Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1987-12-14
1992-02-11
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540467, 540471, 540473, 540474, 540470, 540469, 530387, 530388, 530391, 424 11, 424 8591, C07D25702, A61K 4300, A61K 4000, C07K 1500
Patent
active
050876961
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a conjugate compound comprising a macrocyclic ligand and an antibody, to a metal complex of the conjugate compound and to formulations of the metal complex for use in therapy and diagnosis.
BACKGROUND TO THE INVENTION
It is known to label an antibody with a metal atom, in order to target the metal atom to a specific tissue type, both in vitro and in vivo. Such labelled antibodies have applications in locating specific tissue types (e.g. employing computer-aided tomographic techniques where the metal atom is in some way detectable) and in the treatment of cell disorders (e.g. treating mammalian tumours where the metal atom is a cytotoxic radionucleide).
Conventionally, the metal atom has been complexed to a conjugate compound comprising a ligand covalently attached to an antibody. The ligand may be, for example, an acyclic chelate such as a substituted diethylenetriaminepentaacetic acid (DTPA) (Gansow O. A. et al, Inorg. Chem., (1986), 25, 2772) or ethylenediaminetetraacetic acid (EDTA) (Meares, C. F. et al, Acc. Chem. Res., (1984), 17, 202). Such acylic complexes however tend to be unstable in vivo either as a result of acid-catalysed decomplexation or competitive chelate binding by Ca.sup.2+ or Zn.sup.2+ in serum or as a result of competition from transferrin (Moerlein, S. M. et al, Int. J. Nuc. Med. Biol., (1981), 8, 277). The lack of stability can result in uncomplexed metal atoms in the body which have a cytotoxic effect on healthy tissue or which markedly reduce the signal-to-noise ratio of an imaging technique. The use of macrocyclic ligands in the labelling of antibodies has been suggested in broad terms (Gansow, O. A. et al, Am. Chem. Soc. Symp. Ser., (1984), 241, 215; Published British patent application GB2122641A; Meares, C. F. et al, Anal. Biochem., (1985), 148, 249-253)).
The object of the present invention is to provide improved conjugate compounds involving macrocyclic ligands capable of binding metals to give complexes which are stable, in vivo.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention there is provided a conjugate compound having the following structure: ##STR1## wherein R.sup.1 is --(CH.sub.2).sub.p --R.sup.6 --(CH.sub.2).sub.q -- where p and q are the same or different and are 0, 1 or 2, and --R.sup.6 -- is --(CH.sub.2).sub.n --, where n is 0 or 1, --NH--, --O--, --S-- or ##STR2## R.sup.1 optionally being alkyl substituted, provided that neither p nor q is 0 unless R.sup.6 is --CH.sub.2 --, optionally alkyl, alkoxyalkyl or hydroxyalkyl substituted, alkoxyalkyl, carboxyalkyl, carboxyalkyl ester, phosphate, sulphonate or phosphonate ##STR3## optionally alkyl substituted, wherein R.sub.7 is --H, alkyl, hydroxyalkyl, or alkoxyalkyl provided that when R.sup.4 is --CH.sub.2 --CH--CH.sub.2 --, R.sup.3 is not carboxyalkyl,
The conjugate compound of the invention provides for complexes of metals or such as Tc, Co, Re, Cu, Au and Ag Pb, Bi, In and Ga which are useful reagents for in vivo imaging and therapy. Particularly preferred are complexes of Tc and Cu.
R.sup.1 is preferably --CH.sub.2 CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 --O--CH.sub.2 CH.sub.2 --. The radicals R.sup.2 are preferably the same and may be --CH.sub.2 CH.sub.2 --. In each case, one or more hydrogen atoms may be replaced with an alkyl hydroxyalkyl or alkoxyalkyl radical, such as lower alkyl radical, for example methyl.
The aromatic ring, where present, in R.sup.4 may be 1,3,5 or 1,3,4 substituted depending to the ring size required and the synthetic route adopted to make the compound.
R.sup.4 may be substituted with lower alkyl such as methyl. R.sup.7 is preferably --H or lower alkyl (C.sub.1 -C.sub.3) such as methyl, but may be higher alkyl such as C.sub.4 -C.sub.15 alkyl.
The linker, R.sup.5, may be any diradical adapted to link the antibody to the macrocyclic part of the conjugate compound such that the binding affinity and specificity of the antibody are not substantially impaired and such that the macrocyclic part of the conjug
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Skrikant V. Deshpande et al.; The Journal of Nuclear Medicine, "Copper-67-Labeled Monoclonal Antibody Lym-1, A Potential Radiopharmaceutical for Cancer Theraphy: Labeling and Biodistribution in RAJI Tumored Mice," vol. 29, No. 2, pp. 217-225 (Feb. 1988).
Franz, J. et al., Abstract from Journal of Nuclear Medicine, Abstract No. 553, vol. 26, No. 5, May 1985.
Franz et al., poster exhibited at 32nd Annual Meeting of the Society of Nuclear Medicine prior to May 1985.
Meares, Claude F., Protein Tailoring for Food and Medicine Uses edited by R. E. Feeny et al., "Attaching Metal Ions to Antibodies", pp. 339-352 (1986).
Goodwin, D. A. et al., Abstract of "In Complex of a New Macrocyclic Bifunctional Chelator TETA", presented at European Nuclear Medicine Congress Meeting at Barbican, London, Sep. 3-6, 1985.
Millican Thomas A.
Parker David
Bond Robert T.
Celltech Limited
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