molecules known as skin sensitizing agents, such as TNCB, poison ivy catechol, oxazolone, etc., may penetrate the intact stratum corneum, subsequently binding to proteins in the underlying epidermis and activating Langerhans cells.
Captured protein antigens are internalized and degraded by the Langerhans cells to yield small peptides which are incorporated into the peptide binding grooves of MHC molecules. The MHC-peptide complexes are then inserted into the plasma membranes for presentation to T cell receptors. During their migration to the lymph nodes, the Langerhans cells differentiate into mature dendritic cells, losing their phagocytic properties and instead, expressing high levels of MHC class I and II molecules as well as costimulatory and adhesion molecules, essential for effective antigen presentation (Udey,
Clin. Exp. Immunol.
107:6-8, 1997). While it is now well known that Langerhans cells migrate from the epithelium to the T cell areas of the draining lymph nodes, relatively little is known about the signals which induce migration and differentiation of the Langerhans cells. In any event, once in the lymph nodes, the differentiated Langerhans cells bearing MHC-peptide complexes activate primary CD4+ helper T cells and CD8+ cytolytic T cells. These newly differentiated Langerhans cells which are recent immigrants to the lymph nodes are the most potent inducers of T cell immunity known.
It has recently been demonstrated that mouse or human dendritic cells exposed to tumor antigens or peptides are effective inducers of tumor-specific immunity that can eliminate or suppress even established tumors (Young and Inaba,
J Exp. Med.
183:7-11, 1996; Zitvogel et al.,
J. Exp. Med
183:87-97, 1996; Celluzzi et al.,
J. Exp. Med
183:283-287, 1996; and Paglia et al.,
J. Exp. Med
183:317-322, 1996; incorporated herein by reference). In these studies, dendritic cells from bone marrow or blood were harvested, expanded in tissue culture, exposed to tumor antigens in vitro, and finally re-injected into the donor. Such individualized therapy is necessary in an outbred population to ensure that the appropriate, syngeneic MHC molecules are used for an individual's T cells and target tumor cells. While highly effective, this individualized procedure is too cumbersome, time consuming and costly to be a broadly applicable therapeutic measure.
SUMMARY OF THE INVENTION
A topical vaccination procedure is disclosed for enhancing an immune response against an antigen. Antigens from tumors, viral and bacterial pathogens, as well as parasites are encompassed within the scope of the present invention. The method involves administering the antigen in conjunction with: 1) a means for enhancing penetration of the antigen through the skin or mucous membranes, and 2) an agent for inducing Langerhans cell migration to the lymph nodes. The antigen is preferably a peptide of 3-20 amino acid residues in length, but can be any length that the Langerhans cell can process or insert into an MHC binding groove and which a T cell can recognize. The antigen is preferably administered at a concentration range of about 1 &mgr;g/ml to about 100 mg/ml.
Means for enhancing penetration of the antigen include, use of a lipophilic vehicle or penetration enhancer, such as dimethylsulfoxide (DMSO) or azone, low frequency ultrasound, electroporation, iontophoresis, intraepidermal delivery, and combinations thereof. Preferably, peptide penetration of the stratum corneum is facilitated by dimethylsulfoxide in combination with one of the physical transdermal delivery means.
Agents which induce Langerhans cell migration are selected from the group consisting of dibutylphthalate, dibutyl-D-tartarate, N,N-diethyl-toluamide, dibutylfumarate, di(2-ethylhexyl)fumarate, diisooctylmaleate, diethylhexylmaleate, diisooctylfumarate, benzoic acid, benzalkoniumchloride, camphor, bihenylmaleate, dioctylphthalate, dibutylmaleate, dioctymaleate, dibutylsuccinate, dioctylsuccinate, dinonylphthalate, diisononylphthalate, dimethylphthalate, diethylphthalate, dipropylphthalate, diphenylphthalate, dibenzylbutylphthalate, and diethylmethylphthalate. Low frequency ultrasound may also be employed as an inducer of Langerhans cell migration. Preferably, dibutylphthalate is administered to induce Langerhans cell migration.
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Christina Celluzzi, et al., Peptide-Pulsed Dendritic Cells Induce Antigen-specific CTL-Mediated Protective Tumor Immunity, J. Exp. Med., vol. 183, pp. 283-287 (1996).
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Huff Sheela
Knobbe Martens Olson & Bear LLP
Torrey Pines Institute For Molecular Studies
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