Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2001-06-18
2004-01-13
Peselev, Elli (Department: 1623)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S391100
Reexamination Certificate
active
06677435
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The field of this invention is prodrug activation. More particularly, the present invention pertains to a compound that includes an active therapeutic agent attached to a blocking group, methods for making such compounds and methods of converting such compounds to active therapeutic agents using antibodies having aldolase activity.
BACKGROUND OF THE INVENTION
Drug therapy can be limited by nonspecific toxicity. To overcome this limitation, several approaches towards a site-selective therapy have been suggested. Selective therapy can be based on the enzymatic activation of a prodrug at a target site. Unless the target displays a specific enzymatic activity that can be used for prodrug activation (Denmeade et al.,
Cancer Res
58, 2537-2540, 1998), the enzymatic activity has to be conjugated to an antibody that binds to a target cell surface antigen selectively expressed at the target site. The antibody-enzyme conjugate is injected first. Once it has accumulated at the site and has been cleared from the periphery, the prodrug is administered. The prodrug is selectively activated by the targeted enzymatic activity. One molecule of enzyme catalyzes the activation of many molecules of prodrug. This inherent amplification feature of the system allows the generation of high drug concentrations at the target site. The concept of antibody-directed enzyme prodrug therapy, termed ADEPT, has been developed by Bagshawe, Senter, and others (Bagshawe et al.,
Br. J. Cancer
58, 700-703, 1988; Senter et al.,
Proc. Natl. Acad. Sci. USA
85, 4842-4846, 1988; Niculescu-Duvaz, et al.,
Adv. Drug Delivery Rev.
26,151-172, 1997). A number of antigens that are expressed on the surface of cells have been shown to be effective targets for antibody-mediated therapy. Thus, the antibody component is not the critical parameter for ADEPT. By contrast, the requirements for the enzyme component for ADEPT are difficult to achieve. First of all, selective prodrug activation requires the catalysis of a reaction that must not be accomplished by endogenous enzymes in blood and normal tissue of the patient. Enzymes of non-mammalian origin that meet these needs are, however, likely to be highly immunogenic, a fact that makes repeated administration impossible. There is a need in the art, therefore, for improved ADEPT compounds and methods.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound according to formula I, below
In formula I, X is a heteroatom of a target molecule and Y is absent or a self-immolative linker such as shown below:
Each R is independently hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
5
-C
6
aryl or a heterocycle containing five or six ring atoms. In one embodiment, the heteroatom is a nitrogen, oxygen or sulfur atom in a functional group of the target molecule. Preferred target molecules are therapeutic agents or fluorescent molecules. Exemplary and preferred therapeutic agents include anti-tumor agents such as a cytotoxic agent, a microtubule stabilizing agent or an antibiotic. A preferred antibiotic is an anthracycline antibiotic such as doxorubicin or a therapeutically active analog thereof. A preferred microtubule stabilizing agent is paclitaxel, epothilone, or a therapeutically active analog thereof.
In another aspect, a compound of the present invention includes a compound having the structure II, below
where X, Y and R are as defined in reference to formula I.
An especially preferred compound of this invention has the structure
where R
9
is CH
3
, CH
2
F, CH
2
Cl, CH
2
CH
3
, CH
2
OOCCH
3
or CH═CH
2
and each B is independently H,
where Y and R are as defined above and with the proviso that two Bs are H.
In another aspect, this invention provides a of converting an inactive molecule to an active molecule. The process includes the step of exposing the inactive molecule to an agent that catalyzes a retro-Michael reaction. A preferred inactive molecule is a compound according to formula I or II, above. A preferred agent that catalyzes a retro-Michael reaction is a protein. A preferred is an antibody, the catalytic activity of which is inhibited by a &bgr;-diketone compound. Exemplary and preferred such antibodies are 38C2 or 33F12. The process can occur in vitro, in situ or in vivo. In one embodiment, the antibody is a bifunctional antibody that specifically immunoreacts with a cell surface antigen of a target cell such as a tumor cell or a virus-infected cell. The antibody can be a single chain antibody.
REFERENCES:
patent: 5001115 (1991-03-01), Sloan
Senter, et al., “Anti-tumor Effects on Antibody-Alkaline Phosphatase Conjugates in Combination with Etoposide Phosphate”,Proc. Natl. Acad. Sci. USA 85: 4842-4846 (1988).
Bagshawe, et al., “A Cytotoxic Agent can be Generated Selectively at Cancer Sites”,Br. J. Cancer 58: 700-703 (1988).
Miyashita, et al., “Prodrug Activation via Catalytic Antibodies”,Proc. Natl. Acad. Sci. USA 90: 5337-5340 (1993).
Campbell, et al., “Antibody-Catalyzed Prodrug Activation”,J. Am. Chem. Soc. 116: 2165-2166 (1994).
Wentworth, et al., “Toward Antibody-Directed “Abzyme” Prodrug Therapy, ADAPT: Carbamate Prodrug Activation by a Catalytic Antibody and its in vitro Application to Human Tumor Cell Killing”,Proc. Natl. Acad. Sci. USA 93: 799-803 (1996).
Niculescu-Duvaz, et al., “Antibody-Directed Enzyme Prodrug Therapy (ADEPT): A Review”,Adv. Drug. Del. Rev. 26: 151-172 (1997).
Denmeade, et al., “Enzyme Activation of a Doxorubicin-Peptide Prodrug by Prostate-Specific Antigen”,Cancer Res. 58: 2537-2540 (1998).
List, et al., “Aldol Sensors for the Rapid Generation of Tunable Fluorescence by Antibody Catalysis”,Proc. Natl. Acad. Sci. USA 95: 15351-15355 (1998).
Barbas, III Carlos F.
Lerner Richard A.
List Benjamin
Rader Christoph
Shabat Doron
Northrup Thomas E.
Peselev Elli
The Scripps Research Institute
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