Antibodies and antigen-binding fragments of antibodies that bind GCC are disclosed. The invention also provides therapeutic and diagnostic methods utilizing the antibodies and antigen-binding fragments provided herein.
대표청구항▼
1. Isolated nucleic acid sequences that encode: a) an anti-GCC antibody molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-148-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable r
1. Isolated nucleic acid sequences that encode: a) an anti-GCC antibody molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-148-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable region (SEQ ID NO: 15) of antibody MIL-44-67-4; orb) an anti-GCC antibody molecule, comprising (i) light chain CDR1 (SEQ ID NO: 27), CDR2 (SEQ ID NO: 28), and CDR3 (SEQ ID NO: 29), and heavy chain CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 22), and CDR3 (SEQ ID NO: 23) of antibody MIL-44-148-2, or(ii) light chain CDR1 (SEQ ID NO: 39), CDR2 (SEQ ID NO: 40), and CDR3 (SEQ ID NO: 41) and heavy chain CDR1 (SEQ ID NO: 33), CDR2 (SEQ ID NO: 34), and CDR3 (SEQ ID NO: 35) of antibody MIL-44-67-4. 2. A cell comprising the isolated nucleic acid sequences of claim 1. 3. A method of producing an antibody molecule comprising culturing the cell of claim 2 under conditions that allow production of an antibody molecule, thereby producing: a) an anti-GCC antibody molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-148-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable region (SEQ ID NO: 15) of antibody MIL-44-67-4; orb) an anti-GCC antibody molecule, comprising (i) light chain CDR1 (SEQ ID NO: 27), CDR2 (SEQ ID NO: 28), and CDR3 (SEQ ID NO: 29), and heavy chain CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 22), and CDR3 (SEQ ID NO: 23) of antibody MIL-44-148-2, or(ii) light chain CDR1 (SEQ ID NO: 39), CDR2 (SEQ ID NO: 40), and CDR3 (SEQ ID NO: 41) and heavy chain CDR1 (SEQ ID NO: 33), CDR2 (SEQ ID NO: 34), and CDR3 (SEQ ID NO: 35) of antibody MIL-44-67-4. 4. A vector comprising one or both of the light chain and heavy chain of: a) an anti-GCC body molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-148-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable region (SEQ ID NO: 15) of antibody MIL-44-67-4; orb) an anti-GCC antibody molecule, comprising (i) light chain CDR1 (SEQ ID NO: 27), CDR2 (SEQ ID NO: 28), and CDR3 (SEQ ID NO: 29), and heavy chain CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 22), and CDR3 (SEQ ID NO: 23) of antibody MIL-44-148-2, or(ii) light chain CDR1 (SEQ ID NO: 39), CDR2 (SEQ ID NO: 40), and CDR3 (SEQ ID NO: 41) and heavy chain CDR1 (SEQ ID NO: 33), CDR2 (SEQ ID NO: 34), and CDR3 (SEQ ID NO: 35) of antibody MIL-44-67-4. 5. A method of detecting a GCC molecule comprising contacting the molecule with: a) an anti-GCC body molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-148-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable region (SEQ ID NO: 15) of antibody MIL-44-67-4; orb) an anti-GCC antibody molecule, comprising (i) light chain CDR1 (SEQ ID NO: 27), CDR2 (SEQ ID NO: 28), and CDR3 (SEQ ID NO: 29), and heavy chain CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 22), and CDR3 (SEQ ID NO: 23) of antibody MIL-44-148-2, or(ii) light chain CDR1 (SEQ ID NO: 39), CDR2 (SEQ ID NO: 40), and CDR3 (SEQ ID NO: 41) and heavy chain CDR1 (SEQ ID NO: 33), CDR2 (SEQ ID NO: 34), and CDR3 (SEQ ID NO: 35) of antibody MIL-44-67-4. 6. The method of claim 5, wherein said method comprises an immunohistochemistry assay using a biological sample derived from a patient suspected of having a GCC expressing cancer. 7. The method of claim 6, wherein said biological sample is a tumor biopsy. 8. The method of claim 6, further comprising the step of quantifying GCC expression in said biological sample. 9. The method of claim 8, wherein said quantification of GCC expression comprises apical GCC expression, cytoplasmic GCC expression, or both. 10. The method of claim 8, wherein said quantification step comprises an H-score approach. 11. The method of claim 6, wherein said GCC expressing cancer is selected from the group consisting of: colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, ovarian cancer, lung cancer, a gastrointestinal neuroendocrine tumor, and a bronchopulmonary neuroendocrine tumor. 12. A method of treating a patient having cancer characterized by GCC-expressing tumor cells, comprising: a. detecting GCC expression on a sample of tumor cells from the patient by contacting said sample with;(1) an anti-GCC antibody molecule, comprising (i) a light chain variable region (SEQ ID NO: 13) and a heavy chain variable region (SEQ ID NO: 11) of antibody MIL-44-145-2; or(ii) a light chain variable region (SEQ ID NO: 17) and a heavy chain variable region (SEQ ID NO: 15) of antibody MIL-44-67-4; or(2) an anti-GCC antibody molecule, comprising (i) light chain CDR1 (SEQ ID NO: 27), CDR2 (SEQ ID NO: 28), and CDR3 (SEQ ID NO: 29), and heavy chain CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 22), and CDR3 (SEQ ID NO: 23) of antibody MIL-44-148-2, or(ii) light chain CDR1 (SEQ ID NO: 39), CDR2 (SEQ ID NO: 40), and CDR3 (SEQ ID NO: 41) and heavy chain CDR1 (SEQ ID NO: 33), CDR2 (SEQ ID NO: 34), and CDR3 (SEQ ID NO: 35) of antibody MIL-44-67-4; andb. administering a therapeutic anti-CGG antibody molecule conjugated to a toxin if the tumor cells express GCC on the cell surface.
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