Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1994-07-05
2001-12-11
Huff, Sheela (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388150
Reexamination Certificate
active
06329508
ABSTRACT:
BACKGROUND
The capillaries that supply blood to the tissues of the brain constitute the blood brain barrier (Goldstein et al. (1986)
Scientific American
255:74-83; Pardridge, W. M. (1986)
Endocrin. Rev
. 7:314-330). The endothelial cells which form the brain capillaries are different from those found in other tissues in the body. Brain capillary endothelial cells are joined together by tight intercellular junctions which form a continuous wall against the passive movement of substances from the blood to the brain. These cells are also different in that they have few pinocytic vesicles which in other tissues allow somewhat unselective transport across the capillary wall. Also lacking are continuous gaps or channels running through the cells which would allow unrestricted passage.
The blood-brain barrier functions to ensure that the environment of the brain is constantly controlled. The levels of various substances in the blood, such as hormones, amino acids and ions, undergo frequent small fluctuations which can be brought about by activities such as eating and exercise (Goldstein et al, cited supra). If the brain were not protected by the blood brain barrier from these variations in serum composition, the result could be uncontrolled neural activity.
The isolation of the brain from the bloodstream is not complete. If this were the case, the brain would be unable to function properly due to a lack of nutrients and because of the need to exchange chemicals with the rest of the body. The presence of specific transport systems within the capillary endothelial cells assures that the brain receives, in a controlled manner, all of the compounds required for normal growth and function. In many instances, these transport systems consist of membrane-associated receptors which, upon binding of their respective ligand, are internalized by the cell (Pardridge, W. M., cited supra). Vesicles containing the receptor-ligand complex then migrate to the abluminal surface of the endothelial cell where the ligand is released.
The problem posed by the blood-brain barrier is that, in the process of protecting the brain, it excludes many potentially useful therapeutic agents. Presently, only substances which are sufficiently lipophilic can penetrate the blood-brain barrier (Goldstein et al, cited supra; Pardridge, W. M., cited supra). Some drugs can be modified to make them more lipophilic and thereby increase their ability to cross the blood brain barrier. However, each modification has to be tested individually on each drug and the modification can alter the activity of the drug. The modification can also have a very general effect in that it will increase the ability of the compound to cross all cellular membranes, not only those of brain capillary endothelial cells.
SUMMARY OF THE INVENTION
The present invention pertains to a method for delivering a neuropharmaceutical or diagnostic agent across the blood brain barrier to the brain of a host. The method comprises administering to the host a therapeutically effective amount of an antibody-neuropharmaceutical or diagnostic agent conjugate wherein the antibody is reactive with a transferrin receptor and the antibody is a chimera between the variable region from one animal source and the constant region from a different animal source. The conjugate is administered under conditions whereby binding of the antibody to a transferrin receptor on a brain capillary endothelial cell occurs and the neuropharmaceutical agent is transferred across the blood brain barrier in a pharmaceutically active form. Other aspects of this invention include a delivery system comprising an antibody reactive with a transferrin receptor linked to a neuropharmaceutical agent and methods for treating hosts afflicted with a disease associated with a neurological disorder.
In embodiments of the present invention, the antibody that is reactive with a transferrin receptor is a chimeric antibody. This antibody is composed of a variable region, immunologically reactive with the transferrin receptor, that is derived from one animal source and a constant region that is derived from an animal source other than the one which provided the variable region. The chimeric antibodies of this invention can exist either as isolated entities or as conjugates with a neuropharmaceutical agent for transferal across the blood brain barrier. In the latter mode, the chimeric antibody-neuropharmaceutical agent conjugate forms a delivery system for delivering the neuropharmaceutical agent across the blood brain barrier.
Presently available means for delivering therapeutic agents to the brain are limited in that they are invasive. The delivery system of the present invention is non-invasive and can utilize readily available antibodies reactive with a transferrin receptor as carriers for neuropharmaceutical agents. The delivery system is advantageous in that the antibodies are capable of transporting neuropharmaceutical agents across the blood brain barrier without being susceptible to premature release of the neuropharmaceutical agent prior to reaching the brain-side of the blood brain barrier. Further, if the therapeutic activity of the agent to be delivered to the brain is not altered by the addition of a linker, a noncleavable linker can be used to link the neuropharmaceutical agent to the antibody.
REFERENCES:
patent: 4292425 (1981-09-01), Buckler et al.
patent: 4434156 (1984-02-01), Trowbridge
patent: 4444744 (1984-04-01), Goldenberg
patent: 4545985 (1985-10-01), Pastan et al.
patent: 4569789 (1986-02-01), Blattler et al.
patent: 4626507 (1986-12-01), Trowbridge et al.
patent: 4631190 (1986-12-01), Shen et al.
patent: 4801575 (1989-01-01), Pardridge
patent: 4816567 (1989-03-01), Cabilly et al.
patent: 4892827 (1990-01-01), Pastan et al.
patent: 4902505 (1990-02-01), Pardridge et al.
patent: 4992255 (1991-02-01), Pardridge
patent: 5004697 (1991-04-01), Pardridge
patent: 5028697 (1991-07-01), Johnson et al.
patent: 5087616 (1992-02-01), Myers et al.
patent: 5091513 (1992-02-01), Huston et al.
patent: 5130129 (1992-07-01), Pardridge
patent: 5132405 (1992-07-01), Huston et al.
patent: 5141736 (1992-08-01), Iwasa et al.
patent: 5154924 (1992-10-01), Friden
patent: 5182107 (1993-01-01), Friden
patent: 0094844 (1983-11-01), None
patent: 0175560 (1986-03-01), None
patent: 0253202 (1988-01-01), None
patent: 0286418 (1988-10-01), None
patent: 0286441 (1988-10-01), None
patent: 0324625 (1989-07-01), None
patent: 0327169 (1989-08-01), None
patent: 0328147 (1989-08-01), None
patent: 0336383 (1989-10-01), None
patent: 0449769 (1991-10-01), None
patent: 1564666 (1980-09-01), None
patent: 86/01409 (1986-03-01), None
patent: 88/07365 (1988-10-01), None
patent: 91/03259 (1991-03-01), None
patent: 91/04753 (1991-04-01), None
patent: 91/09965 (1991-07-01), None
patent: 91/14438 (1991-10-01), None
Hoogenboom, H.R. et al., “Construction and Expression of Antibody-Tumor Necrosis Factor Fusion Proteins,”Molecular Immunology,28(9): 1027-1037 (Sep. 1991).
Trowbridge, I.S. et al., “Anti-transferrin Receptor Monoclonal Antibody and Toxin-antibody Conjugates Affect Growth of Human Tumour Cells,”Nature,294: 171-173 (Nov. 1981).
Zovickian, J. et al., “Potent and Specific Killing of Human Malignant Brain Tumor Cells by an Anti-Transferrin Receptor Antibody-Ricin Immunotaxin,”J. Neurosurg.,66: 850-861 (1987).
Raso, V. et al., “Monensin is Obligatory for the Cytotoxic Action of a Disulfide Linked Methotrexate-Anti-Transferrin Receptor Conjugate,”Biochem. Biophy. Res. Comm.,150(1): 104-110 (Jan. 15, 1988).
Alkan, S.S. et al., “Antiviral and Antiproliferative Effects of Interferons Delivered via Monoclonal Antibodies,”J. Interferon Res.,4(3): 355-363 (1984).
Capon, D.J. et al., “Designing CD4 Immunoadhesins for AIDS Therapy,”Nature,337: 525-531 (Feb. 9, 1989).
Pietersz, G.A. et al., “Novel Synthesis and in Vitro Characterization of Disulfide-Linked Ricin-Monoclonal Antibody Conjugates Devoid of Galactose Binding Activity,”Cancer Res.,48: 4469-4476 (Aug. 15, 1988).
Pietersz, G.A. et al., “The Use of Monoclonal Antibody Conjugates f
Alkermes, Inc.
Hamilton Brook Smith & Reynolds P.C.
Huff Sheela
LandOfFree
Transferrin receptor reactive chimeric antibodies does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transferrin receptor reactive chimeric antibodies, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transferrin receptor reactive chimeric antibodies will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2563820