Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Reexamination Certificate
1998-06-11
2001-02-27
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
C530S327000, C530S328000, C530S329000, C530S330000, C530S332000, C514S002600, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06194543
ABSTRACT:
BACKGROUND OF THE INVENTION
Tam et al. in
Proc. Natl. Acad. Sci. USA
(1985) 85, 5409 5413 describe a compound including a dendritically linked polylysine component, to the focal lysine of which is attached a lipophilic moiety, through a peptide bond to the carboxylic acid group of that lysine unit. To the terminal branches of the dendritic moiety there may be attached peptide antigens to provide an active ingredient for a vaccine having improved antigenicity.
In WO-A-94/02506, Toth et al describes an improvement of Tam's invention, in which the anchor component is formed from lipophilic amino acids. This allows the compound to be synthesized using conventional solid state peptide synthetic techniques, in the first stages of which the lipophilic amino acids are linked to form, for instance, a three unit linear oligo peptide, a focal lysine unit is joined to the final lipophilic amino acid and the dendritic core moiety is then linked to the two amine groups of the focal lysine unit. The peptide antigens may subsequently be synthesized directly onto the terminal branches of the dendritic core, all the steps being carried out without cleavage of the polypeptide from the solid substrate carrier. The synthetic process used to make Toth et al's product required the use of starting amino acid reagents with the same protecting group blocking the two amine groups of lysine reagents. Consequently during the steps in which the dendritic component is synthesized, the same reagent is added to each of the amine moieties.
In the product of Toth et al, it was essential for the lipidic amino acids to be joined directly to one another by peptide bonds, and that a lipidic amino acid can be joined to a carrier substrate so that synthesis involves linkage of that until LO the carrier by a peptide bond and linkage of another lipid amino acid unit to the dendritic moiety by a peptide bond. Consequently solid state peptide synthesis methods can be used to conjugate each of the components of the final product to one another. By contrast, in Tam et al, whilst the dendritic polylysine and the peptide antigen can be synthesized using solid state peptide synthetic methods, the polylysine-polyantigen compound must be cleaved from the carrier substrate prior to conjugation to the lipophilic anchor moiety, through the carboxylic acid unit of the focal lysine group. The reagent, from which Tam's lipophilic anchor is synthesized, has only one reactive group.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to polypeptide compounds which have dendritically linked units formed from amino acids having reactive groups, for instance carboxylic acid or amine groups, in their side chains. Each molecule comprises two dendrons. To at least two of the terminal branches of one of the dandrons there are attached anchor groups, each of which comprises at least one lipophilic group. The terminal units of the at least one other dendron may be unconjugated or may be conjugated to ligons of various types. The dendrons are attached at a core which may include a linear oligo peptide, optionally having pendant sugar molecules.
REFERENCES:
patent: 4289872 (1981-09-01), Denkewalter
patent: 5114713 (1992-05-01), Sinigaglia
patent: 5338532 (1994-08-01), Tomalia
patent: 5488126 (1996-01-01), Subramanian
patent: 5580563 (1996-12-01), Tam
patent: 5795582 (1998-08-01), Wright
patent: WO89/10348 (1989-11-01), None
patent: WO93/22343 (1993-11-01), None
patent: WO94/02506 (1994-02-01), None
patent: WO94/11015 (1994-05-01), None
patent: WO95/00540 (1995-01-01), None
CRS Symposium, Las Vegas, Jun. 21-25, 1998; A Dendrimer Carrier; Preliminary Investigations on Biodistribution and Stability; T. Sakthivel, A.T. Florence and I. Toth.
EUFEPS Conference, Milan, Italy, Sep. 11-13, 1998; Oral Absorption of a Novel Dendrimer Carrier; T. Sakthivel, A.T. Florence and I. Toth.
2nd European Workshop on Particulate Systems Paris, May 22-23, 1998 An Investigation into Novel Lipidic Dendrimer Carrier; T. Sakthivel, I. Toth and A.T. Florence.
“A Novel Chemical Approach to Drug Delivery: Lipidic Amino Acid Conjugates”; Istvan Toth; Journal of Drug Targeting; 1994; vol. 2, pp. 217-239.
“Immunogenicity Evaluation of a Lipidic Amino Acid-Based Synthetic Peptide Vaccine for Chalamydia Tracomatis”; Guangming Zhong, et al.;The Journal of Immunology; vol. 151, 3728-3736; No., 7; Oct. 1, 1993.
“Macromolecular Assemblage in the Design of a Synthetic AIDS Vaccine”; Jean-Philippe DeFoort, et al.;Proc. Natl. Acad, Sci. USA; vol. 89; pp. 3879-3883; May 1992 (Biochemistry).
“Synethic Peptide Vaccine Design: Synthesis and Properties of a High-Density Multiple Antigenic Peptide System”: James P. Tam;Proc. Natl. Acad. Sci. USA;vol. 85 pp. 5409-5413; Aug. 1998 (Biochemistry).
Florence Alexander T.
Sakthivel Thiagarajan
Toth Istvan
Wilderspin Andrew F.
Low Christopher S. F.
Lukton David
Ostrolenk Faber Gerb & Soffen, LLP
The school of Pharmacy University
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