Claims for Patent: 9,555,112

Summary for Patent: 9,555,112

Title:	Monoclonal antibodies against HER2 epitope and methods of use thereof
Abstract:	This invention provides fully human monoclonal antibodies that recognize HER2. The invention further provides methods of using such monoclonal antibodies in a variety of therapeutic, diagnostic, and prophylactic indications.
Inventor(s):	Bodyak; Natalya D. (Brookline, MA), DeVit; Michael J. (Sudbury, MA), Krauland; Eric M. (Lebanon, NH), Lowinger; Timothy B. (Carlisle, MA), Park; Peter U. (Somerville, MA), Prinz; Bianka (Lebanon, NH), Yurkovetskiy; Aleksandr V. (Littleton, MA)
Assignee:	Mersana Therapeutics, Inc. (Cambridge, MA)
Application Number:	14/742,947
Patent Claims:	1. A method of alleviating a symptom of a cancer in a subject in need thereof, the method comprising administering a conjugate to the subject in an amount sufficient to alleviate the symptom of the cancer, wherein the conjugate comprises an isolated antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor and one or more therapeutic or diagnostic agents (D), wherein each D is independently connected directly or indirectly to the antibody or antigen binding fragment thereof, and wherein the antibody or antigen binding fragment thereof comprises a CDRH1 comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 25); a CDRH2 comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 26); a CDRH3 comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 27); a CDRL1 comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 28); a CDRL2 comprising the amino acid sequence GASSRAT (SEQ ID NO: 21); and a CDRL3 comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 29). 2. The method of claim 1, wherein the subject is human. 3. The method of claim 1, wherein the cancer is selected from the group consisting of anal cancer, astrocytoma, leukemia, lymphoma, head and neck cancer, liver cancer, testicular cancer, cervical cancer, sarcoma, hemangioma, esophageal cancer, eye cancer, laryngeal cancer, mouth cancer, mesothelioma, skin cancer, myeloma, oral cancer, rectal cancer, throat cancer, bladder cancer, breast cancer, uterine cancer, ovarian, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), colon cancer, pancreatic cancer, renal cancer, and gastric cancer. 4. The method of claim 1, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, non-small cell lung cancer (NSCLC), and ovarian cancer. 5. The method of claim 1 further comprising administering a second agent to the subject. 6. The method of claim 5, wherein the second agent is at least a second antibody or antigen binding fragment thereof that specifically binds HER2. 7. The method of claim 6, wherein the second antibody or antigen binding fragment thereof is a HER2 antibody, a HER2 dimerization inhibitor antibody, or a combination of a HER2 antibody and a HER2 dimerization inhibitor antibody. 8. The method of claim 7, wherein the HER2 antibody, the HER2 dimerization inhibitor antibody or the combination of a HER2 antibody and a HER2 dimerization inhibitor antibody comprises trastuzumab or pertuzumab or a combination thereof. 9. The method of claim 1, wherein the subject is identified as having low HER2 expression. 10. The method of claim 1, wherein the subject is identified as having a scoring of 1+ or 2+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and wherein the HER2 gene is not amplified in the test cell population. 11. The method of claim 1, wherein the subject is refractory to chemotherapy. 12. The method of claim 1, wherein the subject is resistant to treatment with trastuzumab emtansine. 13. The method of claim 1, wherein the subject is not resistant to treatment with trastuzumab emtansine. 14. The method of claim 1, wherein the subject is identified as having a scoring of 2+ or 3+ for HER2 expression as detected by immunohistochemistry (IHC) analysis performed on a test cell population, and wherein the HER2 gene is amplified or mutated in the test cell population. 15. The method of claim 1, wherein the antibody or antigen binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 14. 16. The method of claim 1, wherein the antibody or antigen binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain comprising the amino acid sequence of SEQ ID NO: 6. 17. The method of claim 1, wherein the antibody or antigen binding fragment thereof is a monoclonal antibody, a domain antibody, a single chain antibody, a Fab fragment, a F(ab').sub.2 fragment, a scFv, a scFv-Fc, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody. 18. The method of claim 1, wherein the antibody or antigen binding fragment thereof is a rabbit, mouse, chimeric, humanized or fully human monoclonal antibody. 19. The method of claim 1, wherein the antibody or antigen binding fragment thereof is an IgG isotype. 20. The method of claim 1, wherein the antibody or antigen binding fragment thereof is an IgG1 isotype. 21. The method of claim 1, wherein the conjugate further comprises one or more polymeric scaffolds connected both to the antibody or antigen binding fragment thereof and to one or more D, wherein each of the one or more D is independently connected to the antibody or antigen binding fragment thereof via the one or more polymeric scaffolds. 22. The method of claim 21, wherein each of the one or more polymeric scaffolds independently comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from about 2 kDa to about 40 kDa. 23. The method of claim 22, wherein each of the one or more polymeric scaffolds independently is of Formula (Ic): ##STR00064## wherein: L.sup.D1 is a carbonyl-containing moiety; each occurrence of ##STR00065## is independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; and the ##STR00066## between L.sup.D1 and D denotes direct or indirect attachment of D to L.sup.D1; each occurrence of ##STR00067## is independently a second linker not yet connected to the isolated antibody or antigen binding fragment thereof, in which L.sup.P2 is a moiety containing a functional group that is yet to form a covalent bond with a functional group of the isolated antibody or antigen binding fragment thereof, and the between L.sup.D1 and L.sup.P2 denotes direct or indirect attachment of L.sup.P2 to L.sup.D1, and each occurrence of the second linker is distinct from each occurrence of the first linker; each occurrence of ##STR00068## is independently a third linker that connects each D-carrying polymeric scaffold to the isolated antibody or antigen binding fragment thereof, in which the terminal attached to L.sup.P2 denotes direct or indirect attachment of L.sup.P2 to the isolated antibody or antigen binding fragment thereof upon formation of a covalent bond between a functional group of L.sup.P2 and a functional group of the isolated antibody or antigen binding fragment thereof; and each occurrence of the third linker is distinct from each occurrence of the first linker; m is an integer from 1 to about 300, m.sub.1 is an integer from 1 to about 140, m.sub.2 is an integer from 1 to about 40, m.sub.3 is an integer from 0 to about 18, m.sub.4 is an integer from 1 to about 10; the sum of m, m.sub.1, m.sub.2, m.sub.3, and m.sub.4 ranges from 15 to 300; and the total number of L.sup.P2 connected to the isolated antibody or antigen binding fragment thereof is 10 or less. 24. The method of claim 23, wherein the sum of m, m.sub.1, m.sub.2, m.sub.3 and m.sub.4 ranges from 15 to 150, m.sub.1 is an integer from 1 to 70, m.sub.2 is an integer from 1 to 20, m.sub.3 is an integer from 0 to 10, and PHF has a molecular weight ranging from about 2 kDa to about 20 kDa. 25. The method of claim 23, wherein the sum of m, m.sub.1, m.sub.z, m.sub.3 and m.sub.4 ranges from 20 to 110, m.sub.1 is an integer from 2 to 50, m.sub.2 is an integer from 2 to 15, m.sub.3 is an integer from 0 to 8; and PHF has a molecular weight ranging from about 3 kDa to about 15 kDa. 26. The method of claim 23, wherein the sum of m, m.sub.1, m.sub.z, m.sub.3 and m.sub.4 ranges from 40 to 75, m.sub.1 is an integer from 2 to 35, m.sub.2 is an integer from 2 to 10, m.sub.3 is an integer from 0 to 5; and PHF has a molecular weight ranging from about 5 kDa to about 10 kDa. 27. The method of claim 23, wherein the functional group of L.sup.P2 is selected from --SR.sup.p, --S--S-LG, ##STR00069## and halo, in which LG is a leaving group, R.sup.p is H or a sulfur protecting group, and one of X.sub.a and X.sub.b is H and the other is a water-soluble maleimido blocking moiety, or X.sub.a and X.sub.b, together with the carbon atoms to which they are attached for a carbon-carbon double bond. 28. The method of claim 23, wherein L.sup.D1 comprises --X--(CH.sub.2).sub.v--C(.dbd.O)-- with X directly connected to the carbonyl group of ##STR00070## in which X is CH.sub.2, O, or NH, and v is an integer from 1 to 6. 29. The method of claim 23, wherein each occurrence of ##STR00071## is independently --C(.dbd.O)--X--(CH.sub.2).sub.v--C(.dbd.O)--NH--(CH.sub.2).sub.u--NHC(.d- bd.O)--(CH.sub.2).sub.w--(OCH.sub.2).sub.x--NHC(.dbd.O)--(CH.sub.2).sub.y-- M, in which X is CH.sub.2, O, or NH, each of v, u, w, x and y independently is an integer from 1 to 6, and M is ##STR00072## wherein one of X.sub.a and X.sub.b is H and the other is a water-soluble maleimido blocking moiety, or X.sub.a and X.sub.b, together with the carbon atoms to which they are attached for a carbon-carbon double bond. 30. The method of claim 29, wherein each of v, u, w, x and y is 2. 31. The method of claim 1, wherein each of the one or more D is a therapeutic agent having a molecular weight of .ltoreq.5 kDa. 32. The method of claim 30, wherein each of the one or more polymeric scaffolds independently is of Formula (Id): ##STR00073## wherein: m.sub.3a is an integer from 0 to about 17, m.sub.3b is an integer from 1 to about 8, and the terminal denotes the direct attachment of the one or more polymeric scaffolds to the isolated antibody or antigen binding fragment thereof. 33. The method of claim 1, wherein at least one of the one or more D is a diagnostic agent. 34. The method of claim 1, wherein the isolated antibody or antigen binding fragment thereof has a molecular weight of 40 kDa or greater. 35. The method of claim 1, wherein each of the one or more D is independently connected to the antibody or antigen binding fragment thereof via a non-polymeric linking moiety. 36. The method of claim 22, wherein each of the one or more polymeric scaffolds independently is of Formula (If): ##STR00074## wherein: m is an integer from 1 to about 300, m.sub.1 is an integer from 1 to about 140, m.sub.2 is an integer from 1 to about 40, m.sub.3a is an integer from 0 to about 17, m.sub.3b is an integer from 1 to about 8; the sum of m.sub.3a and m.sub.3b ranges from 1 and about 18; and the sum of m, m.sub.1, m.sub.2, m.sub.3a, and m.sub.3b ranges from 15 to about 300; the terminal denotes the attachment of one or more polymeric scaffolds to the isolated antibody or antigen binding fragment thereof that specifically binds to an epitope of the human HER2 receptor, wherein the isolated antibody or antigen binding fragment thereof is an isolated anti-HER2 antibody that comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence FTFSSYSMN (SEQ ID NO: 25); a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence YISSSSSTIYYADSVKG (SEQ ID NO: 26); a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GGHGYFDL (SEQ ID NO: 27); a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSSYLA (SEQ ID NO: 28); a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GASSRAT (SEQ ID NO: 21); and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYHHSPLT (SEQ ID NO: 29); and the ratio between the PHF and the antibody is 10 or less. 37. The method of claim 36, wherein the PHF in Formula (If) has a molecular weight ranging from about 2 kDa to about 20 kDa, the sum of m, m.sub.1, m.sub.2, m.sub.3a and m.sub.3b ranges from about 15 to about 150, m.sub.1 is an integer from 1 to about 70, m.sub.2 is an integer from 1 to about 20, m.sub.3a is an integer from 0 to about 9, m.sub.3b is an integer from 1 to about 8, the sum of m.sub.3a and m.sub.3b ranges from 1 and about 10, and the ratio between the PHF and the isolated anti-HER2 antibody is an integer from 2 to about 8. 38. The method of claim 36, wherein the PHF in Formula (If) has a molecular weight ranging from about 3 kDa to about 15 kDa, the sum of m, m.sub.1, m.sub.2, m.sub.3a and m.sub.3b ranges from about 20 to about 110, m.sub.1 is an integer from 2 to about 50, m.sub.2 is an integer from 2 to about 15, m.sub.3a is an integer from 0 to about 7, m.sub.3b is an integer from 1 to about 8, the sum of m.sub.3a and m.sub.3b ranges from 1 and about 8, and the ratio between the PHF and the isolated anti-HER2 antibody or antigen-binding fragment thereof is an integer from 2 to about 8. 39. The method of claim 36, wherein the PHF in Formula (If) has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m.sub.1, m.sub.2, m.sub.3a and m.sub.3b ranges from about 40 to about 75, m.sub.1 is an integer from about 2 to about 35, m.sub.2 is an integer from about 2 to about 10, m.sub.3a is an integer from 0 to about 4, m.sub.3b is an integer from 1 to about 5, the sum of m.sub.3a and m.sub.3b ranges from 1 and about 5, and the ratio between the PHF and the isolated anti-HER2 antibody is an integer from 2 to about 8. 40. The method of claim 36, wherein the PHF in Formula (If) has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m.sub.1, m.sub.2, m.sub.3a and m.sub.3b ranges from about 40 to about 75, m.sub.1 is an integer from about 2 to about 35, m.sub.2 is an integer from about 2 to about 10, m.sub.3a is an integer from 0 to about 4, m.sub.3b is an integer from 1 to about 5, the sum of m.sub.3a and m.sub.3b ranges from 1 and about 5, and the ratio between the PHF and the isolated anti-HER2 antibody is an integer from 2 to about 6. 41. The method of claim 36, wherein the isolated anti-HER2 antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 14. 42. The method of claim 36, wherein the isolated anti-HER2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain comprising the amino acid sequence of SEQ ID NO: 6.

Details for Patent 9,555,112

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-06-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-06-18
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	06/08/2012		2034-06-18
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2034-06-18