Claims for Patent: 10,273,303

Summary for Patent: 10,273,303

Title:	Monovalent antigen binding constructs targeting EGFR and/or HER2 and uses thereof
Abstract:	Provided herein are monovalent antigen-binding constructs targeting EGFR and/or HER2. The monovalent antigen-binding constructs can include at least one antigen-binding polypeptide comprising a heavy chain variable domain, wherein the antigen-bind polypeptide specifically binds EGFR and/or HER2; and a heterodimeric Fc domain, the Fc domain comprising at least two CH3 domains, wherein the Fc domain is coupled, with or without a linker, to the antigen-binding polypeptide. Also provided are methods of making the constructs and methods of using the constructs.
Inventor(s):	Ng; Gordon Yiu Kon (Vancouver, CA), Chan; Peter Wing Yiu (Richmond, CA), Wickman; Grant Raymond (Vancouver, CA)
Assignee:	Zymeworks Inc. (Vancouver, CA)
Application Number:	15/036,174
Patent Claims:	1. A method of treating a subject having an epidermal growth factor receptor (EGFR)-expressing tumor, comprising: contacting the tumor with an effective amount of an isolated monovalent EGFR-binding construct comprising one antigen-binding polypeptide construct comprising a heavy chain variable domain and a light chain variable domain, or a single domain antibody coupled, with or without a linker, to a heterodimeric Fc, the Fc comprising two CH3 sequences comprising one or more asymmetric amino acid substitutions that promote formation of a heterodimeric Fc, wherein the antigen-binding polypeptide construct comprises three variable heavy chain CDRs as set forth in SEQ ID NOs:2, 3 and 4, and three variable light chain CDRs as set forth in SEQ ID NOs:6, 7, and 8, or wherein the antigen-binding polypeptide construct is a single domain antibody having three variable heavy chain CDRs as set forth in SEQ ID NOs:21, 22 and 23. 2. The method of claim 1, wherein the Fc is a heterodimeric human IgG1 Fc, wherein the antigen-binding polypeptide construct binds to an epitope located in the extracellular domain of EGFR, wherein the subject experiences less skin toxicity from the treatment compared to a subject treated with the isolated corresponding monospecific bivalent antigen-binding construct that binds or specifically binds EGFR, and wherein the tumor expresses a first level of cell surface EGFR that is equal to or less than a second level of cell surface EGFR of one or more of the following cell lines: A431, A549, BT474, CACO2, HCT116, JIMT1, MDA-MB-231, SKOV3, MCF7, or SKBR3. 3. The method according to claim 1, wherein the isolated monovalent EGFR-binding construct is OA-CTX (v4353) or OA-EG2 (v1323). 4. The method according to claim 1 wherein the monovalent EGFR-binding construct is afucosylated. 5. The method according to claim 1 wherein the monovalent EGFR-binding construct is conjugated to a drug, optionally wherein the drug is a maytansinoid. 6. The method according to claim 1, wherein a) the tumor expresses a first level of cell surface EGFR that is equal to or less than a second level of cell surface EGFR of one or more of the following cell lines: A431, A549, BT474, CACO2, HCT116, JIMT1, MDA-MB-231, SKOV3, MCF7, or SKBr3; b) the tumor expresses a median of 3.5.times.10.sup.6 or less, 2.8.times.10.sup.6 or less, 1.2.times.10.sup.6 or less, 2.4.times.10.sup.5 or less, 2.6.times.10.sup.5 or less, or 4.2.times.10.sup.4 or less EGFRs per cell, or c) wherein the tumor is an epidermal cell-derived cancer, a lung cancer, a breast cancer, a triple negative breast cancer, a ductal breast cancer, a gastric cancer, an ovarian cancer, a HER2+ cancer, glioblastoma, a cervical cancer, a renal cancer, an uterine cancer, or a colorectal cancer, optionally wherein the tumor is resistant or refractory to trastuzumab and/or pertuzumab and/or cetuximab. 7. The method according to claim 1 wherein a) the treatment results in shrinking the tumor, inhibiting the growth of the tumor, increasing time to progression of the tumor, prolonging disease-free survival of the subject, decreasing metastases, increasing the progression-free survival of the subject, or increasing the overall survival of a population of subjects, and/or b) wherein the subject is administered a fixed dose of the construct and experiences less skin toxicity from the treatment compared to a subject treated with a fixed dose of the corresponding isolated monospecific bivalent antigen-binding construct that binds or specifically binds EGFR, and wherein the fixed dose is determined on a molar basis, or the growth of the subject's keratinocytes is reduced less following treatment with a fixed dose of the construct compared to a subject treated with a fixed dose of the corresponding isolated monospecific bivalent antigen-binding construct that binds or specifically binds EGFR, and wherein the fixed dose is determined on a molar basis. 8. The method according to claim 1 wherein the method further comprises providing an additional agent, optionally wherein the additional agent binds HER2, or wherein the additional agent is pertuzumab or trastuzumab, optionally wherein the additional agent is a second isolated antigen binding construct, optionally wherein a) the second isolated antigen binding construct binds or specifically binds to HER2 or an extracellular domain of HER2, b) the second isolated antigen binding construct binds or specifically binds to ECD2 and/or ECD4 of HER2, or c) the second isolated antigen binding construct is an isolated monovalent antigen binding construct wherein the antigen-binding polypeptide construct of the second isolated antigen binding construct binds or specifically binds HER2 or an extracellular domain of HER2. 9. The method according to claim 5, wherein the maytansinoid is DM1. 10. The method according to claim 1, wherein the monovalent antigen-binding polypeptide construct comprises a VH sequence as set forth in SEQ ID NO:1 and a VL sequence as set forth in SEQ ID NO:5, or wherein the monovalent antigen-binding polypeptide construct comprises a VHH sequence as set forth in SEQ ID NO:20. 11. The method according to claim 1, wherein the isolated monovalent EGFR-binding construct blocks binding of EGF to EGFR on the tumor, blocks constitutive EGFR signaling in the tumor, or results in internalization of the isolated monovalent EGFR-binding construct. 12. The method of claim 1, wherein the Fc isotype is human IgG. 13. The method of claim 10, wherein the monovalent antigen-binding polypeptide construct comprises (1) a HC-1 sequence as set forth in SEQ ID NO:17, a HC-2 sequence as set forth in SEQ ID NO:18, and a LC sequence as set forth in SEQ ID NO:19; or (2) a HC-1 sequence as set forth in SEQ ID NO:30 and a HC-2 sequence as set forth in SEQ ID NO:31. 14. An isolated monovalent antigen-binding construct comprising: one antigen-binding polypeptide construct comprising a heavy chain variable domain and a light chain variable domain, or a single domain antibody, wherein the monovalent antigen-binding polypeptide construct specifically binds epidermal growth factor receptor (EGFR), wherein the monovalent antigen-binding polypeptide construct comprises three variable heavy chain CDRs as set forth in SEQ ID NOs:2, 3 and 4, and three variable light chain CDRs as set forth in SEQ ID NOs:6, 7, and 8, or wherein the monovalent antigen-binding polypeptide construct is a single domain antibody having three variable heavy chain CDRs as set forth in SEQ ID NOs:21, 22 and 23; and a heterodimeric Fc, the Fc comprising two CH3 sequences comprising one or more asymmetric amino acid substitutions that promote formation of a heterodimeric Fc, wherein the Fc is coupled, with or without a linker, to the antigen-binding polypeptide. 15. The construct according to claim 14, wherein the monovalent antigen-binding polypeptide construct (1) comprises a VH sequence as set forth in SEQ ID NO:1 and a VL sequence as set forth in SEQ ID NO:5, or (2) comprises a VHH sequence as set forth in SEQ ID NO:20. 16. The construct of claim 14, wherein the Fc isotype is human IgG. 17. The construct of claim 15, wherein the monovalent antigen-binding polypeptide construct comprises (1) a HC-1 sequence as set forth in SEQ ID NO:17, a HC-2 sequence as set forth in SEQ ID NO:18, and a LC sequence as set forth in SEQ ID NO:19; or (2) a HC-1 sequence as set forth in SEQ ID NO:30 and a HC-2 sequence as set forth in SEQ ID NO:31. 18. A pharmaceutical composition comprising the isolated monovalent antigen-binding construct of claim 14 and a pharmaceutically acceptable carrier. 19. A vector or set of vectors comprising one or more polynucleotides encoding the isolated monovalent antigen-binding construct according to claim 14. 20. An isolated cell comprising one or more polynucleotides encoding the isolated monovalent antigen-binding construct according to claim 14. 21. A method of obtaining the isolated monovalent antigen-binding construct according to claim 14, the method comprising the steps of: (a) obtaining a host cell culture, wherein the host cell comprises one or more nucleic acid sequences encoding the antigen-binding construct; (b) culturing the host cell culture under conditions sufficient to express the isolated monovalent antigen-binding construct; and (c) recovering the antigen-binding construct from the host cell culture.

Details for Patent 10,273,303

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2033-11-13
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2033-11-13
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2033-11-13
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2033-11-13
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	06/08/2012		2033-11-13