Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1999-12-29
2004-03-09
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C435S320100
Reexamination Certificate
active
06703015
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to methods, agents and compositions for treating plaque-forming diseases, including, but not limited to, Alzheimer's disease. More particularly, these methods involve the use of (i) plaque derived antigens cloned and displayed on the surface of a display vehicle for in vivo elicitation of antibodies capable of preventing plaque formnation and of disaggregating existing plaques; and (ii) antibodies raised against plaque derived antigens, cloned and displayed on a display vehicle, and which are capable of preventing plaque formation and of disaggregating existing plaques. The present invention further relates to a method of targeting a display vehicle to the brain of an animal, including man.
Alzheimer's Disease—Clinical Overview:
Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. Broadly speaking, the disease falls into two categories: late onset, which occurs in old age (typically above 65 years) and early onset, which develops well before the senile period, e.g., between 35 and 60 years. In both types. of the disease, the pathology is similar, but the abnormalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neutrophils up to 150 mm across with extracellular amyloid deposits at the center, visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of tau protein consisting of two filaments twisted about each other in pairs.
Senile Plaques and Other Amyloid Plaques:
The principal constituent of the senile plaques is a peptide termed A&bgr; or beta-amyloid peptide (&bgr;AP). The amyloid beta peptide is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer's disease (See, e.g., Goate et al., Nature 349,704, 1991, valine
717
to isoleucine; Chartier Harlan et al. Nature 353, 844, 1991, valine
717
to glycine; Murrell et al., Science 254, 97, 1991, valine
717
to phenylalanine; Mullan et al., Nature Genet. 1, 345, 1992, a double mutation changing lysine
595
-methionine
596
to asparagine
595
-leucine
596
).
Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to beta-amyloid, particularly processing of APP to increased amounts of the long form of beta-amyloid (i.e., A&bgr;1-42 and A&bgr;1-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form beta-amyloid (see Hardy, TINS 20, 154, 1997). These observations indicate that beta-amyloid, and particularly its long form, is a causative element in Alzheimer's disease.
Amyloid deposits comprise a peptide aggregated to an insoluble mass. The nature of the peptide varies in different diseases but in most cases, the aggregate has a beta-pleated sheet structure and stains with Congo Red dye. In addition to Alzheimer's disease (AD), both late and early onset, other diseases characterized by amyloid deposits are, for example, SAA amyloidosis, hereditary Icelandic syndrome, multiple myeloma, and spongiform encephalopathies, including mad cow disease, Creutzfeldt Jakob disease, sheep scrapie, and mink spongiform encephalopathy (see, for example, Weissmann et al., Curr. Opin. Neurobiol. 7, 695-700, 1997; Smits et al., Veterinary Quarterly 19, 101-105, 1997; Nathanson et al., Am. J. Epidemiol. 145, 959-969, 1997).
The peptides forming the aggregates in these other diseases are serum amyloid A, cystantin C and IgG kappa light chain, respectively, for the first three, and prion protein for the others.
Other peptides or proteins with evidence of self aggregation are also known, such as, but not limited to, amylin (Young A A. et al., 1994, FEBS Lett, 343(3);237-41); bombesin, caerulein, cholecystokinin octapeptide, eledoisin, gastrin-related pentapeptide, gastrin tetrapeptide, somatostatin (reduced), substance P; and peptide, luteinizing hormone releasing hormone, somatostatin N-Tyr (Banks and Kastin, Prog Brain Res., 91:139-4, 1992).
Treatment:
U.S. Pat. No. 5,688,561 to Solomon teaches methods of identifying monoclonal antibodies effective in disaggregating protein aggregates and preventing aggregation of such proteins. Specifically, U.S. Pat. No. 5,688,561 demonstrates anti-beta-amyloid monoclonal antibodies effective in disaggregating beta-amyloid plaques and preventing beta-amyloid plaque formation in vitro. U.S. Pat. No. 5,688,561 stipulates the in vivo use of such antibodies to prevent plaque formation by aggregation of beta-amyloid or to disaggregate beta-amyloid plaques which have already formed. These teachings do not, however, identify an epitope to be employed to generate such antibodies. In addition, these teachings do not provide means with which to enable the penetration of such antibodies into the brain through the blood brain barrier (BBB). Furthermore, this patent fails to teach the use of phage display technology as a delivery method for antigens or antibodies. Yet furthermore. no experimental results demonstrating the in vivo effectiveness of such antibodies are demonstrated by U.S. Pat. No. 5,688,561.
EP 526511 by McMichael teaches administration of homeopathic dosages (less than or equal to 10
−2
mg/day) of beta-amyloid to patients with pre-established AD. In a typical human with about 5 liters of plasma, even the upper limit of this dosage would be expected to generate a concentration of no more than 2 pg/ml. The normal concentration of beta-amyloid in human plasma is typically in the range of 50-200 pg/ml (Seubert et al., Nature 359, 325-327 1992). Because this proposed dosage would barely alter the level of endogenous circulating beta-amyloid and because EP 526511 does not recommend the use of an adjuvant, it seems implausible that any therapeutic benefit would result therefrom.
PCT/US98/25386 by Schenk and a Nature paper by Schenk et al. (Nature, 400:173-177, 1999) teach administration of beta-amyloid immunogens to a patient in order to generate antibodies to prevent formation of plaques or dissolve existing plaques. According to Schenk, 50 to 100 mg of antigen are required, 1 to 10 mg if an adjuvant is employed. These teachings also stipulate that a similar effect may be achieved by direct administration of antibodies against beta-amyloid, in both cases disregarding the blood brain barrier which, under normal circumstances, prevents the penetration of antibodies into the brain.
It is also important to note that these teachings are typically restricted to the use of “ . . . any of the naturally occurring forms of beta-amyloid peptide, and particularly the human forms (i.e., A&bgr;39, A&bgr;40, A&bgr;41, A&bgr;42 or A&bgr;43)” or “ . . . longer polypeptides that include, for example, a beta-amyloid peptide, active fragment or analog together with other amino acids”, or “multimers of monomeric immunogenic agents”.
These teachings ignore, however, earlier data teaching that the first 28 amino acids of beta-amyloid are sufficient to elicit antibodies which both disaggregate and inhibit aggregation of beta-amyloid plaques in vitro (Hanan and Solomon, Amyloid: Int. J. Exp. Clin. Invest. 3:130-133, 1996; Solomon et al., Proc. Natl. Acad. Sci. U.S.A. 93:452-455, 1996; Solomon et al., Proc. Natl. Acad. Sci. U.S.A. 94:4109-4112, 1997).
Schenk and Schenk et al. both fail to teach the use of the N-terminal epitope of beta-amyloid plaques which is known to be a sequential epitope composed of only four amino acid residues (EFRH, SEQ ID NO:1) located at positions 3-6 of the beta-amyloid peptide (Frenkel D., J. Neuroimmunol., 88:85-90,1998). Antibodies against this epitope have subsequently been shown to disaggregate beta-amyloid fibrils, restore beta-amyloid plaques solubiliz
Frenkel Dan
Solomon Beka
Browdy and Neimark , P.L.L.C.
Crouch Deborah
Ramot at Tel-Aviv University Ltd.
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