Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,...
Reexamination Certificate
1993-05-14
2001-04-10
Achutamurthy, Ponnathapura (Department: 1652)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
C530S391700, C530S391900
Reexamination Certificate
active
06214345
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides drug-ligand conjugates wherein the ligand is connected to the drug moiety through a peptide linker made up of a protein peptide specifier, a carboxylic acyl unit, and a self-immolating spacer, and which conjugates are activated by lysosomal enzymes.
2. Description of the Art
Bipartate compounds consisting of a carrier or linker moiety and a drug moiety are known. These compounds have been particularly useful in the formation of immunoconjugates directed against tumor associated antigens. In certain cases, however, bipartate compounds may be unstable due to the inherent nature of the bond linking the antibodies to the drug or due to the electronic or steric features of the drug moiety which may hinder hydrolysis of the bond by the desired target enzyme. Katzenellenbogen,
J. Amer. Chem. Soc.,
(1981) 24: 479-480.
SUMMARY OF THE INVENTION
The present invention provides tumor specific, drug-ligand conjugates composed of a ligand, a drug, and a peptide linker, which conjugate is selectively activatible at the site of the tumor.
The drug-ligand conjugates of this invention comprise at least one drug molecule, a ligand capable of targeting a selected cell population, and a peptide linker which contains a carboxylic acyl, and a protein peptide specifier. The peptide linker may also contain a self-immolating spacer which spaces the protein peptide sequence and the drug.
The ligand is linked to the carboxylic acyl unit via a thioether-containing linker unit arm, which thioether bond is created by reaction of a sulfhydryl group on the ligand. In a preferred embodiment, the targeting ligand is attached directly to the peptide linker through a covalent thioether bond.
An aspect of the present invention provides drug conjugates which are selectively activatible at the site of the tumor.
Another aspect of the invention provides tumor-specific drug conjugates which are highly selective substrates for drug-activating enzymatic cleavage by one or more tumor-associated enzymes.
A further aspect of the invention provides tumor-specific drug conjugates wherein the activating enzyme is one which is present in the tumor in sufficient amounts to generate cytotoxic levels of free drug in the vicinity of the tumor.
Another aspect of the invention provides tumor-specific drug conjugates which tumor specificity arises solely from the ligand.
Another aspect of the invention provides tumor-specific drug conjugates which are stable to adventitious proteases in blood.
A still further aspect of the present invention provides a tumor-specific drug conjugate in accordance with the preceding aspects, which is considerably less toxic than the activated drug.
In another aspect the present invention provides a method for the production of the drug conjugates and pharmaceutical compositions and methods for delivering the conjugates to target cells in which a modification in biological process is desired, such as in the treatment of diseases such as cancer.
The present invention also provides a method for delivering to the site of tumor cells in a warm-blooded animal an active antitumor drug by administering to said warm-blooded animal the drug-ligand conjugate according to this invention.
In one embodiment the drug moiety is an anthracycline antibiotic, the ligand is an antibody, A is a carboxylic acyl unit, Y is Phe, Z is Lys, and n is 5.
In a preferred embodiments the anthracycline drug moiety is doxorubicin, the ligand moiety is a chimeric antibody, A is carboxylic acyl unit, Y is Phe, Z is Lys, and n is 5.
In another preferred embodiment the drug moiety is taxol, the ligand is an antibody, Y is Phe, Z is Lys and n is 5.
In another preferred embodiment the drug moiety is mitomycin C, the ligand is an antibody, Y is Phe, Z is Lys and n is 5.
The above and other aspects of the present invention are achieved by derivatizing an antitumor agent linked to a ligand through a peptide linker, made up of a protein peptide sequence and a self-immolating spacer, at a reactive site appropriate for inhibiting the pharmacological activity of the antitumor agent to thereby convert the antitumor agent into a pharmacologically inactive peptidyl derivative conjugate. The peptide linker has an amino acid residue sequence specifically tailored so as to render the peptidyl derivative a selective substrate for drug-activating enzymatic cleavage by one or more lysosomal proteases, such as cathepsin B, C or D. The enzymatic cleavage reaction will remove the peptide linker moiety from the drug conjugate and effect release of the antitumor agent in pharmacologically active form selectively at the tumor site. In comparison with ligand-drug linkers which rely on simple acid hydrolysis for drug release this new method provides significantly less systemic toxicity due to premature linker hydrolysis in the blood, consequently a greater amount of drug is delivered to the tumor site, and the method results in a longer storage life and simplified handling conditions for the conjugate.
The drug-ligand conjugates of the present invention show significantly less systemic toxicity than biparte conjugates and free drug. The conjugates of the invention retain both specificity and therapeutic drug activity for the treatment of a selected target cell population. They may be used in a pharmaceutical composition, such as one comprising a pharmaceutically effective amount of a compound of Formula (I) below, associated with a pharmaceutically acceptable carrier, diluent or excipient.
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Dubowchik Gene Michael
Firestone Raymond Armand
Achutamurthy Ponnathapura
Bogden James M.
Bristol-Myers Squibb Co.
Savitsky Thomas R.
Sher Audrey F.
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