US-20260124316-A1 - FULLY HUMAN MONOCLONAL ANTIBODIES AGAINST HUMAN HER-2 AND METHODS FOR USING THE SAME

US20260124316A1US 20260124316 A1US20260124316 A1US 20260124316A1US-20260124316-A1

Abstract

Described herein are antibodies, particularly monoclonal antibodies, that specifically bind to human HER2 and are useful for the treatment of cancer in patients.

Inventors

Ginette Serrero

Assignees

A & G PHARMACEUTICAL, INC.

Dates

Publication Date: 20260507
Application Date: 20250821

Claims (19)

1 . A method for treating, preventing, inhibiting, and/or ameliorating cancer, wherein the cancer is resistant to trastuzumab or pertuzumab and/or consists essentially of cells that do not bind to trastuzumab and/or pertuzumab and/or expresses low levels of HER2, the method being carried out in a mammal comprising administering to the mammal at least one effective dose of a pharmaceutical composition comprising at least one antibody or derivative comprising a combination of amino acid sequences selected from the group consisting of: a) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 2, and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 11D7); b) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 7 and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 2A2); c) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 9 and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 12E3); d) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 10 and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 2D7); e) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 12, and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 3G7); f) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:1, 13, and 3 and a light chain variable region comprising CDR sequences SEQ ID NOs:4, 5, and 6 (antibody 8C1); g) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:14, 15 and 16 and a light chain variable region comprising CDR sequences SEQ ID NOs:17, 18, and 19 (antibody 2A1); h) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:20, 21 and 22 and a light chain variable region comprising CDR sequences SEQ ID NOs:23, 24, and 25 (antibody 7F9); i) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:26, 27, and 28 and a light chain variable region comprising CDR sequences SEQ ID NOs:29, 30, and 31 (antibody 9E4); j) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:32, 33, 34 and a light chain variable region comprising CDR sequences SEQ ID NOs:35, 36 and 37 (antibody 11C9); k) a heavy chain variable region comprising the CDR sequences SEQ ID NOs:32, 38, and 39 and a light chain variable region comprising CDR sequences SEQ ID NOs:35, 36 and 40 (antibody 12A6); l) a heavy chain variable region comprising SEQ ID NO:41 and a light chain variable region comprising SEQ ID NOs:42 (antibody 11D7); m) a heavy chain variable region comprising SEQ ID NO:43 and a light chain variable region comprising SEQ ID NOs:44 (antibody 2A2); n) a heavy chain variable region comprising SEQ ID NO:45 and a light chain variable region comprising SEQ ID NOs:46 (antibody 12E3); o) a heavy chain variable region comprising SEQ ID NO:47 and a light chain variable region comprising SEQ ID NOs:48 (antibody 2D7); p) a heavy chain variable region comprising SEQ ID NO:49 and a light chain variable region comprising SEQ ID NOs:50 (antibody 3G7); q) a heavy chain variable region comprising SEQ ID NO:51 and a light chain variable region comprising SEQ ID NOs:52 (antibody 8C1); r) a heavy chain variable region comprising SEQ ID NO:53 and a light chain variable region comprising SEQ ID NOs:54 (antibody 2A1); s) a heavy chain variable region comprising SEQ ID NO:55 and a light chain variable region comprising SEQ ID NOs:56 (antibody 7F9); t) a heavy chain variable region comprising SEQ ID NO:57 and a light chain variable region comprising SEQ ID NOs:58 (antibody 9E4); u) a heavy chain variable region comprising SEQ ID NO:59 and a light chain variable region comprising SEQ ID NOs:60 (antibody 11C9); v) a heavy chain variable region comprising SEQ ID NO:61 and a light chain variable region comprising SEQ ID NOs:62 (antibody 12A6); w) encoded by a heavy chain variable region and corresponding a light chain variable region encoded by any of polynucleotides of SEQ ID NOS. 63-84; and/or a conservatively substituted derivative thereof optionally comprising up to three amino acid substitutions in one or more CDRs thereof and/or up to ten amino acid substitutions of a heavy and/or light chain thereof; wherein: the antibody or antigen binding fragment thereof specifically binds to human HER2; and/or, the antibody or antigen binding fragment thereof exhibits biological activities that are not exhibited by and/or bind to epitopes that are not bound by trastuzumab and/or pertuzumab.
2 . The method of claim 1 wherein the at least one antibody or derivative is internalized into a cell that expresses HER2 in vitro and/or in vivo.
3 . The method of claim 1 wherein the at least one antibody or derivative competes with trastuzumab or pertuzumab for binding to HER2 receptor on the cell.
4 . The method of claim 3 wherein the at least one antibody or derivative competes with trastuzumab is selected from the group consisting of 11D7, 2A2, 12E3, 2D7, 3G7, and 8C1.
5 . The method of claim 1 wherein the at least one antibody or derivative does not compete with trastuzumab and/or pertuzumab for binding to HER2 receptor on the cell.
6 . The method of claim 5 wherein the at least one antibody or derivative does not compete with trastuzumab and/or pertuzumab selected from the group consisting of antibodies 2A1, 7F9, 9E4, 11C9, and 12A6.
7 . The method of claim 1 wherein the at least one antibody or derivative is an isolated monoclonal antibody.
8 . The method of claim 7 wherein the monoclonal antibody is a human monoclonal antibody.
9 . The method of claim 1 wherein said antibody is derived from a human antibody, human IgG, human IgG1, human IgG2, human IgG2a, human IgG2b, human IgG3, human IgG4, human IgM, human IgA, human IgA1, human IgA2, human IgD, human IgE, canine antibody, canine IgGA, canine IgGB, canine IgGC, canine IgGD, chicken antibody, chicken IgA, chicken IgD, chicken IgE, chicken IgG, chicken IgM, chicken IgY, goat antibody, goat IgG, mouse antibody, mouse IgG, pig antibody, rat antibody, llaman antibody, alpacan antibody, shark antibody and a camel antibody.
10 . The method of claim 1 wherein the derivative is selected from the group consisting of an F ab , F ab2 , Fab′ single chain antibody, Fv, single chain, mono-specific antibody, bispecific antibody, trimeric antibody, multi-specific antibody, multivalent antibody, chimeric antibody, canine-human chimeric antibody, canine-mouse chimeric antibody, antibody comprising a canine Fc, humanized antibody, human antibody, caninized antibody, CDR-grafted antibody, shark antibody, and a nanobody.
11 . The method of claim 1 wherein the at least one antibody or derivative comprises at least one effector moiety attached thereto, optionally wherein the effector moiety is selected from the group consisting of a cytotoxic drug, mertansine (DM1), an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, DM4, a taxane, a benzodiazepine, a benzodiazepine containing drug, a pyrrolo[1,4]benzodiazepine (PBD), an indolinobenzodiazepine an oxazolidinobenzodiazepine, a vinca alkaloids, toxin, diphtheria A chain, exotoxin A chain, ricin A chain, abrin A chain, curcin, crotin, phenomycin, enomycin, and radiochemical.
12 . The method of claim 1 wherein the at least one antibody or derivative is administered as an antibody-drug conjugate, optionally wherein the conjugate is internalized into a cell.
13 . The method of claim 12 comprising administering at least one first antibody or derivative and trastuzumab.
14 . The method of claim 12 comprising administering at least one first antibody or derivative and pertuzumab.
15 . The method of claim 12 comprising administering at least two types of antibodies and/or derivatives, wherein at least one type of antibody is internalized into a cell that expresses HER2 in vitro and/or in vivo and/or does not compete with trastuzumab for binding to HER2, optionally wherein the at least two types of antibodies bind to different epitopes on HER2.
16 . The method of claim 15 wherein at least one type of antibody or derivative is internalized into a cell that expresses HER2 in vitro and/or in vivo and/or at least one type of antibody or derivative competes with trastuzumab and/or pertuzumab for binding to HER2 receptor on the cell.
17 . The method of claim 15 , comprising administering at least one antibody selected from the group consisting of 11 D7, 2A2, 12E3, 2D7, 3G7, and 8C1 and/or at least one antibody selected from the group consisting of 2A1, 7F9, 9E4, 11C9, and 12A6; the method optionally further comprising administering trastuzumab and/or and pertuzumab and/or at least one other agent having biological activity against cells that express HER2.
18 . The method of claim 1 wherein multiple doses are administered to the animal; and/or, the antibody is administered in a dosage amount of about 0.1 to 50 mg/kg.
19 . The method of claim 6 wherein the at least one antibody or derivative binds to domain I and/or domain III of the HER2 receptor expressed on cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/685,564, filed Aug. 21, 2024, which is hereby incorporated in its entirety by reference for all purposes. SEQUENCE LISTING A Sequence Listing conforming to the rules of WIPO Standard ST.26 is hereby incorporated by reference. Said Sequence Listing has been filed as an electronic document via PatentCenter encoded as XML in UTF-8 text. The electronic document, created on Aug. 18, 2025, is entitled “AG_036-US_ST26.xml”, and is 138,800 bytes in size. FIELD OF THE DISCLOSURE This disclosure relates to antibodies, including fully human monoclonal antibodies (mAbs), that specifically bind to and internalize human epidermal growth factor-2, also known as HER-2, as well as methods of manufacturing (e.g., cell lines) and using the antibodies (e.g., treating cancer). BACKGROUND OF THE DISCLOSURE The human epidermal growth factor receptor (HER) family of receptors plays a central role in the pathogenesis of several human cancers. They are involved in cellular proliferation and differentiation by acting through multiple signaling pathways. The superfamily is composed of four major members HER1 (also known as Epidermal Growth Factor Receptor EGFR), HER2, HER3 and HER4 also call erbB1, erbB2, ErbB3 and ErbB4. All the members are characterized by a cysteine-rich extracellular domain including the ligand binding site, a transmembrane lipophilic region and an intracellular domain with a tyrosine kinase enzymatic activity. The HER receptors exist as monomers on the cell surface. Upon ligand binding, the receptors homo or heterodimerize with other HER members leading to phosphorylation. HER2 is a 125 amino-acid, 185 kDa transmembrane glycoprotein located on chromosome 17q12. It is overexpressed in many tissues to facilitate excessive/uncontrolled growth and tumorigenesis. HER2 has no known direct activating ligand and maybe constitutively activated or become active upon heterodimerization with other HER members leading to autophosphorylation of tyrosine residues within the intracellular domain triggering a variety of signaling pathways namely MAP-K, PI3K resulting in cellular proliferation, survival, migration, and angiogenesis. HER2 is overexpressed in several cancers. Most studies have been carried out with breast cancers after it was found that HER2 induced mammary carcinogenesis in vitro and in vivo. Overexpression with or without gene amplification occurs in 15-30% of breast cancers and this has both prognostic and predictive implications. HER2 overexpression and amplification is associated with shorter disease-free and overall survivals and with resistance to certain hormonal agents as well as increased risk of metastasis to the brain. In addition to being overexpressed in breast cancers, HER2 overexpression has been reported in gastric cancer, esophageal cancer, ovarian cancer and endometrial cancer. In lung cancer, overexpression as well as HER2 mutation has been reported in 30% of adenocarcinomas. Similar observation has been reported with bladder carcinomas. However clinical trials of HER2 therapy for lung and bladder cancers have had limited success so far. Two categories of treatment targeting HER2 and its biological activity have been developed, FDA approved and are used in the standard of care: monoclonal antibodies raised against HER2 and small molecule tyrosine kinase inhibitors targeting HER2 and EGFR such as lapatinib and neratinib and targeting all members of the HER family such as Afatinib. Trastuzumab also named Herceptin is a humanized anti-HER2 monoclonal antibody that binds to domain IV of the extracellular segment of the HER2, blocking its signaling. Its mechanisms of action include inhibition of HER2 dependent cell signaling, inhibition of PI3K-AKT pathway, inhibition of angiogenesis and antibody-dependent cellular toxicity. Trastuzumab was approved along with a companion diagnostic for breast cancer patients overexpressing Her2 as 3+ by immunohistochemistry (IHC) or positive by Fluorescence In Situ Hybridization (FISH). It is administered in combination therapy with standard of care chemotherapeutic agents. Trastuzumab was also approved as combination therapy for treatment of HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Pertuzumab is a humanized anti-HER2 monoclonal antibody that blocks the activation of HER2 receptor by inhibiting its dimerization. It elicits action at a different ligand binding site from trastuzumab. It is approved for in combination with trastuzumab and docetaxel in Her2 positive metastatic breast cancer patients. The antibody drug conjugate Ado-trastuzumab Emtansine was developed based on the fact that anti-HER2 antibody trastuzumab is internalizing and that as such it can deliver a cytotoxic payload to the cells leading to cell killing. Ado-Trastuzumab-Emtansine (Kadcyla) consists of trastuzumab conjugated to the drug mertansin