Conjugates possessing ortho ligating functionality and complexes thereof
AssigneeThe Dow Chemical Company
InventorsDavid A. Wilson, Joseph R. Garlich, R. Keith Frank, Kenneth McMillan
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Abstract
A group of functionalized amine chelants having ortho ligating functionality that form complexes with rare-earth type metal ions are disclosed. The complexes can be covalently attached to an antibody or antibody fragment and used for therapeutic and/or diagnostic purposes. In addition certain of the chelant-radionuclide complexes can be effectively employed in compositions useful as therapeutic and/or diagnostic agents for calcific tumors and/or relief of bone pain.
Claims43
A complex comprising a chelant possessing ortho ligating functionality having the formula ##STR27## wherein:
- Z is an electrophilic or nucleophilic moiety which allows for covalent attachment to an antibody or fragment thereof or a synthetic linker which does not interfere with the formation of complexation with a radionuclide and which can be attached to an antibody or fragment thereof;
- X is hydrogen, C.sub.1 -C.sub.3 alkyl or CR.sub.3 R.sub.4 CO.sub.2 H;
- R.sub.1, R.sub.2, R.sub.3 and R.sub.4 each are independently hydrogen, hydroxy, CO.sub.2 H or a C.sub.1 -C.sub.3 alkyl group;
- R.sub.5 is hydrogen or (CR.sub.1 R.sub.2).sub.n CR.sub.3 R.sub.4 B';
- B represents a linear or branched polyalkylene polyamine capable of chelating a metal ion where at least one of the amine hydrogens has been substituted with a CR.sub.3 R.sub.4 CO.sub.2 H group;
- B' represents a linear or branched amine or polyalkylene polyamine capable of chelating a metal ion where at least one of the amine hydrogens has been substituted with a CR.sub.3 R.sub.4 CO.sub.2 H group;
- n is 0 or 1;
- or
- a pharmaceutically acceptable salt thereof;
- and
- complexed with a metal ion selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y or Sc.
A conjugate comprising a complex having a bifunctional chelant possessing ortho ligating functionality having the formula ##STR28## wherein:
- Z is an electrophilic or nucleophilic moiety which is attached to an antibody or fragment thereof or a synthetic linker which does not interfere with the formation of complexation with a radionuclide and which is attached to an antibody or fragment thereof;
- X is hydrogen, C.sub.1 -C.sub.3 alkyl or CR.sub.3 R.sub.4 CO.sub.2 H;
- R.sub.1, R.sub.2, R.sub.3 and R.sub.4 each are independently hydrogen, hydroxy, CO.sub.2 H or a C.sub.1 -C.sub.3 alkyl group;
- R.sub.5 is hydrogen or (CR.sub.1 R.sub.2).sub.n CR.sub.3 R.sub.4 B';
- B represents a linear or branched polyalkylene polyamine capable of chelating a metal ion where at least one of the amine hydrogens has been substituted with a CR.sub.3 R.sub.4 CO.sub.2 H group;
- B' represents a linear or branched amine or polyalkylene polyamine capable of chelating a metal ion where at least one of the amine hydrogens has been substituted with a CR.sub.3 R.sub.4 CO.sub.2 H group;
- n is 0 or 1;
- or
- a pharmaceutically acceptable salt thereof;
- complexed with a metal ion selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y or Sc;
- and
- covalently attached to an antibody or antibody fragment.
A complex which comprises a chelant possessing ortho ligating functionality having the formula ##STR29## wherein Z' is selected from the group consisting of hydrogen, NH.sub.2, NO.sub.2, NHC(O)CH.sub.3 or N(R').sub.2, where R' is hydrogen and C.sub.1 -C.sub.3 alkyl;
- X is selected from the group consisting of hydrogen, C.sub.1 -C.sub.3 alkyl and CR.sub.3 R.sub.4 COOH;
- R'.sub.1 is selected from the group consisting of hydrogen and COOH;
- R'.sub.3, R'.sub.4 and R'.sub.5 are independently selected from the group consisting of hydrogen and CR.sub.3 R.sub.4 COOH, with the proviso that at least one of R'.sub.1, R'.sub.3, R'.sub.4 and R'.sub.5 is hydrogen;
- or
- a pharmaceutically acceptable salt thereof;
- complexed with a metal ion selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc.
A complex which comprises a chelant possessing ortho ligating functionality having the formula ##STR30## wherein Z' is hydrogen, NH.sub.2, NO.sub.2, NHC(O)CH.sub.3 or N(R').sub.2, where R' is hydrogen or C.sub.1 -C.sub.3 alkyl;
- X is hydrogen or C.sub.1 -C.sub.3 alkyl or CR.sub.3 R.sub.4 COOH;
- R'.sub.1 and R'.sub.2 each are hydrogen or COOH, with the proviso that at least one is COOH;
- R'.sub.3, R'.sub.4, R'.sub.5 and R'.sub.6 are independently hydrogen or CR.sub.3 R.sub.4 COOH, with the proviso that at least three are CR.sub.3 R.sub.4 COOH;
- or a pharmaceutically acceptable salt thereof;
- complexed with a metal ion selected from the group consisting of La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y or Sc.
Dependencies are inferred from the claim text.