Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-12-20
2001-09-18
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S955000, C514S960000, C530S300000, C530S311000, C530S324000, C424S422000, C424S464000, C424S468000
Reexamination Certificate
active
06291428
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to peptides capable of promoting the attraction and adhesion of bone-forming cells, to promote bone ingrowth, osseointegration, and healing in surgical procedures involving bone and bone implants, including teeth.
BACKGROUND OF THE INVENTION
The use of surgical prosthetic devices, otherwise known as implants, is well known in various surgical applications, such as reconstructive surgery, for example, in the replacement of hip joints or the like. Use of surgical prosthetic devices such as plates, nails, pins, screws, and specially formed parts are commonly implanted into the skeletal structure of animals for the replacement of missing structural parts, or as permanent anchoring devices for maintaining a fixed relationship between the portions of a fractured bone. Rapid integration of these devices with the patient's natural bone, referred to as osseointegration, is desired, so that the strength of the interface is rapidly and maximally achieved. This reduces healing time, recovery time, and failure rate of the implant. These principles also apply to dental implants.
The application of cell adhesion domains (such as the RGD motif) to tissue engineering has become a subject of intense interest. The RGD (argininyl-glycinyl-aspartyl or Agr-Gly-Asp) tripeptide sequence (found in extracellular matrix clycoproteins such as type I collagen, bone sialoprotein [BSP], osteopontin, osteonectin, vitronectin, fibronectin, etc.) binds to cell surface integrins such as &agr;
5
&bgr;
3
(reviewed by Butler, Connect. Tissue Res., 23:123-136, 1989 and Butler, J. Biol. Buccale, 19:83-89, 1991). Certain of these proteins may participate by acting as a seed or regulator of mineral crystal growth and/or by directing cells and their associated functions to specific sites within the tissue. The presence of the tripeptide sequence RGD, the distribution of these proteins, and their association with mineral suggest that these phosphoproteins may have a multifunctional role during mineralized tissue formation whereby they may, firstly, initiate and regulate mineralization, and secondly, direct dynamics by mediating cell attachment to the matrix (McKee et al., Anat. Rec., 234:479-492, 1992 and McKee et al., J. Bone Miner. Res., 8:485-496, 1992).
It is towards the identification of peptides capable of promoting bone mineralization and osseointegration of bone implants that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
In its broadest aspect, the invention is directed to the peptide YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) and fragments of YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) which include at least the sequence GEPRGD (SEQ ID NO;1). Thus, peptides of the invention may have the basic structure X
1
EPRGX
2
(SEQ ID NO:198), where X
1
is YESENG (SEQ ID NO:181) or any C-terminal segment thereof, and X
2
is DNYRAYEDEYSYFKG (SEQ ID NO:182)or any N-terminal segment thereof Selections of X
1
therefore include
1
EPRGDNYRAY(SEQ ID NO:181), ESENG (SEQ ID NO:184), SENG (SEQ ID NO:185), ENG, NG, or G. Selections of X
2
include DNYRAYEDEYSYFKG (SEQ ID NO:182), DNYRAYEDEYSYFK (SEQ ID NO:187), DNYRAYEDEYSYF (SEQ ID NO:188), DNYRAYEDEYSY (SEQ ID NO:189), DNYRAYEDEYS (SEQ ID NO:190), DNYRAYEDEY (SEQ ID NO:191), DNYRAYEDE (SEQ ID NO:192), DNYRAYED (SEQ ID NO:193), DNYRAYE (SEQ ID NO:194), DNYRAY (SEQ ID NO:195), DNYRA (SEQ ID NO:196), DNYR (SEQ ID NO:197), DNY, DN, or D. X
1
and X
2
may be independently selected from the aforementioned selections.
Preferred peptides include GEPRGD (SEQ ID NO:1), ENGEPRGDNY (SEQ ID NO:2), YESENGEPRGDNYRAY (SEQ ID NO:3) and YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4).
The aforementioned peptides may include at least one conservatively-substituted amino acid other than in the RGD sequence.
In another aspect of the invention, the peptides may have a C-terminal amide group. Thus, the invention embraces the peptide YESENGEPRGDNYRAYEDEYSYFKGamide (SEQ ID NO:8) and fragments of YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) which include at least the sequence GEPRGD (SEQ ID NO:1), and have a C-terminal amide. Thus, peptides of the invention may have the basic structure X
1
EPRGX
2
amide (SEQ ID NO:199), where X
1
is YESENG (SEQ ID NO:181) or any C-terminal segment thereof, and X
2
is DNYRAYEDEYSYFKG (SEQ ID NO:182) or any N-terminal segment thereof. Selections of X
1
therefore include (SEQ ID NO:181), ESENG (SEQ ID NO:184), SENG (SEQ ID NO:185), ENG, NG, or G. Selections of X
2
include DNYRAYEDEYSYFKG (SEQ ID NO:182), DNYRAYEDEYSYFK (SEQ ID NO:187), DNYRAYEDEYSYF (SEQ ID NO:188), DNYRAYEDEYSY (SEQ ID NO:1889), DNYRAYEDEYS (SEQ ID NO:190), DNYRAYEDEY (SEQ ID NO:191), DNYRAYEDE (SEQ ID NO:192), DNYRAYED (SEQ ID NO:193), DNYRAYE (SEQ ID NO:194), DNYRAY (SEQ ID NO:195), DNYRA (SEQ ID NO:196), DNYR (SEQ ID NO:197), DNY, DN, or D. X
1
and X
2
may be independently selected from the aforementioned selections.
The aforementioned peptides may include at least one conservatively-substituted amino acid other than in the RGD sequence.
Preferred embodiments include GEPRGDamide (SEQ ID NO:5), ENGEPRGDNYamide (SEQ ID NO:6), YESENGEPRGDNYRAYamide (SEQ ID NO:7) and YESENGEPRGDNYRAYEDEYSYFKGamide (SEQ ID NO:8).
In another aspect, the invention is directed to a pharmaceutical composition comprising the peptide YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4), fragments of the sequence YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) comprising at least the sequence GEPRGD (SEQ ID NO:1), or any of the foregoing peptides comprising at least one conservative amino acid substitution other than in the RGD sequence; and a pharmaceutically acceptable carrier. Such peptides may include a C-terminal amide group. The carrier may be for example a gel or matrix, such as by way of non-limiting example polymcthylmethacrylate, polylactide/polyglycolide, gelatin, or demineralized bone matrix. The peptide may be covalently bound to the carrier. The pharmaceutical composition may further include a growth factor, such as a bone morphogenetic protein. Non-limiting examples of such pharmaceutical compositions comprising the peptide include GEPRGD (SEQ ID NO:1), ENGEPRGDNY (SEQ ID NO:2), YESENGEPRGDNYRAY (SEQ ID NO:3) or YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4), or a C-terminal amide of any of the foregoing, such as GEPRGDamide (SEQ ID NO:5), ENGEPRGDNYamide (SEQ ID NO:6), YESENGEPRGDNYRAYamide (SEQ ID NO:7) or YESENGEPRGDNYRAYEDEYSYFKGamide (SEQ ID NO:8).
In another aspect, the invention is directed to a composition for promoting bone mineralization comprising a bone matrix implant material and at least one peptide that is YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4), a fragment of YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) comprising at least GEPRGD (SEQ ID NO:1), or any of the foregoing peptides which have at least one conservative amino acid substitution. Examples of suitable peptides, including those with C-terminal amide groups, arc as described hereinabove. The implant material may be a titanium, demineralized bone matrix, coral bone substitute, or biopolymers. The composition may be coated on the implant material, or covalently bound to the implant material.
In a still further aspect of the invention, a method for promoting the mineralization of bone at a site within the body is provided, comprising administering to the site a pharmaceutical composition comprising the peptide YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4), a fragment of YESENGEPRGDNYRAYEDEYSYFKG (SEQ ID NO:4) comprising at least GEPRGD (SEQ ID NO:1), or any of the foregoing peptides comprising at least one conservative amino acid substitution other than in the RGD sequence. The peptide may have a C-terminal amide group. The body may be an animal; vertebrate animals are preferred and humans most preferred. The aforementioned method may be used for a treatment such as but not limited to fracture repair, promoting bone ingrowth into a prosthesis, or promoting the integra
Boskey Adele
Macaulay William B.
Merrifield Elizabeth
Carlson Karen Cochrane
Klauber & Jackson
Robinson Patricia
The Hospital for Special Surgery
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