RADIO-PHARMACEUTICAL COMPLEXES

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 CD22 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 at least one of the following sequences:

Light Chain:

(Seq ID 1)

DIQLT QSPSSLAVSAGENVT MSC KSSQSVLYSANHKNYLA W YQQKPGQS

P KLLIY WASTRES G VPDRFTGS G S GT D F TLTISRVQVEDLAIYY C HQYL

SSWT FGGG TKLEIKR

(Seq ID 2)

DIQLT QSPSSLASAAVEDRT MSC KSSQSVLYSANHKNYLA W YQQKPGQK

A KLLIY WASTRES G VPSRFSGS G S GT D F TFTISSLQPEDIATYY C HQYL

SSWT FGGG TKLEIKR

Heavy Chain:

(Seq ID 3)

QVQLQ ESGAELSKPGASVKMSCK A SG YTFT SYWLH WIK QRPGQGL EWIG

YINPRNDYTEYNQNFKD KA TLT AD KSSSTAY MQLSS LT SED SAVYYCA R

RDITTFY WG QGTTLTVSS

(Seq ID 4)

QVQL QQSGAEVKKPGSSVKVSCK A SG YTFT SYWLH W VRQAPGQGL EWIG

YINPRNDYTEYNQNFKD KA TITADESTNTAY M E LSS LR SED TAFYFCA R

RDITTFY WG QGTTVTVSS

(Seq ID 5)

QVQL VQSGAEVKKPGSSVKVSCK A SG YTFT SYWLH WVRQAPGQGL EWIG

YINPRNDYTEYNQNFKD KA TITADESTNTAY M E LSS LR SED TAFYFCA R

RDITTFY WG QGTTVTVSS

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 CD22 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 including Non-Hodgkin's Lymphoma or B-cell neoplasms.

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 CD22 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, including Non-Hodgkin's Lymphoma or B-cell neoplasms.

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 including Non-Hodgkin's Lymphoma or B-cell neoplasms.

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 CD22 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 CD22 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 CD22 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 chelate and the antibody.

28 . The method of claim 27 wherein said ester or amide linkage is formed by means of at least one activated ester group, for example formed by means of at least one N-hydroxy maleimide, carbodiimide or azodicarboxylate coupling reagent.