Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-08-30
2003-04-22
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650, C424S009100, C530S330000
Reexamination Certificate
active
06551574
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tuftsin receptor-specific peptide constructs which are conformationally fixed on complexation with a metal ion. The constructs, which may be peptidomimetic in nature, are useful in pharmaceutical and radiopharmaceutical applications.
Throughout this application, various publications are referred to, each of which is hereby incorporated by reference in its entirety into this application to more fully describe the state of the art to which the invention pertains.
BACKGROUND OF THE INVENTION
Tuftsin Receptor Peptide Construct. Ser. No. 08/660,697 teaches certain locally restricted peptides, in which the biological-function domain and metal-peptide backbone are combined, and the biological-function domain is specific for the tuftsin receptor found on polymorphonuclear (PMN) granulocytes, monocytes and macrophages.
Native tuftsin is a tetrapeptide of the sequence Thr-Lys-Pro-Arg (SEQ ID NO.1), located as residues 289-292 of the Fc region of the heavy chain of leukokinin (a cytophilic &ggr;-globulin). It is liberated by a combination of two cleavages. The C-terminal peptide bond is cleaved in the spleen by splenic enzyme and subsequent cleavage of the N-terminal peptide bond by enzyme leukokininase which occurs on the membranes of the granulocytes where it acts to stimulate phagocytosis. The tuftsin sequence stimulates macrophages and polymorphonuclear granulocytes towards phagocytosis. This sequence thus has a role in the immune system response for fighting infections and bacteria and other invasions. There are specific tuftsin receptors present on granulocytes and macrophages. The receptor density is approximately 50,000-100,000 per cell, with the receptor-tuftsin complex reported to internalize after binding. Thus a peptide specific for the tuftsin receptor may be used in the treatment of certain diseases, as is disclosed generally in U.S. Pat. No. 4,390,528 to V A Najjar and U.S. Pat. No. 5,028,593 to K Nishioka, the teachings of which are incorporated herein by reference.
The '697 application teaches a precursor peptide, incorporating both a metal ion-binding backbone and a tuftsin receptor-specific biological-function domain, which tuftsin receptor-specific domain is biologically active only on labeling or complexing the metal ion-binding backbone with a metal ion, of the following general formula:
R
1
-Aaa-Bbb-Ccc-Ddd-Eee-R
2
Where:
Aaa
=
L- or D-configuration residue selected from Thr,
Cys, Pen, Pro, or Ser and corresponding des-amino
derivatives.
Bbb
=
L- or D-configuration residue with a positively
charged side chain, and containing an N for metal
ion complexation, such as Arg, Lys, Orn, homoArg,
S-(2-aminoethyl)Cys, O-(2-aminoethyl)Ser and
other similar basic amino acids, and derivatives
thereof.
Ccc
=
L- or D-configuration residue with an un-charged
side chain, and containing an N for metal ion
complexation, such as Gly, Ala, Aib, Val, Nle, Leu
and similar amino acids with un-charged side
chains.
Ddd
=
L- or D-configuration residue, providing an S, and
preferably an S and N, for metal ion complexation,
or alternatively two Ns for metal ion complexation,
such as Cys, HomoCys, Pen, His and other synthetic
or derivatized amino acids.
Eee
=
L- or D-configuration residue with a positively
charged side chain, such as L- or D-isomers of Arg,
Lys, Orn, homoArg, S-(2-aminoethyl)Cys, O-(2-
aminoethyl)Ser and other similar basic amino acids,
and their corresponding des-carboxyl derivatives. A
similar aliphatic or aromatic chain with a basic
functional group can also be substituted.
R
1
=
H, alkyl, aryl, alkylcarbonyl, arylcarbonyl,
alkyloxycarbonyl, aryloxycarbonyl, or a polymer
such as PEG, PVA, or polyamino acid, attached
directly or through a carbonyl group. R
1
does not
exist if Aaa is a des-amino amino acid.
R
2
=
amide, substituted amide, ester, or a polymer such
as PEG, PVA, or polyamino acid. R
2
does not exist
if Eee is a des-carboxyl amino acid.
One representative peptide from this series was the sequence Thr-D-Lys-Gly-D-Cys-Arg (SEQ ID NO.2). This peptide displayed very high affinity (K
D
=1-5 nM) for human leukocytes after its binding to reduced TcO[V]. When complexed to radioactive
99m
TcO[V], the peptide localizes to the site of inflammation or infection on i.v. administration. The affinity of the peptide which is not complexed to a metal ion is on the order of K
D
=10
−4
M.
The structure of the Thr-D-Lys-Gly-D-Cys-Arg (SEQ ID NO.2) peptide after binding to technetium is as follows:
The '697 application teaches that this peptide can similarly be labeled with Re, and that similar peptides can also be designed and synthesized using an N
4
metal ion-binding domain, such as Thr-D-Lys-Gly-D-His-Arg (SEQ ID NO.3). Tuftsin receptor-specific peptides disclosed in '697 include Thr-D-Lys-Gly-D-Cys-Arg (SEQ ID NO.2), Thr-D-Lys-Gly-D-His-Arg (SEQ ID NO.3) and Pro-D-Lys-Gly-D-Cys-Arg (SEQ ID NO.4).
The peptides taught in '697 may be complexed with a non-radioactive ionic form of rhenium or another suitable isotope, thereby creating a non-radioactive metallopeptide drug for the treatment of disease. Such peptides may also be radiolabeled with a diagnostic metal ion, such as
99m
Tc, and used to determine sites of concentration of granulocytes and macrophages, such as infections and inflammations, or radiolabeled with a therapeutic metal ion, such as
186
Re or
188
Re, and used in the treatment of disease.
In addition, tuftin has analgesic and other central nervous system effects. See, e.g., Herman et al., “Central Effects of Tuftsin,” in
Antineoplastic, Immunogenic and Other Effects of the Tetrapeptide Tuftsin: a Natural Macrophage Activator,
Najjar V A and Freidkin M, eds., New York Academy of Sciences, 1983 [hereinafter
Antineoplastic],
156-163; Paradowski et al., “The Influence of Tuftsin on Blood Pressure in Animals,” in
Antineoplastic,
164-167; Fridkin and Najjar,
Crit. Rev. Biochem. Med. Biol.,
24 (1989). Herein disclosed are novel peptides and peptidomimetics which are specific for the tuftsin receptor and may be used as an analgesic and in the treatment of various other central nervous system conditions.
SUMMARY OF THE INVENTION
Metallopeptides. The present invention provides tuftsin receptor-specific peptides which comprise a metal ion-binding backbone for complexing with a metal ion, the peptide further comprising a tuftsin receptor-specific biological-function domain, in which the tuftsin receptor-specific domain is conformationally constrained on complexing the metal ion-binding backbone with the metal ion. The metal ion-binding backbone includes two or more contiguous amino acids available for complexing with a metal ion, provided such that the peptide is specific for the tuftsin receptor on complexing the metal ion-binding backbone with a metal ion. The tuftsin receptor-specific domain may be sychnological or rhegnylogical.
The present invention encompasses manufactured peptides and pharmaceutically acceptable salts thereof which are characterized by having a metal ion-binding backbone with two or more contiguous amino acids available for complexing with a metal ion, and a tuftsin receptor-specific biological-function domain which is conformationally constrained on complexing the metal ion-binding backbone with a metal ion. In general, at least a portion of the peptide is conformationally constrained in a secondary structure on complexing the metal ion-binding backbone with the metal ion. The peptide may have a conformationally constrained global structure on complexing the metal ion-binding backbone with the metal ion. The tuftsin receptor-specific domain of the peptide is substantially more potent on complexation of the metal ion-binding backbone with the metal ion. The peptide is also substantially more resistant to enzymatic degradation after complexing the metal ion-binding backbone with a metal ion.
Typically, the metal ion-binding backbone is designed so that all of the val
Darby & Darby
Jones Dameron L.
Rhomed Incorporated
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