Compounds for targeting

Details Compounds for targeting Compounds for targeting

1995-12-18

1999-10-26

Hutzell, Paula K.

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

5303911, 5303917, C07K 100, C07K 1600

Patent

active

059731168

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to compounds, some of which may be directly or indirectly cytotoxic combinations of compounds, that have a high avidity for, and can be targeted to, selected cells.


BACKGROUND OF THE PRIOR ART

The cell-specific targeting of compounds which are directly, or indirectly, cytotoxic has been proposed as a way to combat diseases such as cancer. Bagshawe and his co-workers have disclosed (Bagshawe (1987) Br. J. Cancer 56, 531; Bagshawe et al (1988) Br. J. Cancer 58, 700; WO 88/07378) conjugated compounds comprising an antibody or part thereof and an enzyme, the antibody being specific to tumour cell antigens and the enzyme acting to convert an innocuous pro-drug into a cytotoxic compound. The cytotoxic compounds were alkylating agents. eg a benzoic acid mustard released from para-N-bis(2-chloroethyl)aminobenzoyl glutamic acid by the action of Pseudomonas sp. CPG2 enzyme.
An alternative system using different pro-drugs has been disclosed (WO 91/11201) by Epenetos and co-workers. The cytotoxic compounds were cyanogenic monosaccharides or disaccharides, such as the plant compound amygdalin, which release cyanide upon the action of a .beta.-glucosidase and hydroxynitrile lyase.
In a further alternative system, the use of antibody-enzyme conjugates containing the enzyme alkaline phosphatase in conjunction with the pro-drug etoposide 4'-phosphate or 7-(2'-aminoethyl phosphate)mitomycin or a combination thereof have been disclosed (EP 0 302 473; Senter et al (1988) Proc. Natl. Acad. Sci. USA 85, 4842).
Rybak and co-workers have disclosed (Rybak et al (1991) J. Biol. Chem. 266, 21202; WO 91/16069) the cytotoxic potential of a monomeric pancreatic ribonuclease when injected directly into Xenopus oocytes and the cytotoxic potential of monomeric RNase coupled to human transferrin or antibodies directed against the transferrin receptor. The monomeric RNase hybrid proteins were cytotoxic to human erythroleukaemia cells in vitro.
Other approaches are the in vivo application of streptavidin conjugated antibodies followed, after an appropriate period, by radioactive biotin (Hnatowich et al (1988) J. Nucl. Med. 29, 1428-1434), or injection of a biotinylated mAb followed by radioactive streptavidin (Paganelli et al (1990) Int. J. Cancer 45, 1184-1189). A pilot radioimmunolocalisation study in non-small cell lung carcinomas was conducted with encouraging results (Kalofonos et al (1990) J. Nucl. Med. 31, 1791-1796).
Apart from these examples, it is rather more common to see biotinylated antibodies and streptavidin-enzyme conjugates which are used in enzyme-linked immunosorbent assays.
These previous systems have used relatively large antibody-enzyme or antibody-streptavidin or antibody-biotin conjugates and may comprise portions of non-mammalian origin which are highly immunoreactive.
Rapid penetrance (Yokota et al (1992) Cancer Res. 52, 3402-3408) and rapid clearance (Colcher et al (1990) J. Natl. Cancer Inst. 82, 1191-1197) has been demonstrated for single chain Fv antibody fragments (ScFv).
In using the cell-specific reagents aforementioned in a therapeutically useful situation one of the requirements that needs to be met is for the cell-specific reagent to accumulate to a sufficiently higher level at the target cell than at other cells. A further requirement is that a directly or indirectly cytotoxic reagent is carried to the target cell, and it is preferred that the said cytotoxic reagent is of high potency.
We have now devised improved systems at least some of which exhibit higher avidities to the selected target cells, and make use of novel, potent directly or indirectly cytotoxic agents.


SUMMARY OF INVENTION

A first aspect of the invention provides a compound comprising a target cell-specific portion and a cytotoxic portion characterised in that the cytotoxic portion has nucleolytic activity.
Suitably, as disclosed below, the cytotoxic portion may have ribonucleolytic activity or it may have DNA endonucleolytic activity.
One aspect of the present invention provides a compound comprising a

REFERENCES:
Hollinger et al, "Diabodies": Small Bivalent and Bispecific Antibody Fragments Proc. Natl. Acad. Scie USA vol. 90, pp.
Rybak et al, "Cytotoxic Potential of Ribonuclease and Ribonuclease Hybrid" J. of Biological Chemistry, vol. 266, pp. 21202-21207.
Worrall et al (JBC, 265: 21889-21895) 1990.
Lazar et al (Mol & Cell Bio, 8: 1247-1252) 1988.
Burgess et al (J. Cell Bio, 111:2129-2138) 1990.
Tao et al. (J. Immunol, 143:2595-2601 1989.
Hird et al (Genes & Cancer, Carney et al Ed, John Wiley & Sons, 1990, pp. 83-89.
Kimmel et al (J. Neurosurg, 66:161-171, 1987).

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