Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof
The present invention relates to novel antibodies, particularly antibodies directed against deletion mutants of epidermal growth factor receptor and particularly to the type III deletion mutant, EGFRvIII. The invention also relates to human monoclonal antibodies directed against deletion mutants of epidermal growth factor receptor and particularly to EGFRvIII. Diagnostic and therapeutic formulations of such antibodies, and immunoconjugates thereof, are also provided.
1. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 142; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 142; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 142;
a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 144; a light chain CDR2 that a CDR2 in SEQ ID NO: 144; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 144; and
a Maytansinoid toxin conjugated to the antibody.
2. The isolated human monoclonal antibody of claim 1 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 121, SEQ ID NO: 123, and SEQ ID NO: 125.
3. The isolated human monoclonal antibody of claim 1 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.
4. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 2; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 2; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 2;
a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 19; a light chain CDR2 that is a CDR2 in SEQ ID NO: 19; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 19; and
a Maytansinoid toxin conjugated to the antibody.
5. The isolated human monoclonal antibody of claim 4 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.
6. The isolated human monoclonal antibody of claim 4 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.
7. The isolated human monoclonal antibody of claim 5 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.
8. A composition comprising:
the antibody of claim 7 ; and
a pharmaceutically acceptable carrier or diluent.
9. A composition comprising:
the antibody of claim 4 ; and
a pharmaceutically acceptable carrier or diluent.
10. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 142; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 142; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 142;
a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 144; a light chain CDR2 that a CDR2 in SEQ ID NO: 144; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 144,
wherein each CDR is defined in accordance with the CDR definition of Kabat or Chothia; and
a Maytansinoid toxin conjugated to the antibody.
11. The isolated human monoclonal antibody of claim 10 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 121, SEQ ID NO: 123, and SEQ ID NO: 125.
12. The isolated human monoclonal antibody of claim 11 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.
13. A composition comprising:
the antibody of claim 12 ; and
a pharmaceutically acceptable carrier or diluent.
14. The isolated human monoclonal antibody of claim 10 , wherein the light chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.
15. The isolated human monoclonal antibody of claim 10 , wherein each CDR is defined in accordance with the CDR definition of Kabat.
16. The isolated human monoclonal antibody of claim 10 , wherein each CDR is defined in accordance with the CDR definition of Chothia.
17. A composition comprising:
the antibody of claim 10 ; and
a pharmaceutically acceptable carrier or diluent.
18. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NO: 2; a heavy chain CDR2 that is a CDR2 in SEQ ID NO: 2; a heavy chain CDR3 that is a CDR3 in SEQ ID NO: 2;
a light chain polypeptide comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NO: 19; a light chain CDR2 that is a CDR2 in SEQ ID NO: 19; and a light chain CDR3 that is a CDR3 in SEQ ID NO: 19,
wherein each CDR is defined in accordance with the CDR definition of Kabat or Chothia; and
a Maytansinoid toxin conjugated to the antibody.
19. The isolated human monoclonal antibody of claim 18 , wherein the heavy chain polypeptide comprises all three of the following amino acid sequences: SEQ ID NO: 108, SEQ ID NO: 110, and SEQ ID NO: 112.
20. The isolated human monoclonal antibody of claim 19 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.
21. A composition comprising:
the antibody of claim 20 ; and
a pharmaceutically acceptable carrier or diluent.
22. The isolated human monoclonal antibody of claim 18 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 103, and SEQ ID NO: 105.
23. The isolated human monoclonal antibody of claim 18 , wherein each CDR is defined in accordance with the CDR definition of Kabat.
24. The isolated human monoclonal antibody of claim 18 , wherein each CDR is defined in accordance with the CDR definition of Chothia.
25. A composition comprising:
the antibody of claim 18 ; and
a pharmaceutically acceptable carrier or diluent.
26. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide, wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 125, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 123, and wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 121;
a light chain polypeptide, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 118, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 116, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 101; and
a Maytansinoid toxin conjugated to the antibody.
27. A composition comprising:
the antibody of claim 26 ; and
a pharmaceutically acceptable carrier or diluent.
28. An isolated human monoclonal antibody that binds to EGFRvIII comprising:
a heavy chain polypeptide, wherein CDR3 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 112, wherein CDR2 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 110, and wherein CDR1 of the heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 108;
a light chain polypeptide, wherein CDR3 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 105, wherein CDR2 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 103, and wherein CDR1 of the light chain polypeptide comprises the amino acid sequence of SEQ ID NO: 101; and
a Maytansinoid toxin conjugated to the antibody.
29. A composition comprising:
the antibody of claim 28 ; and
a pharmaceutically acceptable carrier or diluent.
30. A composition comprising:
the antibody of claim 1 ; and
a pharmaceutically acceptable carrier or diluent.
31. The isolated human monoclonal antibody of claim 2 , wherein the light chain polypeptide comprises all three of the following sequences: SEQ ID NO: 101, SEQ ID NO: 116, and SEQ ID NO: 118.
32. A composition comprising:
the antibody of claim 31 ; and
a pharmaceutically acceptable carrier or diluent.
33. The isolated human monoclonal antibody of claim 1 , wherein the Maytansinoid toxin comprises DM-1.
34. The isolated human monoclonal antibody of claim 4 , wherein the Maytansinoid toxin comprises DM-1.
35. The isolated human monoclonal antibody of claim 10 , wherein the Maytansinoid toxin comprises DM-1.
36. The isolated human monoclonal antibody of claim 18 , wherein the Maytansinoid toxin comprises DM-1.
37. The isolated human monoclonal antibody of claim 26 , wherein the Maytansinoid toxin comprises DM-1.
38. The isolated human monoclonal antibody of claim 28 , wherein the Maytansinoid toxin comprises DM-1.