RADIO-PHARMACEUTICAL COMPLEXES
A tissue-targeting complex comprising a tissue targeting moiety, an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyi solubilising group and wherein the tissue targeting moiety has binding affinity for the CD33 receptor. A corresponding pharmaceutical formulation and method and use in treatment, as well as methods of manufacture are provided.
1 . A tissue-targeting complex comprising a tissue targeting moiety, an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group and wherein the tissue targeting moiety has binding affinity for the CD33 receptor.
2 . The complex as claimed in claim 1 comprising at least one 3,2-HOPO moiety.
3 . The complex as claimed in claim 1 or claim 2 wherein all 4 HOPO moieties comprise hydroxyalkyl solubilising moieties at the N-position.
4 . The complex as claimed in claim 1 or claim 2 comprising an octadentate ligand comprising four chelating moieties of formula I
Wherein R 1 is an optional N-substituent solubilising group which will be present in at least one of the four moieties of formula I; groups R 2 to R 6 are each independently selected from H, OH, ═O, short hydrocarbyl groups, linker moieties and/or coupling moieties wherein one of R 2 to R 6 is OH and one of R 2 to R 6 is ═O.
5 . The complex as claimed in claim 4 wherein at least one of groups R 1 to R 6 is a linker moiety.
6 . The complex as claimed in any of claims 4 to 5 comprising four 3,2-hydroxypyridinone moieties.
7 . The complex as claimed in any preceding claim wherein the N-substituents on each of the four HOPO groups are each independently chosen from HO—, HOCH 2 —, HOCH 2 CH 2 —, HO—CH 2 CH 2 CH 2 —, HO—CH(CH 3 )CH 2 —, HO—CH 2 CH 2 CH 2 CH 2 —, HO—CH(CH 3 )CH 2 CH 2 —, HO—CH(CH 2 CH 3 )CH 2 —, HO—C(CH 3 ) 2 CH 2 —, HO—CH(CH 3 )CH(CH 3 )— and HOCH 2 CH(CH 2 CH 3 )—.
8 . The complex as claimed in any of claims 1 to 7 , wherein said ion of an alpha-emitting thorium radionuclide is the 4+ ion of an alpha-emitting thorium radionuclide such as 227 Th.
9 . A complex as claimed in any of claims 1 to 8 comprising a ligand moiety of formula VI:
Wherein R L is any suitable linker moiety.
10 . A complex as claimed in any preceding claim wherein the tissue targeting moiety is a monoclonal or polyclonal antibody, an antibody fragment (such as Fab, F(ab′) 2 , Fab′ or scFv), or a construct of such antibodies and/or fragments.
11 . A complex as claimed in any preceding claim wherein the tissue targeting moiety comprises at least one peptide chain having at least 90% sequence similarity with one or both of the following sequences:
Fragment variable VH domain:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYNMHWVRQAPGQGLEWIGY
IYPYNGGTGYNQKFKSKATITADESTNTAYMELSSLRSEDTAVYYCARGR
PAMDYWGQGTLVTVSS
Fragment variable VL domain:
DIQMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKL
LIYAASNQGSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQSKEVPW
TFGQGTKVEIK
12 . Use of a tissue targeting complex comprising a tissue targeting moiety, an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group and wherein the tissue targeting moiety has binding affinity for the CD33 receptor, in the manufacture of a medicament for the treatment of hyperplastic or neoplastic disease.
13 . Use as claimed in claim 12 wherein said tissue-targeting complex is a complex as claimed in any of claims 1 to 11 .
14 . Use as claimed in claim 12 or claim 13 wherein said disease is a carcinoma, sarcoma, myeloma, leukemia, lymphoma or mixed type cancer.
15 . A method of treatment of a human or non-human animal (particularly one in need thereof) comprising administration of at least one tissue-targeting complex comprising a tissue targeting moiety, an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group wherein the tissue targeting moiety has binding affinity for the CD33 receptor.
16 . The method of claim 15 wherein said tissue-targeting complex is a complex as claimed in any of claims 1 to 11 .
17 . The method as claimed in claim 15 or claim 16 for the treatment of hyperplastic or neoplastic disease, such as a carcinoma, sarcoma, myeloma, leukemia, lymphoma or mixed type cancer.
18 . A tissue targeting complex as claimed in any of claims 1 to 11 for use in therapy.
19 . A tissue targeting complex as claimed in claim 18 for use in the treatment of hyperplastic and/or neoplastic disease such as a carcinoma, sarcoma, myeloma, leukemia, lymphoma or mixed type cancer.
20 . A pharmaceutical composition comprising a tissue-targeting complex comprising a tissue targeting moiety, an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group wherein the tissue targeting moiety has binding affinity for the CD33 receptor, together with at least one pharmaceutical carrier or excipient.
21 . The pharmaceutical composition as claimed in claim 20 comprising a tissue-targeting complex is a complex as claimed in any of claims 1 to 11 .
22 . A kit for use in a method according to any of claims 15 to 17 , said kit comprising a tissue targeting moiety, conjugated or conjugatable to an octadentate hydroxypyridinone-containing ligand comprising four HOPO moieties, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group and wherein the tissue targeting moiety has binding affinity for the CD33 receptor, said kit optionally and preferably include an alpha-emitting thorium radionuclide, such as 227 Th.
23 . A method of formation of a tissue-targeting complex, said method comprising coupling a tissue targeting moiety to an octadentate hydroxypyridinone-containing ligand in aqueous solution, the complex comprising four HOPO moieties and the ion of an alpha-emitting thorium radionuclide, where at least one of the four HOPO moieties is substituted at the N-position with a hydroxyalkyl solubilising group and wherein the tissue targeting moiety has binding affinity for the CD33 receptor.
24 . The method of claim 23 comprising preparing a first aqueous solution of octadentate hydroxypyridinone-containing ligand and a second aqueous solution of said tissue targeting moiety and contacting said first and said second aqueous solutions.
25 . The method of claim 24 wherein said contacting is conducted at below 40° C.
26 . The method of claim 24 or claim 25 wherein said contacting is conducted in the substantial absence of any organic solvent.
27 . The method of any of claims 23 to 26 wherein said coupling yields an amide, ester, ether or amine bond between the ligand moiety and the targeting moiety.
28 . The method of claim 27 wherein said amide or ester linkage is formed by means of at least one activated ester group, for example formed by means a N-hydroxy maleimide, carbodiimide or azodicarboxylate coupling reagent.