Methods of using bispecific antigen-binding constructs targeting HER2
Described herein methods of using antigen-binding constructs to treat HER2+ tumors in a subject such as breast, lung, or head and neck tumors. In some aspects, the tumor volume in the subject after receiving at least seven doses of the antigen binding construct is less than the tumor volume of a control subject receiving an equivalent amount of trastuzumab. In some aspects, the survival of the subject receiving the antigen binding construct is increased as compared to a control subject receiving an equivalent amount of a non-specific control antibody or as compared to a control subject not receiving treatment.
1. A method of treating a subject having a tumor, the method comprising administering to the subject an effective amount of an antigen binding construct comprising:
a first antigen-binding polypeptide construct which monovalently and specifically binds a HER2 (human epidermal growth factor receptor 2) ECD2 (extracellular domain 2) region on a HER2-expressing cell and comprising a first heavy chain variable domain comprising SEQ ID NO:99 and a first light chain variable domain comprising SEQ ID NO:71, and
a second antigen-binding polypeptide construct which monovalently and specifically binds a HER2 ECD4 (extracellular domain 4) region on a HER2-expressing cell and comprising a second heavy chain variable domain comprising SEQ ID NO:305 and a second light chain variable domain comprising SEQ ID NO:297, and
first and second linker polypeptides, wherein the first linker polypeptide is operably linked to the first antigen-binding polypeptide construct, and the second linker polypeptide is operably linked to the second antigen-binding polypeptide construct;
wherein the first antigen binding polypeptide construct is a Fab and the second antigen binding polypeptide construct is an scFv, and
wherein tumor growth is decreased as compared to a control receiving an equivalent amount of a non-specific control antibody, as compared to a control receiving an equivalent amount of trastuzumab, or as compared to a control not receiving treatment; and
wherein the antigen binding construct is administered to the subject once every 14 days at a dose of at least 10 mg of antigen binding construct per kg of body weight or once every 14 days at a dose of at least 15 mg of antigen binding construct per kg of body weight or once every 14 days at a dose of at least 20 mg of antigen binding construct per kg of body weight or once every 21 days at a dose of at least 15 mg of antigen binding construct per kg of body weight or once every 21 days at a dose of at least 20 mg of antigen binding construct per kg of body weight.
2. The method of claim 1 wherein the antigen binding construct comprises the full length sequences of v10000 as set forth in SEQ ID NOS: 97, 295, and 69.
3. The method of claim 1 , wherein the antigen binding construct consists of the full length sequences of v10000 as set forth in SEQ ID NOS: 97, 295, and 69.
4. The method of claim 1 , wherein the antigen binding construct is administered intravenously.
5. The method of claim 1 , wherein the tumor is a HER2 1+ tumor, a HER2 2+ tumor or a HER2 3+ tumor.
6. The method of claim 5 , wherein the antigen binding construct binds to the HER2 1+ tumor, the HER2 2+ tumor or the HER2 3+ tumor at levels that are about 1.5 to 1.6-fold greater than an anti-HER2 monospecific Full-Sized Antibody (FSA).
7. The method of claim 1 , wherein the tumor is a gastric or breast cancer.
8. A method of treating a subject having a tumor comprising administering to the subject a pharmaceutical composition comprising an effective amount of an antigen binding construct and a pharmaceutically acceptable carrier,
wherein the antigen binding construct comprises:
a first antigen-binding polypeptide construct which monovalently and specifically binds a HER2 (human epidermal growth factor receptor 2) ECD2 (extracellular domain 2) region on a HER2-expressing cell and comprising a first heavy chain variable domain comprising SEQ ID NO:99 and a first light chain variable domain comprising SEQ ID NO:71, and
a second antigen-binding polypeptide construct which monovalently and specifically binds a HER2 ECD4 (extracellular domain 4) region on a HER2-expressing cell and comprising a second heavy chain variable domain comprising SEQ ID NO:305 and a second light chain variable domain comprising SEQ ID NO:297, and
first and second linker polypeptides, wherein the first linker polypeptide is operably linked to the first antigen-binding polypeptide construct, and the second linker polypeptide is operably linked to the second antigen-binding polypeptide construct;
wherein the first antigen binding polypeptide construct is a Fab and the second antigen binding polypeptide construct is an scFv, and
wherein tumor growth is decreased as compared to a control receiving an equivalent amount of a non-specific control antibody, as compared to a control receiving an equivalent amount of trastuzumab, or as compared to a control not receiving treatment; and
wherein the antigen binding construct is administered to the subject once every 14 days at a dose of at least 10 mg of antigen binding construct per kg of body weight or once every 14 days at a dose of at least 15 mg of antigen binding construct per kg of body weight or once every 14 days at a dose of at least 20 mg of antigen binding construct per kg of body weight or once every 21 days at a dose of at least 15 mg of antigen binding construct per kg of body weight or once every 21 days at a dose of at least 20 mg of antigen binding construct per kg of body weight.
9. The method of claim 8 , wherein the antigen binding construct comprises the full length sequences of v10000 as set forth in SEQ ID NOS: 97, 295, and 69, and wherein the antigen binding construct is administered intravenously.
10. The method of claim 9 , wherein the tumor is a gastric tumor.
11. The method of claim 9 , wherein the antigen binding construct is administered to the subject once every 14 days at a dose of at least 10 mg of antigen binding construct per kg of body weight.
12. The method of claim 9 , wherein the antigen binding construct is administered to the subject once every 14 days at a dose of at least 15 mg of antigen binding construct per kg of body weight.
13. The method of claim 9 , wherein the antigen binding construct is administered to the subject once every 14 days at a dose of at least 20 mg of antigen binding construct per kg of body weight.
14. The method of claim 9 , wherein the antigen binding construct is administered to the subject once every 21 days at a dose of at least 20 mg of antigen binding construct per kg of body weight.
15. The method of claim 9 , wherein the tumor is breast cancer, and wherein the antigen binding construct is administered to the subject once every 21 days at a dose of at least 15 mg of antigen binding construct per kg of body weight, or once every 21 days at a dose of at least 20 mg of antigen binding construct per kg of body weight.
16. The method of claim 15 , wherein the tumor is a HER2 1+ tumor, a HER2 2+ tumor or a HER2 3+ tumor.
17. The method of claim 16 , wherein the tumor is HER2-gene amplified.
18. The method of claim 17 , wherein the tumor is chemotherapy resistant breast cancer.
19. The method of claim 15 , wherein the tumor is resistant to an anti-HER2 treatment.
20. The method of claim 19 , wherein the tumor is HER2 3+ trastuzumab-resistant or HER2 2+ trastuzumab-resistant metastatic breast cancer.
21. The method of claim 19 , wherein the tumor is trastuzumab-resistant, pertuzumab-resistant, or trastuzumab and pertuzumab-resistant breast cancer.
22. The method of claim 15 , wherein the tumor is invasive ductal or metastatic breast cancer.
23. The method of claim 9 , wherein the tumor is a HER3+ tumor.