FAP-activated anti-tumour compounds

Details FAP-activated anti-tumour compounds FAP-activated anti-tumour compounds

2000-04-21

2003-09-02

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

4 to 5 amino acid residues in defined sequence

C530S329000, C530S330000, C548S535000, C514S017400, C514S018700, C514S019300, C514S152000

Reexamination Certificate

active

06613879

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of tumour treatment by administration of a prodrug that is converted into a drug at the site of the tumour. In particular, the invention relates to prodrugs which may be converted into a drug by the catalytic action of FAP&agr;, their manufacture and pharmaceutical use.
BACKGROUND AND PRIOR ART
The human fibroblast activation protein (FAP&agr;) is a M, 95,000 cell surface molecule originally identified with monoclonal antibody (mAb) F19 (Rettig et al. (1988)
Proc. Natl. Acad. Sci. USA
85, 3110-3114; Rettig et al. (1993)
Cancer Res
. 53, 3327-3335). The FAP&agr; cDNA codes for a type II integral membrane protein with a large extracellular domain, trans-membrane segment, and short cytoplasmic tail (Scanlan et al. (1994)
Proc. Natl. Acad. Sci. USA
91, 5657-5661; WO 97/34927). FAP&agr; shows 48% amino acid sequence identity to the T-cell activation antigen CD26, also known as dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5), a membrane-bound protein with dipeptidyl peptidase activity (Scanlan et al., loc. cit.). FAP&agr; has enzymatic activity and is a member of the serine protease family, with serine 624 being critical for enzymatic function (WO 97/34927). Work using a membrane overlay assay revealed that FAP&agr; dimers are able to cleave Ala-Pro-7-amino-4-trifluoromethyl coumarin, Gly-Pro-7-amino-4-trifluoromethyl coumarin, and Lys-Pro-7-amino-4-trifluoromethyl coumarin dipeptides (WO 97/34927).
FAP&agr; is selectively expressed in reactive stromal fibroblasts of many histological types of human epithelial cancers, granulation tissue of healing wounds, and malignant cells of certain bone and soft tissue sarcomas. Normal adult tissues are generally devoid of detectable FAP&agr;, but some foetal mesenchymal tissues transiently express the molecule. In contrast, most of the common types of epithelial cancers, including >90% of breast, non-small-cell lung, and colorectal carcinomas, contain FAP&agr;-reactive stromal fibroblasts (Scanlan et al., loc. cit.). These FAP&agr;
+
fibroblasts accompany newly formed tumour blood vessels, forming a distinct cellular compartment interposed between the tumour capillary endothelium and the basal aspect of malignant epithelial cell clusters (Welt et al. (1994)
J. Clin. Oncol
. 12(6), 1193-1203). While FAP&agr;
+
stromal fibroblasts are found in both primary and metastatic carcinomas, the benign and premalignant epithelial lesions tested (Welt et al., loc. cit.), such as fibroadenomas of the breast and colorectal adenomas, only rarely contain FAP&agr;
+
stromal cells. Based on the restricted distribution pattern of FAP&agr; in normal tissues and its uniform expression in the supporting stroma of many malignant tumours, clinical trials with
131
I-labeled mAb F19 have been initiated in patients with metastatic colon carcinomas (Welt et al., loc. cit.).
For new cancer therapies based on cytotoxic or cytostatic drugs, a major consideration is to increase the therapeutic index by improving the efficacy of cancerous tissue killing and/or reducing the toxicity for normal tissue of the cytotoxic or cytostatic agents. To increase specificity of tumour tissue killing and reduce toxicity in normal tissues, trigger mechanisms can be designed so that the toxic agents synthesised in their prodrug or inactive forms are rendered active when and where required, notably in the cancerous tissues (Panchal (1998)
Biochem. Pharmacol
. 55, 247-252). Triggering mechanisms may include either exogenous factors such as light or chemicals or endogenous cellular factors, such as enzymes with restricted expression in cancer tissues. Another concept, that has been further elaborated, is called ‘antibody-directed enzyme prodrug therapy’ (ADEPT) or ‘antibody-directed catalysis’ (ADC) (Huennekens (1994)
Trends Biotechnol
. 12, 234-239; Bagshawe (1994)
Clin. Pharmacokinet
. 27, 368-376; Wang et al. (1992)
Cancer Res
. 52, 4484-4491; Sperker et al. (1997)
Clin. Pharmacokinet
. 33(1), 18-31). In ADEPT, an antibody directed at a tumour-associated antigen is used to target a specific enzyme to the tumour site. The tumour-located enzyme converts a subsequently administered prodrug into an active cytotoxic agent. The antibody-enzyme conjugate (AEC) binds to a target antigen on cell membranes or to free antigen in extracellular fluid (ECF). A time interval between giving the AEC and prodrug allows for the AEC to be cleared from normal tissues so that the prodrug is not activated in the normal tissues or blood. However, some disadvantages of ADEPT are related to the properties of the AEC (Bagshawe, loc. cit.). For example, in humans, only a small fraction of the administered dose of the targeting ACE binds to tumour tissue and the remainder is distributed through body fluids from which it is cleared with significant time delays. Even very low concentrations of targeted enzyme can catalyse enough prodrug to have toxic effects because plasma and normal ECF volumes are much greater than those of tumour ECF. The AEC may also be immunogenic, thus preventing repeat administration, in many instances.
The International patent applications WO 97/12624 and WO 97/14416 disclose oligopeptides including the following penta- and hexapeptide (SEQ.ID.NOs.: 151 and 177: hArg-Tyr-Gln-Ser-Ser-Pro; hArg-Tyr-Gln-Ser-Pro;), comprising amino acid sequences, which are recognized and proteolytically cleaved by free prostate specific antigen (PSA) and therapeutic agents which comprise conjugates of such oligopeptides and known therapeutic or cytotoxic agents. These oligopeptide conjugates which comprise at least one glutamineserine moiety are useful for treatment of prostate cancer only.
The problem underlying the present invention was to provide methods and means for improving normal tissue tolerability of cytotoxic or cytostatic agents with known efficacy against a broad range of tumour tissues.
DISCLOSURE OF THE INVENTION
The present invention relates to enzyme-activated anti-tumour compounds. In particular, the invention provides prodrugs that are capable of being converted into drugs by the catalytic action of endogenous fibroblast activating protein alpha (FAP&agr;) shown to reside in human cancer tissues. Preferably, a prodrug of the present invention is capable of being converted into a drug by the catalytic action of FAP&agr;, said prodrug having a cleavage site which is recognised by FAP&agr;, and said drug being cytotoxic or cytostatic against cancer cells under physiological conditions.
In the context of this invention, a “drug” shall mean a chemical compound that may be administered to humans or animals as an aid in the treatment of disease. In particular, a drug is an active pharmacological agent.
The term “cytotoxic compound” shall mean a chemical compound which is toxic to living cells, in particular a drug that destroys or kills cells. The term “cytostatic compound” shall mean a compound that suppresses cell growth and multiplication and thus inhibits the proliferation of cells. Examples for cytotoxic or cytostatic compounds suitable for the present invention are anthracycline derivatives such as doxorubicin, analogs of methotrexate such as methothrexate, pritrexime, trimetrexate or DDMP, melphalan, analogs of cisplatin such as cisplatin, JM216, JM335, bis(platinum) or carboplatin, analogs of purines and pyrimidines such as cytarbine, gemcitabine, azacitidine, 6-thioguanine, flurdarabine or 2-deoxycoformycin, and analogs of other chemotherapeutic agents such as 9-aminocamptothecin, D,L-aminoglutethimide, trimethoprim, pyrimethamine, mitomycin C, mitoxantrone, cyclophosphanamide, 5-fluorouracil, extramustine, podophyllotoxin, bleomycin or taxol.
A “prodrug” shall mean a compound that, on administration, must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. In particular, a prodrug is a precursor of a drug. In the context of the present invention, the prodrug is significantly less cytotoxic or cytostatic than the drug it is converted into upon the catalyt

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