HER2/neu-Specific Antibodies and Methods of Using Same
This invention relates to antibodies that specifically bind HER2/neu, and particularly chimeric 4D5 antibodies to HER2/neu, which have reduced glycosylation as compared to known 4D5 antibodies. The invention also relates to methods of using the 4D5 antibodies and compositions comprising them in the diagnosis, prognosis and therapy of diseases such as cancer, autoimmune diseases, inflammatory disorders, and infectious disease.
1 . A method of treating a HER2/neu-expressing cancer in a subject in need thereof, comprising administering to the subject:
a) a first dose of 10, 15, or 18 mg/kg of a chimeric 4D5 antibody; and
b) a second dose of 10, 15, or 18 mg/kg of the chimeric 4D5 antibody administered to the subject, wherein the second dose is administered three weeks (±3 days) following the administration of the first dose;
wherein the chimeric 4D5 antibody comprises a light chain variable domain having the amino acid sequence of SEQ ID NO:4, and a heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:11, and SEQ ID NO:13.
2 . The method of claim 1 , wherein the first or second dose is 10 mg/kg.
3 . The method of claim 1 , wherein the first or second dose is 15 mg/kg.
4 . The method of claim 1 , wherein the first or second dose is 18 mg/kg.
5 . The method of claim 1 , wherein the method further comprises administering to the subject one ore more subsequent doses of 10, 15 or 18 mg/kg of the chimeric 4D5 antibody, wherein the one or more subsequent doses are administered three weeks (±3 days) following the administration of the second dose, or previous subsequent dose.
6 . The method of claim 1 , wherein the chimeric 4D5 antibody is administered by intravenous infusion.
7 . The method of claim 6 , wherein the intravenous infusion is over a period of 30-180 minutes.
8 . The method of claim 1 , wherein the chimeric 4D5 antibody comprises a light chain having the amino acid sequence of SEQ ID NO:2, and a heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13,
9 . The method of claim 1 , wherein the HER2/neu-expressing cancer is breast cancer, prostate cancer, uterine cancer, ovarian cancer, colon cancer, endometrial cancer, adrenal carcinoma, non-small cell lung cancer, head and neck cancer, laryngeal cancer, liver cancer, renal cancer, glioblastoma, or pancreatic cancer.
10 . The method of claim 1 , wherein said treatment further comprises the step of administering a second therapeutic agent simultaneously or sequentially with the chimeric 4D5 antibody, wherein said second therapeutic agent is selected from the group consisting of an anti-angiogenic agent, an anti-neoplastic agent, a chemotherapeutic agent, and a cytotoxic agent.
11 . A method of treating a HER2/neu-expressing cancer in a subject in need thereof, comprising administering to the subject:
a) a first dose of 10, 15, or 18 mg/kg of a chimeric 4D5 antibody; and
b) a second lower dose of the chimeric 4D5 antibody administered to the subject, wherein the second dose is adminstered three weeks (±3 days) following the administration of the first dose;
wherein the chimeric 4D5 antibody comprises a light chain variable domain having the amino acid sequence of SEQ ID NO:4, and a heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:11, and SEQ ID NO:13.
11 . The method of claim 11 , wherein the first dose is 10 mg/kg and the second lower dose is less than 10 mg/kg.
13 . The method of claim 11 , wherein the first dose is 15 mg/kg and the second lower dose is less than 15 mg/kg.
14 . The method of claim 11 , wherein the first dose is 18 mg/kg and the second lower dose is less than 18 mg/kg.
15 . The method of claim 11 , wherein the method further comprises administering to the subject one or more subsequent lower doses of the chimeric 4D5 antibody, wherein the one or more subsequent lower doses are administered three weeks (±3 days) following the administration of the second lower dose, or previous subsequent lower dose.
16 . The method of claim 11 , wherein the chimeric 4D5 antibody is administered by intravenous infusion.
17 . The method of claim 16 , wherein the intravenous infusion is over a period of 30-180 minutes.
18 . The method of claim 11 , wherein the chimeric 4D5 antibody comprises a light chain having the amino acid sequence of SEQ ID NO:2, and a heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO:9, SEQ ID NO:11 or SEQ ID NO:13,
19 . The method of claim 11 , wherein the HER2/neu-expressing cancer is breast cancer, prostate cancer, uterine cancer, ovarian cancer, colon cancer, endometrial cancer, adrenal carcinoma, non-small cell lung cancer, head and neck cancer, laryngeal cancer, liver cancer, renal cancer, glioblastoma, or pancreatic cancer.
20 . The method of claim 11 , wherein said treatment further comprises the step of administering a second therapeutic agent simultaneously or sequentially with the chimeric 4D5 antibody, wherein said second therapeutic agent is selected from the group consisting of an anti-angiogenic agent, an anti-neoplastic agent, a chemotherapeutic agent, and a cytotoxic agent.