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Generated: August 20, 2019

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Claims for Patent: 8,735,551

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Summary for Patent: 8,735,551
Title:Antibodies for epidermal growth factor receptor 3 (HER3)
Abstract: The present invention relates to antibodies or fragments thereof that target a conformational epitope of a HER receptor. In particular, the invention relates to antibodies or fragments thereof that target a conformational epitope of HER3 receptor and compositions and methods of use thereof.
Inventor(s): Garner; Andrew Paul (Cambridge, MA), Sprague; Elizabeth Anne Reisinger (Cambridge, MA), Ettenberg; Seth Alexander (Cambridge, MA), Kunz; Christian (Munich, DE), Haubst; Nicole (Munich, DE), Elis; Winfried (Munchen-Pasing, DE)
Assignee: Novartis AG (Basel, CH)
Application Number:13/214,413
Patent Claims:1. An isolated monoclonal antibody or antigen binding fragment thereof that recognizes a conformational epitope of a HER3 receptor, wherein the conformational epitope comprises amino acid residues 265-277, and 315 within domain 2 and amino acid residues 571, 582-584, 596-597, 600-602, and 609-615 within domain 4 of the HER3 receptor of SEQ ID NO: 1, and wherein the antibody or fragment thereof blocks both ligand-dependent and ligand-independent signal transduction.

2. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1, wherein the antibody or fragment thereof binds to the inactive state of the HER3 receptor.

3. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1, wherein the antibody or fragment thereof stabilizes the HER3 receptor in the inactive state.

4. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1, which when the antibody or antigen binding fragment thereof is bound to the HER3 receptor allows a HER3 ligand to concurrently bind to a ligand binding site on the HER3 receptor.

5. The isolated monoclonal antibody or antigen binding fragment thereof of claim 4, wherein the HER3 ligand is selected from the group consisting of neuregulin 1 (NRG), neuregulin 2, betacellulin, heparin-binding epidermal growth factor, and epiregulin.

6. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1, wherein the VH of the antibody or fragment thereof binds the following HER3 receptor residues: Asn266, Lys267, Leu268, Thr269, Gln271, Glu273, Pro274, Asn275, Pro276, His277, Asn315, Asp571, Pro583, His584, Ala596, and Lys597 of SEQ ID NO: 1.

7. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1, wherein the VL of the antibody or fragment thereof binds the following HER3 receptor residues: Tyr265, Lys267, Leu268, Phe270, Gly582, Pro583, Lys597, Ile600, Lys602, Glu609, Arg611, Pro612, Cys613, His614, and Glu615 of SEQ ID NO: 1.

8. An isolated monoclonal antibody or antigen binding fragment thereof that recognizes a conformational epitope of a HER3 receptor, wherein the conformational epitope comprises amino acid residues 265-277, and 315 within domain 2 and amino acid residues 571, 582-584, 596-597, 600-602, and 609-615 within domain 4 of the HER3 receptor of SEQ ID NO:1, wherein binding of the antibody or fragment thereof to the HER3 receptor in the absence of a HER3 ligand reduces ligand-independent formation of a HER2-HER3 protein complex in a cell which expresses HER2 and HER3.

9. The isolated monoclonal antibody or antigen binding fragment thereof of claim 8, wherein the antibody or fragment thereof stabilizes the HER3 receptor in an inactive state such that the HER3 receptor fails to dimerize with the HER2 receptor to form a HER2-HER3 protein complex.

10. The isolated monoclonal antibody or antigen binding fragment thereof of claim 9, wherein the failure to form a HER2-HER3 protein complex prevents activation of signal transduction.

11. An isolated monoclonal antibody or antigen binding fragment thereof that recognizes a conformational epitope of a HER3 receptor, wherein the conformational epitope comprises amino acid residues 265-277, and 315 within domain 2 and amino acid residues 571, 582-584, 596-597, 600-602, and 609-615 within domain 4 of the HER3 receptor of SEQ ID NO:1, wherein binding of the antibody or fragment thereof to the HER3 receptor in the presence of a HER3 ligand reduces ligand-dependent formation of a HER2-HER3 protein complex in a cell which expresses HER2 and HER3.

12. The isolated monoclonal antibody or antigen binding fragment thereof of claim 11, wherein the antibody or fragment thereof stabilizes the HER3 receptor in an inactive state such that the HER3 receptor fails to dimerize with the HER2 receptor in the presence of a HER3 ligand to form a HER2-HER3 protein complex.

13. The isolated monoclonal antibody or antigen binding fragment thereof of claim 11, wherein the failure to form a HER2-HER3 protein complex prevents activation of signal transduction.

14. The isolated monoclonal antibody or antigen binding fragment thereof of claim 11, wherein the ligand is selected from the group consisting of neuregulin 1 (NRG), neuregulin 2, betacellulin, heparin-binding epidermal growth factor, and epiregulin.

15. The isolated monoclonal antibody or antigen binding fragment thereof of claim 11, wherein the antibody or fragment thereof inhibits phosphorylation of HER3 as assessed by a HER3 ligand-independent phosphorylation assay.

16. The isolated monoclonal antibody or antigen binding fragment thereof of claim 15, wherein the HER3 ligand-independent phosphorylation assay uses HER2 amplified cells, wherein the HER2 amplified cells are SK-Br-3 cells.

17. An isolated monoclonal antibody or antigen binding fragment thereof that recognizes a conformational epitope of a HER3 receptor, wherein the conformational epitope comprises amino acid residues 265-277, and 315 within domain 2 and amino acid residues 571, 582-584, 596-597, 600-602, and 609-615 within domain 4 of the HER3 receptor of SEQ ID NO:1, and wherein the antibody or fragment thereof inhibits phosphorylation of HER3 as assessed by HER3 ligand-dependent phosphorylation assay.

18. The isolated monoclonal antibody or antigen binding fragment thereof of claim 17, wherein the HER3 ligand-dependent phosphorylation assay uses stimulated MCF7 cells in the presence of neuregulin (NRG).

19. An isolated anti-HER3 monoclonal antibody or antigen binding fragment thereof, binds to the same conformational epitope as an anti-HER3 antibody comprising a VH of SEQ ID NO: 141 and VL of SEQ ID NO: 140.

20. An isolated monoclonal antibody or antigen binding fragment thereof to HER3 receptor, comprising a heavy chain variable region CDR1 of SEQ ID NO: 128; CDR2 of SEQ ID NO: 129; CDR3 of SEQ ID NO: 130; and a light chain variable region CDR1 of SEQ ID NO: 131; CDR2 of SEQ ID NO: 132; and CDR3 of SEQ ID NO: 133.

21. The isolated antigen binding fragment of claim 1, wherein the fragment is selected from the group consisting of Fab, F(ab.sub.2)', and scFV.

22. A pharmaceutical composition comprising a monoclonal antibody or antigen binding fragment thereof of any one of claims 1-5, 6, 8-18, 19, 20, and 21 and a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, further comprising an additional therapeutic agent.

24. The pharmaceutical composition of claim 23, wherein the additional therapeutic agent is a HER2 inhibitor.

25. The pharmaceutical composition of claim 23, wherein the additional therapeutic agent is a HER2 inhibitor selected from the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib, lapatinib or lapatinib ditosylate.

26. The pharmaceutical composition of claim 23, wherein the additional therapeutic agent is an mTOR inhibitor selected from the group consisting of Temsirolimus, ridaforolimus and everolimus.

27. The pharmaceutical composition of claim 23, wherein the additional therapeutic agent is a PI3 kinase inhibitor selected from the group consisting of GDC 0941, BEZ235, BMK120 and BYL719.

28. A method of treating a breast or pancreatic cancer comprising selecting a human subject having an HER3 receptor expressing breast or pancreatic cancer, administering to the subject an effective amount of a composition comprising an antibody or antigen binding fragment thereof of any one of 1-5, 6, 7, 8-18, 19, 20 and 21 and a pharmaceutically acceptable carrier.

29. The method of claim 28, wherein the cancer is breast cancer.

30. The method of claim 28, wherein the cancer is pancreatic cancer.

31. The isolated monoclonal antibody or antigen binding fragment thereof of any one of claims 1-5, 6, 7, 8-18, 19, 20 and 21, wherein the antibody or antigen binding fragment thereof is a recombinant antibody or antigen binding fragment.

Details for Patent 8,735,551

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech HERCEPTIN trastuzumab VIAL; INTRAVENOUS 103792 001 1998-09-25 ➤ Sign Up Novartis AG (Basel, CH) 2036-04-30 RX Orphan search
Genentech PERJETA pertuzumab VIAL; SINGLE-USE 125409 001 2012-06-08 ➤ Sign Up Novartis AG (Basel, CH) 2036-04-30 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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