Multi-functional antibodies

1. A method of treating a subject with cancer by administration of a macrocyclic metal chelate, said method comprising the steps of:

(a) administering to said subject an antibody comprising an antigen recognition domain that recognizes said macrocyclic metal chelate, wherein said antibody comprises:

i) a light chain comprising:

a) a first CDR having the sequence of SEQ ID NO:2;

b) a second CDR having a sequence selected from the group consisting of:

i) SEQ ID NO:3; and

ii) SEQ ID NO:3 containing a cysteine substitution wherein position 2 is substituted by a cysteine;

c) a third CDR having the sequence of SEQ ID NO:4;

ii) a heavy chain comprising:

a) a first CDR having the sequence of SEQ ID NO:6;

b) a second CDR having a sequence selected from the group consisting of:

i) SEQ ID NO:7;

ii) SEQ ID NO: 7 containing a cysteine substitution wherein position 5 has been substituted by a cysteine;

iii) SEQ ID NO:7 containing a cysteine substitution wherein position 6 has been substituted by a cysteine; and

iv) SEQ ID NO:7 containing a cysteine substitution wherein position 7 has been substituted by a cysteine;

c) a third CDR having the sequence of SEQ ID NO:8; wherein said antibody comprises at least one of said cysteine substitutions, and wherein said antibody binds substituted or unsubstituted 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA); and

a targeting moiety that binds specifically to a cancer cell by binding with a member selected from a cell surface receptor and cell surface antigen, thereby forming a cell-antibody complex; and

(b) administering to said subject said macrocyclic metal chelate, wherein the macrocyclic metal chelate is a substituted or unsubstituted 1,4,7,10-tetraazacyclododecane-N,N′,N″N′″-tetraacetic acid (DOTA) complexed to a metal ion.

2. The method of claim 1 , wherein said substituted or unsubstituted 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA) has the formula:

wherein

R 1a and R 4a are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and linker moieties;

X is a member selected from a lanthanide ion, an actinide ion, an alkaline earth metal ion, and a group IIIb transition metal ion;

Z 1 , Z 2 , Z 3 and Z 4 are members independently selected from OR 1 and NR 1 R 2 in which

R 1 and R 2 are members independently selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;

n is a member selected from 0 and 1.

3. The method of claim 2 , wherein the carbon atom marked * is of S configuration.

4. The method of claim 1 , wherein said targeting moiety binds specifically to said cell surface antigen.

5. The method of claim 1 , wherein the targeting moiety is covalently attached to said antibody.

6. The method of claim 4 , wherein the targeting moiety is a second antibody.

7. The method of claim 5 , wherein the targeting moiety specifically binds to a protein on a cancer cell.

8. The method of claim 1 , wherein the subject is a mammal.

9. The method of claim 8 , wherein the mammal is a human.

10. The method according to claim 1 wherein said antibody has the structure:

(Ab) n -L-T

wherein,

n′ is an integer selected from 1 to 10;

Ab represents said antibody;

L is a member selected from a chemical bond and a linking group that may contain one or more functional groups; and

T is said targeting moiety.

11. The method of claim 10 , wherein said targeting moiety is a second antibody that binds specifically to a cell surface antigen.

12. The method according to claim 10 wherein said antibody is administered to said subject as a pharmaceutical composition comprising said antibody and a pharmaceutically acceptable carrier.

13. The method according to claim 2 , wherein

R 1a and R 4a are H;

Z 1 , Z 2 , Z 3 and Z 4 are OH;

and n is 1.

14. The method according to claim 13 , wherein said targeting moiety is a second antibody that binds specifically to a cell surface antigen.

15. The method according to claim 14 , wherein said targeting moiety is anti-CEA.

16. The method according to claim 13 , wherein said targeting moiety is anti-CEA.

17. The method according to claim 2 , wherein R 1a is a member independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and linker moieties.

18. The method according to claim 2 , wherein R 4a is a member independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and linker moieties.

19. The method according to claim 2 , wherein said DOTA further comprises an arylalkyl moiety having a structure according to the formula:

wherein

R c is an unsubstituted unbranched alkyl linker;

R 3 , R 4 , R 5 , R 6 and R 7 are members independently selected from H, halogen, NO 2 , CN, X 1 R 8 , NR 9 R 10 , and C(X 2 )R 11 ,

wherein

X 1 is a member selected from O, NH, and S;

X 2 is a member selected from O, S, and NH;

R 8 and R 9 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkyl and C(Z 3 )R 12

wherein

Z 3 is a member selected from O, S and NH;

R 12 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and OR 13

wherein

R 13 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R 10 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and OH, and

R 9 and R 10 taken together are optionally (═C═S);

R 11 is a member selected from H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, OR 14 , and NR 15 R 16 ,

wherein

R 14 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and C(O)R 17 ,

wherein

R 17 is a member selected from substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl; and

R 15 and R 16 are members independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl.