ANTI-NOTCH2 antibodies and methods of using them

Abstract

This invention provides anti-Notch2 antibodies and methods of using them.

Description

ANTI-NOTCH2 antibodies and methods of using them Reference to related requests

[0001] This application claims priority to U.S. Provisional Application No. 63 / 053,034, filed July 17, 2020, which is incorporated herein by reference in its entirety. Field of invention

[0002] The present invention relates to anti-Notch2 antibodies and methods of using them. Background

[0003] The Notch receptor family is a class of evolutionarily conserved transmembrane receptors that transduce signals affecting growth in a variety of organisms, from sea urchins to humans. Notch receptors and their ligands, Delta and Serrate (known as Jagged in mammals), are transmembrane proteins with large extracellular domains that contain epidermal growth factor (EGF)-like repeats. The number of Notch paralogs varies among species. For example, there are four Notch receptors in mammals (NotCH1-Notch4), two in Caenorhabditis elegans (LIN-12 and GLP-1), and one in Drosophila melanogaster (Notch). Notch receptors are proteolytically cleaved or processed by a furin-like protease at an S1 site on the N-terminal side of the transmembrane domain during translocation to the cell surface, generating an extracellular Notch subunit (ECN) and a transmembrane Notch subunit (NTM). These two subunits remain non-covalently linked to form the mature heterodimeric cell surface receptor.Notch receptors and the signaling pathway have been reviewed, for example, in Aster et al., Annu. Rev. Pathol. Mech. Dis. 3:587-613, 2008, and Bolos et al., Endocrine Reviews 28:339-363, 2007.

[0004] Notch2 ECN subunits contain 36 N-terminal EGF-like repeats, followed by three back-to-back Lin 12 / Notch repeat (LNR) units with face-repeating sequences that precede the S1 site. Each LNR unit contains three disulfide bonds and a group of conserved polar acidic residues that are predicted to modulate a calcium ion. Binding sites for activating ligands are located within the EGF repeat region.

[0005] Binding of a Notch ligand to the ECN subunit initiates two consecutive proteolytic cleavages that occur during transmembrane-regulated proteolysis. The first cleavage by a metalloprotease (ADAM10 or ADAM17) at the S2 site exposes the transmembrane Notch subunit to a second cleavage at the S3 site near the inner surface of the plasma membrane. Cleavage at the S3 site, catalyzed by a multiprotein complex containing presenilin and nicastrin and enhancing the activity of γ-secretase, releases the intracellular portion of the transmembrane Notch subunit, allowing it to translocate to the nucleus and activate transcription of target genes. (For a review of Notch proteolytic cleavage, see, e.g., Sisodia et al., Nat. Rev. Neurosci. 3:281-290, 2002)

[0006] Five Notch ligands of the Delta-like and Jagged classes have been identified in humans (Jagged1 (also called Serrate1), Jagged2 (also called Serrate2), Delta-like-1 (also called DLL1), Delta-like-3 (also called DLL3), and Delta-like-4 (also called DLL4)). Each ligand is a single-pass transmembrane protein with a conserved N-terminal Delta, Serrate, LAG-2 (DSL) motif that is essential for Notch binding. A set of EGF-like units that are C-terminal to the DSL motif precede the membrane-spanning fragment. Unlike Notch receptors, the ligands have short cytoplasmic tails of 70–215 amino acids at the C-terminus. In addition, other types of ligands have been reported (e.g., DNER, NB3, and F3 / contactin). (For a review of Notch ligands and ligand-mediated Notch activation, see, e.g., D'Souza et al., Oncogene 27:5148-5167, 2008.)

[0007] The Notch pathway functions during diverse developmental and physiological processes, including those affecting neurogenesis in flies and vertebrates. In general, Notch signaling is involved in lateral inhibition, lineage decisions, and the establishment of boundaries between cell groups (see, for example, Bray, Molecular Cell Biology 7:678-679, 2006). Inhibition of Jagged-Notch signaling has been shown to induce a rapid depletion of secretory rod-like cells and an increase in ciliated cells in the airways of the mammalian respiratory tract. Blockade of Jagged has been shown to reverse metaplasia in a preclinical model of asthma. See Lafkas et al., Nature 528:127-131 (2015).

[0008] Muco-obstructive lung diseases are characterized by cough, sputum production, diffuse mucus obstruction, chronic inflammation, airway wall ectasia, and recurrent bacterial infections. In healthy individuals, the mucus layer in the lungs rapidly moves from the distal airways to the trachea. In individuals with muco-obstructive diseases, epithelial defects in fluid-ion transport or mucin secretion, or both, result in excessive mucus thickening, impaired mucus transport, and impaired mucus adhesion to airway surfaces. This condition results in mucus accumulation in the small airways that is not cleared by coughing, leading to airway obstruction, infection, and inflammation.

[0009] There remains a need for the treatment of obstructive pulmonary disease. The invention disclosed herein fulfills this need and provides other advantages. Summary

[00010] This invention provides anti-Notch2 antibodies and methods of using them.

[00011] In some embodiments, an isolated antibody that binds to human Notch2 is provided, wherein the antibody inhibits Jagged1-mediated signaling but does not inhibit DLL1-mediated signaling. In some embodiments, an isolated antibody that binds to human Notch2 is provided, wherein the antibody inhibits Jagged1-mediated signaling to a greater extent than DLL1-mediated signaling. In some embodiments, the antibody is capable of achieving a maximal inhibition of Jagged1-mediated signaling of 100%, and a maximal inhibition of DLL1-mediated signaling of less than 80%, or less than 70%, or less than 60%. In some examples, the antibody does not inhibit the binding of Jagged1 to Notch2. In some examples, the antibody does not inhibit the binding of DLL1 to Notch2.In some embodiments, an isolated antibody is provided, wherein, when the antibody is formatted as a bivalent IgG antibody consisting of two heavy chains and two light chains, it inhibits Jagged1-mediated signaling, but does not inhibit DLL1-mediated signaling.

[00012] In some embodiments, the antibody binds to an epitope within the EGF7 repeat of Notch2. In some embodiments, the antibody binds to an epitope within amino acids 260-296 of Notch2. In some embodiments, the antibody binds to a discontinuous epitope within amino acids 260-296 of Notch2.

[00013] In some embodiments, an isolated antibody that binds to Notch2 is provided, wherein the antibody binds to an epitope within the EGF7 repeat of Notch2. In some embodiments, the antibody binds to an epitope within amino acids 260-296 of Notch2. In some embodiments, the antibody binds to a discontinuous epitope within amino acids 260-296 of Notch2.

[00014] In some examples, the antibody that binds to Notch2 contacts arginine 268 (R268) of human Notch2. In some examples, the antibody does not bind to Notch2 containing lysine 268 (K268). In some examples, the antibody binds to a polypeptide comprising the amino acid sequence of SEQ ID NO: 74 and does not bind to a polypeptide comprising the amino acid sequence of SEQ ID NO: 77. In some examples, the antibody binds to human Notch2 and cynomolgus monkey Notch2. In some examples, the antibody does not bind to murine Notch2. In some samples, the antibody does not bind to guinea pig Notch2. In some samples, the antibody does not bind to human Notch1 or human Notch3.

[00015] In some embodiments, the antibody binds to human Notch2 with an affinity (KD) of less than 20 nM, less than 15 nM, less than 10 nM, or less than 5 nM, as measured by surface plasmon resonance.

[00016] In some embodiments, the antibody inhibits Jagged1-mediated signaling with an IC50 of less than 20 nM, less than 15 nM, less than 10 nM, or less than 5 nM. In some embodiments, inhibition of Jagged1-mediated signaling is determined using a high-content screening (HCS) assay.

[00017] In some embodiments, an antibody that binds to Notch2 is comprised of: a) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3; b) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35; c) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43; d) a heavy chain variable domain (VH) consisting of (a) CDR-H1 containing the amino acid sequence of SEQ ID NO: 53, (b) CDR-H2 containing the amino acid sequence of SEQ ID NO: 54, and (c) CDR-H3 containing the amino acid sequence of SEQ ID NO: 55, and a light chain variable domain (VL) consisting of (d) CDR-L1 containing the amino acid sequence of SEQ ID NO: 49, (e) CDR-L2 containing the amino acid sequence of SEQ ID NO: 50, and (f) CDR-L3 containing the amino acid sequence of SEQ ID NO: 51 or 52; or e) A heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61.

[00018] In some embodiments, the antibody comprises: a) A VH sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 14; b) a VL sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 13; c) a VH sequence as defined in (a) and a VL sequence as defined in (b); d) a VH sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 17-24, 26, 28, 30, and 32; e) a VL sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 15, 16, 25, 27, 29, and 31; f) a VH sequence as defined in (d) and a VL sequence as defined in (e); g) a VH sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 40; h) a VL sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 39; i) a VH sequence as defined in (g) and a VL sequence as defined in (h); j) a VH sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOS: 102-106; k) a VL sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NO: 98-100; l) a VH sequence as defined in (j) and a VL sequence as defined in (k); m) a VH sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 48; n) a VL sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 47; o) a VH sequence as defined in (m) and a VL sequence as defined in (n); p) a VH sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 58; q) a VL sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 56 or 57; r) a VH sequence as defined in (p) and a VL sequence as defined in (q); s) a VH sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 66; t) a VL sequence having at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 65; or u) A VH sequence as defined in (s) and a VL sequence as defined in (t).

[00019] In some embodiments, the antibody is composed of: a) a VH sequence comprising the amino acid sequence with SEQ ID NO: 14; b) a VL sequence comprising the amino acid sequence with SEQ ID NO: 13; c) a VH sequence as defined in (a) and a VL sequence as defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOS: 17-24, 26, 28, 30, and 32; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOS: 15, 16, 25, 27, 29, and 31; f) a VH sequence as defined in (d) and a VL sequence as defined in (e); g) a VH sequence comprising the amino acid sequence with SEQ ID NO: 40; h) a VL sequence comprising the amino acid sequence with SEQ ID NO: 39; i) a VH sequence as defined in (g) and a VL sequence as defined in (h); j) a VH sequence comprising an amino acid sequence selected from SEQ ID NOS: 101-106; k) a VL sequence comprising an amino acid sequence selected from SEQ ID NOS: 98-100; l) a VH sequence as defined in (j) and a VL sequence as defined in (k); m) a VH sequence comprising the amino acid sequence with SEQ ID NO: 48; n) a VL sequence comprising the amino acid sequence with sequence ID number: 47; o) a VH sequence as defined in (m) and a VL sequence as defined in (n); p) a VH sequence comprising the amino acid sequence with SEQ ID NO: 58; q) a VL sequence comprising the amino acid sequence with SEQ ID NO: 56 or 57; r) a VH sequence as defined in (p) and a VL sequence as defined in (q); s) a VH sequence comprising the amino acid sequence with SEQ ID NO: 66; t) a VL sequence comprising the amino acid sequence with SEQ ID NO: 65; or u) A VH sequence as defined in (s) and a VL sequence as defined in (t).

[00020] In some embodiments, the antibody is composed of: a) a VH sequence comprising the amino acid sequence with SEQ ID NO: 14; b) a VL sequence comprising the amino acid sequence with SEQ ID NO: 13; c) a VH sequence as defined in (a) and a VL sequence as defined in (b); d) a VH sequence comprising an amino acid sequence selected from SEQ ID NOS: 17-24, 26, 28, 30, and 32; e) a VL sequence comprising an amino acid sequence selected from SEQ ID NOS: 15, 16, 25, 27, 29, and 31; f) a VH sequence as defined in (d) and a VL sequence as defined in (e); g) a VH sequence comprising the amino acid sequence with SEQ ID NO: 40; h) a VL sequence comprising the amino acid sequence with SEQ ID NO: 39; i) a VH sequence as defined in (g) and a VL sequence as defined in (h); j) a VH sequence comprising an amino acid sequence selected from SEQ ID NOS: 101-106; k) a VL sequence comprising an amino acid sequence selected from SEQ ID NOS: 98-100; l) a VH sequence as defined in (j) and a VL sequence as defined in (k); m) a VH sequence comprising the amino acid sequence with SEQ ID NO: 48; n) a VL sequence comprising the amino acid sequence with sequence ID number: 47; o) a VH sequence as defined in (m) and a VL sequence as defined in (n); p) a VH sequence comprising the amino acid sequence with SEQ ID NO: 58; q) a VL sequence comprising the amino acid sequence with SEQ ID NO: 56 or 57; r) a VH sequence as defined in (p) and a VL sequence as defined in (q); s) a VH sequence comprising the amino acid sequence with SEQ ID NO: 66; t) a VL sequence comprising the amino acid sequence with SEQ ID NO: 65; or u) A VH sequence as defined in (s) and a VL sequence as defined in (t).

[00021] In some embodiments, the antibody is composed of: a) a VH sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 17-24, 26, 28, 30, and 32; b) a VL sequence having at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 15, 16, 25, 27, 29, and 31; or c) A VH sequence according to the definition provided in (a) and a VL sequence according to the definition provided in (b).

[00022] In some embodiments, the antibody is composed of: a) a VH sequence comprising an amino acid sequence selected from SEQ ID NOS: 17-24, 26, 28, 30, and 32; b) a VL sequence comprising an amino acid sequence selected from SEQ ID NOS: 15, 16, 25, 27, 29, and 31; or c) A VH sequence according to the definition provided in (a) and a VL sequence according to the definition provided in (b).

[00023] In some embodiments, the antibody: a) contains a VH sequence with sequence ID number: 26 and a VL sequence with sequence ID number: 25; b) contains a VH sequence with SEQ ID NO: 28 and a VL sequence with SEQ ID NO: 27; c) contains a VH sequence with SEQ ID NO: 30 and a VL sequence with SEQ ID NO: 29; or d) Contains a VH sequence with sequence ID number: 32 and a VL sequence with sequence ID number: 31.

[00024] In some embodiments, the antibody that binds to Notch2 is a monoclonal antibody. In some embodiments, the antibody is a humanized or chimeric antibody. In some embodiments, the antibody that binds to Notch2 is an antibody fragment that binds to Notch2. In some embodiments, the antibody fragment is selected from Fv, Fab, Fab', Fab'-SH, and F(ab')2. In some embodiments, the antibody fragment is a Fab, Fab', or Fab'-SH. In some embodiments, the antibody is a full-length antibody.

[00025] In some embodiments, an antibody is provided that competes with an antibody provided herein for binding to human Notch2.

[00026] In some embodiments, an isolated nucleic acid is provided that encodes an antibody that binds to Notch2 provided herein. In some embodiments, a host cell is provided that contains the nucleic acid. In some embodiments, a host cell is provided that expresses an antibody provided herein. In some embodiments, a method for producing an antibody that binds to human Notch2 is provided, comprising culturing the host cell under conditions suitable for expression of the antibody. In some embodiments, the method further comprises isolating the antibody from the host cell. In some embodiments, an antibody produced by the host cell is provided.

[00027] In some embodiments, a pharmaceutical composition or formulation comprising an antibody that binds to Notch2 provided herein and a pharmaceutically acceptable carrier is provided. In some embodiments, the pharmaceutical formulation further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from hypertonic saline, mannitol, palmozyme, N-acetylcysteine, cysteamine, and a bronchodilator.

[00028] In some embodiments, an antibody that binds to Notch2 or a pharmaceutical formulation is provided herein for use as a medicament. In some embodiments, an antibody that binds to Notch2 or a pharmaceutical formulation is provided herein for use in treating a mucocutaneous obstructive pulmonary disease. In some embodiments, the mucocutaneous obstructive pulmonary disease is selected from chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis.

[00029] In some embodiments, the use of an antibody that binds to Notch2 or a pharmaceutical formulation in the manufacture of a medicament for treating a mucocutaneous obstructive pulmonary disease is provided. In some embodiments, the mucocutaneous obstructive pulmonary disease is selected from chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis. In some embodiments, the use of an antibody that binds to Notch2 or a pharmaceutical formulation in the manufacture of a medicament for reducing the number of secretory cells in a subject is provided. In some embodiments, the medicament converts secretory cells to ciliated cells. In some embodiments, the secretory cells in the subject lung are goblet cells. In some embodiments, the secretory cells are goblet cells.

[00030] In some embodiments, a method of treating a subject with a mucocutaneous obstructive lung disease is provided, comprising administering an effective amount of an antibody that binds to Notch2 provided herein or a pharmaceutical formulation provided herein to the subject. In some embodiments, the mucocutaneous obstructive lung disease is selected from chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis. In some embodiments, a method of reducing the number of secretory cells in a subject is provided, comprising administering an effective amount of an antibody that binds to Notch2 provided herein or a pharmaceutical formulation provided herein to the subject, to eliminate secretory cells in the subject. In some examples, this method involves converting secretory cells into ciliated cells. In some examples, the secretory cells in the lung are the subject of the study. In some examples, the secretory cells are goblet cells.In some embodiments, the method also includes administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent is selected from hypertonic saline, mannitol, palmozyme, N-acetylcysteine, cysteamine, and a bronchodilator. A brief explanation of the shapes

[00031] Figure 1A-1B shows alignments of the light chain variable regions (1A) and heavy chain variable regions (1B) of the rat anti-Notch2 antibody 1B2 and some of its derived humanized versions.

[00032] Figure 2A-2B shows the light chain variable region (2A) and heavy chain variable region (2B) of the rat anti-Notch2 antibody designated 3107.

[00033] Figures 3A-3B show alignments of the light chain variable regions (3A) and heavy chain variable regions (3B) of rabbit anti-Notch 2 antibodies designated 2338, 2430, 2430 with a C95dS substitution in the light chain and 2621.

[00034] Figure 4 shows the epitope classification of rat.1B2, rat.3107, rb.2338, rb.2430, rb.2621, and the anti-Notch 2 / 3 antibody OMP-59R5 (tarxtumab, see U.S. Patent No. 8,226,943 B2).

[00035] Fig. 5A-5F show Jagged1-mediated blocking of Notch2 activity (5A, 5C, 5E) and preservation of DLL1-mediated Notch2 activity (5B, 5D, 5F) in a co-culture assay involving cells expressing the Notch2 receptor and cells expressing Jagged1 ligand (5A, 5C, 5E) or DLL1 ligand (5B, 5D, 5F). Figures 5A and 5B show the change in the percentage of Jagged1-mediated signaling activity and DLL1-mediated signaling, respectively, with increasing antibody concentration for the anti-Notch2 antibodies called chimeric 1B2, and the humanized versions hu1B2.v1.DFS, hu1B2.v101, hu1B2.v102, hu1B2.v103, and hu1B2.v104. Figures 5C and 5D show the change in the percentage of Jagged1-mediated signaling activity and DLL1-mediated signaling, respectively, with increasing concentration of the murine anti-Notch2 antibody called 3107. Figures 5E and 5F show the change in the percentage of Jagged1-mediated signaling activity and DLL1-mediated signaling with increasing concentrations of rabbit anti-Notch2 antibodies, designated 2338, 2621, and 2430, respectively.

[00036] Figures 6A-6D show the expression of Muc5b (6A), (6B) Muc5ac, and (6C) Scgb1a1 mRNA in air-liquid interface (ALI) cultures of primary human bronchial epithelial cells exposed to a control anti-gD antibody or a chimeric mouse / human anti-Notch2 antibody designated 1B2; and (6D) immunofluorescence analysis of ALI cultures treated with a control anti-gD antibody (left) and ALI cultures treated with an anti-Notch2 antibody designated 1B2 (right). Sections were stained with anti-Muc5b (green) for goblet cells, with anti-acetylated α-tubulin (red) for ciliated cells, and with DAPI (blue) for nuclear staining. A significant reduction in the number of goblet cells was observed in ALI culture media treated with an anti-Notch2 antibody called 1B2.

[00037] Figures 7A-7B show alignments of the light chain variable regions (7A) and heavy chain variable regions (7B) of the rat anti-Notch2 antibody 3107 and some of its derived humanized versions. Detailed description of the invention I. Definitions

[00038] An "acceptor human framework" for purposes herein is a framework that consists of the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived" from a human immunoglobulin framework or a human consensus framework may consist of the same amino acid sequence from which it was derived, or may contain amino acid sequence changes. In some cases, the number of amino acid changes is 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer. In some cases, the acceptor human framework VL is exactly sequence identical to the human immunoglobulin VL framework sequence or the human consensus framework sequence.

[00039] “Binding affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise noted, “binding affinity” as used herein refers to the intrinsic binding affinity, which represents a 1:1 interaction between members of a binding partner (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can be generally represented by the dissociation constant (KD). Affinity can be measured by methods conventionally known in the art, including those described herein. Specific illustrative and exemplary methods for measuring binding affinity are described below.

[00040] A "fully affinity matured" antibody refers to an antibody that has one or more changes in the complementarity determining regions (CDRs), such as changes that result in enhanced affinity of the antibody for the antigen, compared to a parent antibody that has no changes.

[00041] The terms "anti-Notch2 antibody" and "an antibody that binds to Notch2" refer to an antibody that is capable of binding to Notch2 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting Notch2. In some cases, the extent of binding of an anti-Notch2 antibody to an unrelated, non-Notch2 protein was less than about 10% of the antibody's binding to Notch2, as measured, for example, by surface plasmon resonance (SPR) assay. In certain embodiments, an antibody that binds to Notch2 has a dissociation constant (KD) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10-8 M or less, e.g., from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M). An antibody is said to "specifically" bind to Notch2 when the KD of the antibody is 1 μM or less.In some specific cases, an anti-Notch2 antibody binds to a Notch2 epitope that is conserved among Notch2 from different species.

[00042] The term "antibody" is used herein in the broadest possible sense and encompasses various types of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multiple antibodies capable of binding to multiple antigens (e.g., bivalent antibodies capable of binding to two antigens), and antibody fragments, as long as they exhibit desirable antigen-binding activity.

[00043] An "antibody fragment" refers to a molecule that is not a complete or intact antibody and is composed of a portion of a complete or intact antibody that binds to the same antigen as the complete or intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAbs); and multi-antigen binding multiple antibodies constructed from antibody fragments. For a review of specific antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[00044] The term "epitope" refers to a site on an antigen, whether protein or non-protein, to which an anti-Notch2 antibody binds. Epitopes can be composed of contiguous amino acid sequences (linear epitopes) or of non-contiguous amino acids (i.e., discontinuous epitopes or structural epitopes), for example, those that are spatially adjacent to each other due to antigen folding, i.e., by the tertiary fold of a protein antigen. Linear epitopes typically remain bound by the anti-Notch2 antibody after exposure of the protein antigen to denaturing agents, whereas structural epitopes are typically degraded upon treatment with denaturing agents. An epitope is composed of at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial structure or conformation.

[00045] Screening for antibodies that bind to a specific epitope (i.e., those that bind to the same epitope) can be performed using methods conventional in the art including, but not limited to, alanine scanning, peptide blots (see Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, epitope cleavage, epitope extraction, chemical modification of antigens (see Prot. Sci. 9 (2000) 487-496), and cross-blocking (“Antibodies”, see Harlow and Lane (Cold ‎SPRing Harbor Press, Cold ‎SPRing Harb., NY).

[00046] Antibody structure-based profiling (ASAP), also known as modification-assisted profiling (MAP), allows the classification of a group of monoclonal antibodies that specifically bind to Notch2 based on the binding profile of each antibody from a large population that binds to surfaces of antigens that have been chemically or enzymatically modified (see, e.g., US 2004 / 0101920). Antibodies in each class bind to a similar epitope, which may be a unique epitope that is distinctly different from another class, or may partially overlap with an epitope presented by another group.

[00047] Competitive binding can also be used simply to determine whether an antibody binds to the same epitope on Notch2, or competes for binding to a reference anti-Notch2 antibody. For example, an "antibody that binds to similar epitopes" as a reference anti-Notch2 antibody refers to an antibody that, in a competitive assay, inhibits the binding of the reference anti-Notch2 antibody to its own antigen by 50% or more, and conversely, the reference antibody inhibits the binding of the antibody to its own antigen by 50% or more in a competitive assay. Also, for example, to determine whether an antibody binds to the same epitope as a reference anti-Notch2 antibody, the reference antibody is allowed to bind to Notch2 under saturating conditions. After removing excess amounts of the reference anti-Notch2 antibody, the ability of a target anti-Notch2 antibody to bind to Notch2 was assessed.If the anti-Notch2 antibody is able to bind to Notch2 after saturating the binding of the reference anti-Notch2 antibody, it can be concluded that the anti-Notch2 antibody of interest binds to a different epitope than the reference anti-Notch2 antibody. However, if the anti-Notch2 antibody of interest is unable to bind to Notch2 after saturating the binding of the reference anti-Notch2 antibody, then the anti-Notch2 antibody of interest may bind to the same epitope as the reference anti-Notch2 antibody. To confirm whether the antibody of interest binds to the same epitope or whether binding is not possible for steric reasons, routine experiments (e.g., peptide mutation and binding analyses using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art) can be used. This assay can be performed in two sets, i.e., with both antibodies converted to saturating antibodies.If, in both sets, only the first (saturating) antibody is able to bind to Notch2, then it can be concluded that the target anti-Notch2 antibody and the reference anti-Notch2 antibody compete for binding to Notch2.

[00048] In some cases, two antibodies are considered to bind to the same epitope or an overlapping epitope if a 1, 5, 10, 20, or 100-fold excess of one antibody inhibits the binding of another by at least 50%, at least 75%, at least 90%, or even 99% or more as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).

[00049] In some cases, two antibodies are said to bind to the same epitope if not all of the amino acid mutations in the antigen that reduce or eliminate binding by one antibody also reduce or eliminate binding by the other. Two antibodies are said to have "overlapping epitopes" only if a subset of the amino acid mutations that reduce or eliminate binding by one antibody also reduce or eliminate binding by the other.

[00050] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from one source or species, while the remainder of the light and / or heavy chain is derived from another source or species.

[00051] The "class" of an antibody refers to the type of constant domain or constant region located within its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In some specific cases, the antibody is of the IgG1 isotype. In some specific cases, the antibody is of the IgG1 isotype with mutations P329G, L234A, and L235A to reduce effector function in the Fc region. In other cases, the antibody is of the IgG2 isotype. In some specific cases, the antibody is of the IgG4 isotype with the S228P mutation in the hinge region to improve the stability of the IgG4 antibody. The constant domains of the heavy chain, which belong to different classes of immunoglobulins, are called , , , , and , respectively. The light chain of an antibody can be assigned to one of two types, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[00052] "Effector functions" refer to biological activities that can be attributed to the Fc region of an antibody, which vary depending on the antibody isotype. Antibody effector functions include: binding to C1q and complement-dependent cytotoxicity (CDC); binding to Fc receptors; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[00053] An "effective amount" of an agent, e.g., a pharmaceutical formulation, refers to the effective amount, in terms of the dosage administered and the duration of administration required, that is required to achieve the desired therapeutic or prophylactic results.

[00054] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes both native sequence Fc regions and variant Fc regions. In some cases, a human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, an antibody produced by a host cell expressing a specific nucleic acid molecule encoding a full-length heavy chain may comprise a full-length heavy chain or may comprise a truncated variant of the full-length heavy chain. This may be true when the two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to the EU index).Thus, the C-terminal lysine (Lys447), or glycine (Gly446) and C-terminal lysine (Lys447) of the Fc region may or may not be present. In some cases, a heavy chain including an Fc region as recited herein and incorporated into an antibody according to the present invention comprises a C-terminal glycine-lysine dipeptide (G446 and K447, numbering according to the European Union index). In some cases, a heavy chain including an Fc region as recited herein and incorporated into an antibody according to the present invention comprises an additional C-terminal glycine residue (G446, numbering according to the European Union index). Unless otherwise noted, the numbering of amino acid residues in the Fc region or constant region is based on the European Union numbering system, also known as the European Union index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[00055] "Framework" or "FR" refers to the residues of the variable domain other than the complementarity determining region residues (CDRs). The FR of a variable domain is typically composed of four FR domains: FR1, FR2, FR3, and FR4. Similarly, the CDR and FR sequences typically appear in the VH (or VL) in the following order: FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

[00056] The terms "full-length antibody", "intact antibody", and "complete antibody" are used interchangeably herein and all refer to an antibody that has a similar overall structure to that of a pristine antibody or that has chains that are composed of an Fc region as defined herein.

[00057] The terms "host cell", "host cell line", and "host cell culture" are used interchangeably herein and refer to cells into which exogenous or foreign nucleic acid has been introduced, as well as to the lineage of these cells. Host cells include "transformants" and "transformed cells", which include the original transformed cells and the lineage derived therefrom, regardless of the number of passages. The lineage may not be exactly identical in nucleic acid content to the parent cell, but may contain several mutations. A mutant lineage that has a function or biological activity similar to that screened or selected in the original transformed cell is included herein.

[00058] A "human antibody" is an antibody that has an amino acid sequence identical to an antibody produced by a human or a human cell, or is derived from a non-human source that utilizes human antibody repertoires or other human antibody coding sequences. This definition of human antibody specifically does not include a humanized antibody that is composed of non-human antigen-binding residues.

[00059] A "human consensus framework" is a framework that represents the most common amino acid residues in a selected set of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup referred to in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In some cases, for VL, this subgroup is a subgroup, kappa I or II, as referred to in Kabat et al., supra. In some cases, for VH, the subgroup is a subgroup, kappa I or III, as referred to in Kabat et al., supra.

[00060] A “humanized” antibody refers to a chimeric antibody that is composed of amino acid residues derived from non-human CDRs and amino acid residues derived from human FRs. In certain embodiments, a humanized antibody is composed primarily of at least one, and usually two, variable domains in which all or substantially all of the CDRs correspond to the CDRs of a non-human antibody and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[00061] The term "hypervariable region" or "HVR" as used herein refers to any of the regions of an antibody variable domain that are highly variable in sequence and determine antigen binding specificity, e.g., the "complementarity determining regions" ("CDRs").

[00062] In general, antibodies are composed of six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). Examples of CDRs given herein include: (a) hypervariable loops located at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs located at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigen contacts located at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); and (d) The CDRs are defined by a combination of Chutia and Kabat: positions 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL domain, and 26-35 (H1), 50-65 (H2) and 95-102 (H3) in the VH domain.

[00063] Unless otherwise specified, CDRs are designated according to Kabat et al., supra. One skilled in the art will appreciate that CDR designations can also be designated according to Chotia, supra, McCallum, supra, or any other scientifically acceptable nomenclature system. In some cases, CDR residues include those identified in Figures 1-3 and / or the Table of Certain Sequences herein.

[00064] An "immunoconjugate" is an antibody linked to one or more heterologous or dissimilar molecule(s), including but not limited to, a cytotoxic agent.

[00065] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., human primates and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some cases, the individual or subject is a human.

[00066] An "isolated" antibody is an antibody that has been separated from a component of its natural environment. In some cases, an antibody has been purified to greater than 95% or 99% purity as determined by methods such as electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[00067] The term "nucleic acid molecule" or "polynucleotide" includes any compound and / or material that comprises a polymer of nucleotides. Each nucleotide is composed of a base, particularly a purine or pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T), or uracil (U)), a sugar (i.e., deoxyribose or ribose), and a phosphate group. Often, a nucleic acid molecule is described in terms of the sequence of bases, so that the bases represent the primary structure (linear structure) of a nucleic acid molecule. The sequence of bases is usually indicated from 5' to 3'. Here, the term nucleic acid molecule includes deoxyribonucleic acid (DNA), including, for example, complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), especially messenger RNA (mRNA), synthetic or artificial forms of DNA or RNA, and mixed polymers composed of two or more of these molecules. A nucleic acid molecule may be linear or cyclic.In addition, the term nucleic acid molecule includes sense and antisense strands, as well as single-stranded and double-stranded forms. In addition, the nucleic acid molecule described herein can contain naturally occurring nucleotides or those that do not occur naturally. Examples of non-naturally occurring nucleotides are modified nucleotide bases with phosphate backbone linkages or derivatized sugars or chemically modified residues. Nucleic acid molecules also include DNA and RNA molecules that are a suitable carrier for the direct expression of an antibody of the invention in vitro and / or in vivo, for example, in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) carriers can be modified or unmodified.For example, mRNA can be chemically modified to increase the stability of the carrier RNA and / or the expression of the encoded molecule so that the mRNA can be injected into a subject to produce an antibody in vivo (see, for example, Stadler et al, Nature Medicine 2017, published online 12 June 2017, doi:10.1038 / nm.4356 or EP 2 101 823 B1).

[00068] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule within cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is located extrachromosomally or in a chromosomal location that differs from its natural chromosomal location.

[00069] "Isolated nucleic acid encoding an anti-Notch2 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains of an anti-Notch2 antibody (or fragments thereof), including nucleic acid molecule(s) contained in a single carrier or separate carriers and nucleic acid molecule(s) contained in one or more locations in a host cell.

[00070] The term "monoclonal antibody" as used herein refers to an antibody derived from a population of generally homogeneous antibodies, i.e., all antibodies comprising the population are identical and / or bind to the same epitope, except for possible variant antibodies, e.g., those that have mutated naturally or arise during the production of a monoclonal antibody. These variants are usually present in very small amounts. Unlike polyclonal antibody products, which typically include different antibodies targeting different determinants (epitopes), each monoclonal antibody in a monoclonal antibody product targets a single determinant on an antigen. Therefore, the descriptor "monoclonal" indicates the specificity of the antibody as being derived from a generally homogeneous population of antibodies and should not be interpreted as requiring the production of the antibody using a specific method.For example, monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods using transgenic or transgenic animals carrying all or part of human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies are described herein.

[00071] The term "mucosal obstructive lung disease" refers to a group of diseases characterized by diffuse mucus obstruction, chronic inflammation, airway wall ectasia, and recurrent bacterial infections. In mucosal obstructive lung disease, excessively thick mucus cannot be effectively transported from the distal airways to the trachea and the mucus adheres to the surfaces of the airways, leading to airflow obstruction, infection, and inflammation. Mucosal obstructive lung disease includes chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis.

[00072] A "naked antibody" refers to an antibody that has not been conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radioactive label. A naked antibody may be present in a pharmaceutical formulation.

[00073] “Native antibodies” refer to naturally occurring immunoglobulin molecules with different structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons that are composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable domain (VH), also known as the heavy variable domain or heavy chain variable region, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable domain (VL), also known as the light variable domain or light chain variable region, followed by a constant chain domain (CL).

[00074] The term "Notch2" as used herein refers to any intact Notch2 obtained from a vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise noted. The term includes "full-length" unprocessed Notch2 as well as any form of Notch2 that results from processing within a cell. The term also includes naturally occurring variants of Notch2, e.g., spliced ​​variants or allelic variants. The amino acid sequence of an exemplary human Notch2 is set forth in UniProtKB / Swiss-Prot: Q04721.3 and is set forth herein under SEQ ID NO: 70. An example amino acid sequence of the cynomolgus monkey Notch2 protein is shown in UniProt: A0A2K5U7N0_MACFA. Another example of cynomolgus monkey Notch2 is shown here at SEQ ID NO: 71. An example amino acid sequence of the guinea pig Notch2 protein is shown here at UniProt: H0VU21 and at SEQ ID NO: 72.The amino acid sequence of a sample of the guinea pig Notch2 protein is shown here in UniProt: O35516 and at SEQ ID NO: 73. The amino acid sequence of a sample of rat Notch2 is shown here in UniProt: Q9QW30 and at SEQ ID NO: 81.

[00075] The term "package insert" is used to refer to instructions that are typically included in commercial packages of therapeutic products and contain information about the method of administration, form of administration, dosage, route of administration, combination therapy, contraindications and / or warnings regarding the use of these therapeutic products.

[00076] "Percent amino acid sequence similarity (%)" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a sequence of interest that, after alignment of the sequences and, if necessary, insertion of gaps, to achieve the maximum percent similarity, and without considering any conservative substitutions as part of the sequence similarity for alignment purposes, are exactly the same as residues in the reference polypeptide sequence. Alignment to determine percent amino acid sequence similarity can be achieved in a variety of ways known in the art, for example, using publicly available computer software, such as BLAST, BLAST-2, ALIGN or Megaline (DNASTAR) software or the FASTA program package. Those with expertise in this field can determine the appropriate parameters for sequence alignment, including any algorithms needed to achieve maximal alignment across the entire length of the sequences being compared.Alternatively, percent similarity values ​​can be generated using the ALIGN-2 sequence comparison computer program. The ALIGN-2 sequence comparison computer program was written by Genentech and the source code with user documentation is filed with the United States Copyright Office, Washington, D.C., under No. 20559, where it is registered under U.S. Copyright Registration Number TXU510087 and is described in WO 2001 / 007611.

[00077] Except where otherwise noted, for the purposes herein, percent amino acid sequence similarity was generated using the ggsearch program from the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix. The FASTA program package was written by WR Pearson and DJ Lipman (1988), “Improved Tools for Biological Sequence Analysis”, PNAS 85:2444-2448; WR Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et. al. (1997) Genomics 46:24-36 and is publicly available at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, a public server available at fasta.bioch.virginia.edu / fasta_www2 / index.cgi can be used to compare sequences using the ggsearch program (global protein:protein) and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global alignment rather than a local one.The percentage of amino acid similarity is presented in the header of the alignment output.

[00078] The term "pharmaceutical composition" or "pharmaceutical formulation" refers to a composition that is such as to permit effective biological activity of an active ingredient contained therein and does not contain any additional ingredients that are unacceptably toxic to the individual to whom the pharmaceutical composition or formulation is administered.

[00079] A "pharmaceutically acceptable carrier" refers to a substance in a pharmaceutical composition or formulation that is not the active compound and has no toxic effect on a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[00080] "Treatment" (and all derivatives thereof, such as "treating" or "under treatment") as used herein refers to a clinical intervention that attempts to alter the natural course of a disease in a subject and can be administered to prevent or during the course of a clinical pathology. The desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of the disease, reducing symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, reducing or palliating the condition of the disease, and alleviating or improving the prognosis. In some cases, the antibodies of the invention have been used to delay disease progression or slow the rate of disease progression.

[00081] The term "variable region" or "variable domain" refers to a domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The heavy chain and light chain variable domains (VH and VL, respectively) of a native antibody generally have similar structures, with each domain consisting of four conserved framework regions (FR) and complementarity determining regions (CDRs). (See, for example, Kindt et al. Kuby Immunology, 6thed., WH Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind to a specific antigen may be isolated using a VL or VH domain derived from an antibody that binds to the antigen, respectively, to screen a library of complementary VL or VH domains. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[00082] The term "vector" as used herein refers to a nucleic acid molecule that is capable of replicating another nucleic acid to which it is attached. The term includes a vector as a self-replicating nucleic acid construct as well as a vector integrated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably attached. These vectors are referred to herein as "expression vectors." II.Compositions or Formulations and Methods

[00083] In some embodiments, the invention is based in part on antibodies that bind to Notch2 and inhibit Jagged1-mediated signaling, but do not inhibit DLL1-mediated signaling. The antibodies of the invention are useful, for example, for diagnosing or treating obstructive pulmonary disease. A. Example of anti-Notch2 antibodies

[00084] In some embodiments, the invention provides antibodies that bind to Notch2. In some embodiments, the invention provides isolated antibodies that bind to Notch2. In some embodiments, the invention provides antibodies that specifically bind to Notch2. In certain embodiments, an anti-Notch2 antibody: Inhibits Jagged1-mediated signaling; Does not inhibit DLL1-mediated signaling; Does not inhibit the binding of Jagged1 to Notch2; Does not inhibit DLL1 binding to Notch2; binds to an epitope within the EGF7 repeat of Notch2; Binds to an epitope within amino acids 260-296 of Notch2; Binds to a discontinuous epitope within amino acids 260-296 of Notch2;  Contacts arginine 268 (R268) of human Notch2; Does not bind to a Notch2 containing lysine 268 (268K); binds to a polypeptide containing the amino acid sequence of SEQ ID NO: 74 and does not bind to a polypeptide containing the amino acid sequence of SEQ ID NO: 77; and / or Binds to human Notch2 with an affinity (KD) of less than 20 nM, less than 15 nM, less than 10 nM, or less than 5 nM, as measured by surface plasmon resonance. Antibodies containing one or more CDRs from the 1B2 antibody or humanized versions thereof

[00085] In some embodiments, the invention provides an anti-Notch2 antibody comprising at least one, at least two, at least three, at least four, at least five, or at least six CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[00086] In some cases, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, 12. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12. In some cases, the antibody is comprised of a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In another case, the antibody is comprised of a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2.In another embodiment, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12.

[00087] In some cases, the invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3. In some cases, the antibody comprises (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[00088] In some cases, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; and (b) a VL domain comprising at least one, at least two, or at least three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[00089] In some embodiments, the invention provides an antibody comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

[00090] In certain embodiments, any one or more amino acids of an anti-Notch2 antibody provided above are substituted at the following CDR positions: - In CDR-H2 (SEQ ID NO: 6): position 2 - In CDR-H3 (SEQ ID NO: 8): positions 2, 4, 5, and / or 6 In some special cases, the substitutions are of the conservative type, as presented here. In some special cases, any one or more of the following substitutions can be made in any combination: - In CDR-H2 (SEQ ID NO: 6): S2Q (S51Q based on Kabat numbering) - In CDR-H3 (SEQ ID NO: 8): S2G (S96G based on Kabat numbering); R4K (R98K based on Kabat numbering); W5L (W99L based on Kabat numbering); and / or G6A (G100A based on Kabat numbering).

[00091] In any of the embodiments provided herein, an anti-Notch2 antibody is humanized. In some embodiments, an anti-Notch2 antibody also comprises a human acceptor framework, for example, a human immunoglobulin framework or a human consensus framework. In some embodiments, the anti-Notch2 antibody comprises a VH comprising an FR1 sequence having SEQ ID NO: 92, an FR2 sequence having SEQ ID NO: 93 or 94, an FR3 sequence having SEQ ID NO: 95, 96, or 107, and / or an FR4 sequence having SEQ ID NO: 97. In some cases, an anti-Notch2 antibody is comprised of a VL comprising an FR1 sequence with SEQ ID NO: 87, an FR2 sequence with SEQ ID NO: 88, an FR3 sequence with SEQ ID NO: 89 or 90, and / or an FR4 sequence with SEQ ID NO: 91.

[00092] In some cases, the anti-Notch2 antibody comprises a VH domain comprising one or more heavy chain framework sequences selected from (a) a heavy chain framework region 1 (HC-FR1) having SEQ ID NO: 92, (b) a heavy chain framework region 2 (HC-FR2) having SEQ ID NO: 93 or 94, (c) a heavy chain framework region 3 (HC-FR3) having SEQ ID NO: 95, 96, or 107, and (d) a heavy chain framework region 4 (HC-FR4) having SEQ ID NO: 97.

[00093] In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR1 of SEQ ID NO: 92. In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR2 of SEQ ID NO: 93 or 94. In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR3 of SEQ ID NO: 95, 96 or 107. In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR4 of SEQ ID NO: 97.

[00094] In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 92. In some cases, the VH domain comprises an HC-FR1 having at least 95% sequence similarity to SEQ ID NO: 92. In some cases, the VH domain comprises an HC-FR1 having at least 98% sequence similarity to SEQ ID NO: 92.

[00095] In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 93 or 94. In some cases, the VH domain comprises an HC-FR2 having at least 95% sequence similarity to SEQ ID NO: 93 or 94. In some cases, the VH domain comprises an HC-FR2 having at least 98% sequence similarity to SEQ ID NO: 93 or 94.

[00096] In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 95, 96 or 107. In some cases, the VH domain comprises an HC-FR3 having at least 95% sequence similarity to SEQ ID NO: 95, 96, or 107. In some cases, the VH domain consists of an HC-FR3 having at least 98% sequence similarity to SEQ ID NO: 95, 96, or 107.

[00097] In some cases, an anti-Notch2 antibody comprises a VH domain comprising an HC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 97. In some cases, the VH domain comprises an HC-FR4 having at least 95% sequence similarity to SEQ ID NO: 97. In some cases, the VH domain comprises an HC-FR4 having at least 98% sequence similarity to SEQ ID NO: 97.

[00098] In some cases, the anti-Notch2 antibody comprises a VL domain comprising one or more light chain framework sequences selected from (a) a light chain framework region 1 (LC-FR1) having SEQ ID NO: 87, (b) a light chain framework region 2 (LC-FR2) having SEQ ID NO: 88, (c) a light chain framework region 3 (LC-FR3) having SEQ ID NO: 89 or 90, and (d) a light chain framework region 4 (LC-FR4) having SEQ ID NO: 91.

[00099] In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR1 of SEQ ID NO: 87. In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR2 of SEQ ID NO: 88. In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR3 of SEQ ID NO: 89 or 90. In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR4 of SEQ ID NO: 91. [000100]In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR1 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 87. In some cases, the VL domain comprises an LC-FR1 having at least 95% sequence similarity to SEQ ID NO: 87. In some cases, the VL domain comprises an LC-FR1 having at least 98% sequence similarity to SEQ ID NO: 87. [000101]In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR2 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 88. In some cases, the VL domain comprises an LC-FR2 having at least 95% sequence similarity to SEQ ID NO: 88. In some cases, the VL domain comprises an LC-FR2 having at least 98% sequence similarity to SEQ ID NO: 88. [000102] In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR3 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 89 or 90. In some cases, the VL domain comprises an LC-FR3 having at least 95% sequence similarity to SEQ ID NO: 89 or 90. In some cases, the VL domain comprises an LC-FR3 having at least 98% sequence similarity to SEQ ID NO: 89 or 90. [000103]In some cases, an anti-Notch2 antibody comprises a VL domain comprising an LC-FR4 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence similarity to SEQ ID NO: 91. In some cases, the VL domain comprises an LC-FR1 having at least 95% sequence similarity to SEQ ID NO: 91. In some cases, the VL domain comprises an LC-FR1 having at least 98% sequence similarity to SEQ ID NO: 91. [000104] In some cases, an anti-Notch2 antibody comprises one or more VH CDR sequences having SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32. In another example, an anti-Notch2 antibody comprises one or more VL CDR sequences having SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In another example, an anti-Notch 2 antibody is composed of VH CDR sequences with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, and VL CDR sequences with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. [000105] In another embodiment, an anti-Notch2 antibody comprises the amino acid sequences CDR-H1, CDR-H2, and CDR-H3 of the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32 and the amino acid sequences CDR-L1, CDR-L2, and CDR-L3 of the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. [000106] In some embodiments, an anti-Notch2 antibody comprises one or more heavy chain CDR amino acid sequences from the VH domain having SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain having SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32 are formed. In some cases, the anti-Notch2 antibody comprises three heavy chain CDR amino acid sequences from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32 are formed.In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30 or 32, and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30 or 32. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30 or 32, and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VH domain with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30 or 32. [000107] In some cases, an anti-Notch2 antibody comprises one or more light chain CDR amino acid sequences from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31, and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31, and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31.In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29 or 31 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29 or 31. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29 or 31 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VL domain with SEQ ID NO: 13, 15, 16, 25, 27, 29 or 31. [000108] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with an amino acid sequence of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence having SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In some cases, the VH domain has at least 95% sequence similarity to an amino acid sequence having SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32.In one case, the VH domain has at least 95% sequence similarity to the amino acid sequence having SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. [000109] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6 or 7; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with an amino acid sequence of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31; wherein the antibody specifically binds to Notch2.In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32. In one case, the VH domain has at least 95% sequence similarity to the amino acid sequence with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In some cases, the antibody binds to Notch2 with a dissociation constant (KD) that is at most a 10-fold increase or at most a 10-fold increase compared to the dissociation constant (KD) of an antibody comprising a VH sequence with SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 31 and a VL sequence with SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. [000110] In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32. In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32. In certain embodiments, a VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% similarity, contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2.In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted from SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises the VH sequence of SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32, including post-translational modifications of this sequence. In a particular case, the VH is composed of one, two, or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO: 6 or 7, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO: 8, 9, 10, 11, or 12.In some cases, an anti-Notch2 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In some cases, an anti-Notch2 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31. In certain embodiments, a VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31 are substituted, inserted, and / or deleted therefrom.In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises the VL sequence set forth in SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31, including post-translational modifications of said sequence. In a particular embodiment, the VL comprises one, two, or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO: 1, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO: 2, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO: 3. [000111]In some embodiments, an anti-Notch2 antibody is provided, wherein the antibody comprises a VH sequence as set forth above, and a VL sequence as set forth above. In some embodiments, the antibody comprises the VH and VL sequences set forth in SEQ ID NO: 14, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, or 32 and SEQ ID NO: 13, 15, 16, 25, 27, 29, or 31, respectively, including post-translational modifications of these sequences. Antibodies containing one or more CDRs from antibody 3107 [000112] In some embodiments, the invention provides an anti-Notch2 antibody comprising at least one, at least two, at least three, at least four, at least five, or at least six CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. [000113]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38 and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. In another embodiment, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37.In another embodiment, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38. [000114]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. In some cases, the antibody comprises (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. [000115] In some cases, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; and (b) a VL domain comprising at least one, at least two, or at least three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. [000116] In some embodiments, the invention provides an antibody comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35. [000117]In some cases, an anti-Notch2 antibody comprises one or more VH CDR sequences of SEQ ID NO: 40. In another case, an anti-Notch2 antibody comprises one or more VL CDR sequences of SEQ ID NO: 39. In another example, an anti-Notch2 antibody comprises VH CDR sequences of SEQ ID NO: 40 and VL CDR sequences of SEQ ID NO: 39. [000118] In another embodiment, an anti-Notch2 antibody comprises the amino acid sequences CDR-H1, CDR-H2 and CDR-H3 of the VH domain of SEQ ID NO: 40 and the amino acid sequences CDR-L1, CDR-L2 and CDR-L3 of the VL domain of SEQ ID NO: 39. [000119] In some cases, an anti-Notch2 antibody comprises one or more heavy chain CDR amino acid sequences from a VH domain of SEQ ID NO: 40 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to a framework amino acid sequence from a VH domain selected from SEQ ID NOs: 40 and 101-106. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from a VH domain of SEQ ID NO: 40 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to a framework amino acid sequence from a VH domain selected from SEQ ID NO: 40 and 101-106. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 40 and a framework with at least 95% sequence similarity to a framework amino acid sequence from a VH domain selected from SEQ ID NOs: 40 and 101-106.In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 40 and a framework with at least 98% sequence similarity to a framework amino acid sequence from a VH domain selected from SEQ ID NOs: 40 and 101-106. [000120] In some cases, an anti-Notch2 antibody comprises one or more light chain CDR amino acid sequences from a VL domain of SEQ ID NO: 39 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to a framework amino acid sequence from a VL domain selected from SEQ ID NOs: 39 and 98-100. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from a VL domain of SEQ ID NO: 39 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to a framework amino acid sequence from a VL domain selected from SEQ ID NOs: 39 and 98-100. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 39 and a framework with at least 95% sequence similarity to a framework amino acid sequence from a VL domain selected from SEQ ID NOs: 39 and 98-100.In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 39 and a framework with at least 98% sequence similarity to a framework amino acid sequence from a VL domain selected from SEQ ID NOs: 39 and 98-100. [000121] In some cases, the anti-Notch2 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 40 and 101-106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 39 and 98-100 In some cases, the VH domain has at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOS: 40 and 101-106.In some cases, the VL domain has at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 39 and 98-100. [000122] In some cases, the anti-Notch2 antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 40 and 101-106, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence selected from SEQ ID NOs: 39 and 98-100 wherein the antibody specifically binds to Notch2. In some cases, the VH domain has at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NOS: 40 and 101-106.In some cases, the VL domain has at least 95% sequence similarity to an amino acid sequence selected from SEQ ID NO: 39 and 98-100. In some cases, the antibody binds to Notch2 with a dissociation constant (KD) that is at most a 10-fold decrease or at most a 10-fold increase compared to the dissociation constant (KD) of an antibody comprising a VH sequence of SEQ ID NO: 40 and a VL sequence of SEQ ID NO: 39. [000123]In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOS: 40 and 101-106. In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOS: 40 and 101-106. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in each of SEQ ID NOs: 40 and 101-106 are substituted, inserted, and / or deleted.In some specific cases, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises a VH sequence selected from SEQ ID NOS: 40 and 101-106, including post-translational modifications of this sequence. In a specific case, the VH comprises one, two, or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO: 36, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO: 37, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO: 38. [000124] In some cases, an anti-Notch2 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence selected from SEQ ID NOS: 39 and 98-100. In some cases, an anti-Notch2 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOS: 39 and 98-100. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in each of SEQ ID NOs: 39 and 98-100 are substituted, inserted, and / or deleted.In some specific cases, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises a VL sequence selected from SEQ ID NOS: 39 and 98-100, including post-translational modifications of this sequence. In a specific case, the VL comprises one, two, or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO: 33, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO: 34, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO: 35. [000125]In some embodiments, an anti-Notch2 antibody is provided, wherein the antibody comprises a VH sequence as set forth above, and a VL sequence as set forth above. In some embodiments, the antibody comprises the VH and VL sequences set forth in SEQ ID NO: 40 and SEQ ID NO: 39, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises a VH sequence selected from SEQ ID NO: 101-106 and a VL sequence selected from SEQ ID NO: 98-100, including post-translational modifications of those sequences. Antibodies containing one or more CDRs from antibody 2338 [000126] In some embodiments, the invention provides an anti-Notch2 antibody comprising at least one, at least two, at least three, at least four, at least five, or at least six CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. [000127] In some cases, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46 and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. In another embodiment, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45.In another embodiment, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46. [000128]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. In some cases, the antibody comprises (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. [000129] In some cases, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46; and (b) a VL domain comprising at least one, at least two, or at least three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. [000130]In some embodiments, the invention provides an antibody comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43. [000131]In some cases, an anti-Notch2 antibody comprises one or more VH CDR sequences of SEQ ID NO: 48. In another case, an anti-Notch2 antibody comprises one or more VL CDR sequences of SEQ ID NO: 47. In another example, an anti-Notch2 antibody comprises VH CDR sequences of SEQ ID NO: 48 and VL CDR sequences of SEQ ID NO: 47. [000132] In another embodiment, an anti-Notch2 antibody comprises the amino acid sequences CDR-H1, CDR-H2 and CDR-H3 of the VH domain of SEQ ID NO: 48 and the amino acid sequences CDR-L1, CDR-L2 and CDR-L3 of the VL domain of SEQ ID NO: 47. [000133] In some cases, an anti-Notch2 antibody comprises one or more heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 48 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 48. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 48 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 48. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 48 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 48.In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 48 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 48. [000134] In some cases, an anti-Notch2 antibody comprises one or more light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 47 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 47. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 47 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 47. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 47 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 47.In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 47 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 47. [000135] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 48, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 47. In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 48. In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 47. [000136] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 48, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 47. wherein the antibody specifically binds to Notch2. In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 48.In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 47. In some cases, the antibody binds to Notch2 with a dissociation constant (KD) that is at most a 10-fold decrease or at most a 10-fold increase compared to the dissociation constant (KD) of an antibody comprising a VH sequence of SEQ ID NO: 48 and a VL sequence of SEQ ID NO: 47. [000137]In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to the amino acid sequence of SEQ ID NO: 48. In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 48. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 48 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).Optionally, the anti-Notch2 antibody comprises the VH sequence of SEQ ID NO: 48, including post-translational modifications of this sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO: 44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO: 45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO: 46. In some cases, an anti-Notch2 antibody is provided, wherein the antibody comprises a variable light chain (VL) domain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 47. In some cases, an anti-Notch2 antibody comprises a variable light chain (VHL) domain sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 47.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 47 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises the VL sequence of SEQ ID NO: 47, including post-translational modifications of this sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO: 41, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO: 42, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO: 43. [000138]In some embodiments, an anti-Notch2 antibody is provided, wherein the antibody comprises a VH sequence as set forth above, and a VL sequence as set forth above. In some embodiments, the antibody comprises the VH and VL sequences of SEQ ID NO: 48 and SEQ ID NO: 47, respectively, including post-translational modifications of these sequences. Antibodies containing one or more CDRs from antibody 2430 [000139] In some embodiments, the invention provides an anti-Notch2 antibody comprising at least one, at least two, at least three, at least four, at least five, or at least six CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. [000140]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55 and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. In another embodiment, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54.In another embodiment, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55. [000141]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. In some cases, the antibody comprises (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. [000142] In some cases, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55; and (b) a VL domain comprising at least one, at least two, or at least three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. [000143] In some embodiments, the invention provides an antibody comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52. [000144]In some instances, an anti-Notch2 antibody comprises one or more VH CDR sequences of SEQ ID NO: 58. In another instance, an anti-Notch2 antibody comprises one or more VL CDR sequences of SEQ ID NO: 56 or 57. In another instance, an anti-Notch2 antibody comprises VH CDR sequences of SEQ ID NO: 58 and VL CDR sequences of SEQ ID NO: 56 or 57. [000145] In another embodiment, an anti-Notch2 antibody comprises the amino acid sequences CDR-H1, CDR-H2 and CDR-H3 of the VH domain of SEQ ID NO: 58 and the amino acid sequences CDR-L1, CDR-L2 and CDR-L3 of the VL domain of SEQ ID NO: 56 or 57. [000146] In some cases, an anti-Notch2 antibody comprises one or more heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 58 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 58. In some cases, the anti-Notch2 antibody is composed of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 58 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 58. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 58 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 58.In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 58 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 58. [000147] In some cases, an anti-Notch2 antibody comprises one or more light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 56 or 57 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 56 or 57. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain with SEQ ID NO: 56 or 57 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain with SEQ ID NO: 56 or 57. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 56 or 57 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 56 or 57.In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 56 or 57 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 56 or 57. [000148] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 58, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 56 or 57. In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 58. In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 56 or 57. [000149] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 58, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 56 or 57; wherein the antibody specifically binds to Notch2. In some cases, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 58.In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 56 or 57. In some cases, the antibody binds to Notch2 with a dissociation constant (KD) that is at most a 10-fold decrease or at most a 10-fold increase compared to the dissociation constant (KD) of an antibody comprising a VH sequence of SEQ ID NO: 58 and a VL sequence of SEQ ID NO: 56 or 57. [000150]In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to the amino acid sequence of SEQ ID NO: 58. In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 58 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).Optionally, the anti-Notch2 antibody comprises the VH sequence of SEQ ID NO: 58, including post-translational modifications of this sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO: 53, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO: 54, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO: 55. In some cases, an anti-Notch2 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to the amino acid sequence of SEQ ID NO: 56 or 57. In some cases, an anti-Notch2 antibody comprises a light chain variable domain (VL) sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 56 or 57.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids within SEQ ID NO: 56 or 57 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises the VL sequence of SEQ ID NO: 56 or 57, including post-translational modifications of this sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO: 49, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO: 50, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO: 51 or 52. [000151]In some embodiments, an anti-Notch2 antibody is provided, wherein the antibody comprises a VH sequence as set forth above, and a VL sequence as set forth above. In some embodiments, the antibody comprises the VH and VL sequences of SEQ ID NO: 58 and SEQ ID NO: 56 or 57, respectively, including post-translational modifications of these sequences. Antibodies containing one or more CDRs from antibody 2621 [000152] In some embodiments, the invention provides an anti-Notch2 antibody comprising at least one, at least two, at least three, at least four, at least five, or at least six CDRs selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. [000153]In some cases, the invention provides an antibody comprising at least one, at least two, or all three VH CDR sequences selected from (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 59. In some cases, the antibody comprises CDR-H3 comprising the amino acid sequence of SEQ ID NO: 60 and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. In another embodiment, the antibody comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64, a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63.In another embodiment, the antibody comprises (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64. [000154]In some embodiments, the invention provides an antibody comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody comprises (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60; and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. [000155] In some cases, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64; and (b) a VL domain comprising at least one, at least two, or at least three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. [000156] In some embodiments, the invention provides an antibody comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. [000157]In some instances, an anti-Notch2 antibody comprises one or more VH CDR sequences of SEQ ID NO: 66. In another instance, an anti-Notch2 antibody comprises one or more VL CDR sequences of SEQ ID NO: 65. In another instance, an anti-Notch2 antibody comprises VH CDR sequences of SEQ ID NO: 66 and VL CDR sequences of SEQ ID NO: 65. [000158] In another embodiment, an anti-Notch2 antibody comprises the amino acid sequences CDR-H1, CDR-H2 and CDR-H3 of the VH domain of SEQ ID NO: 66 and the amino acid sequences CDR-L1, CDR-L2 and CDR-L3 of the VL domain of SEQ ID NO: 65. [000159] In some cases, an anti-Notch2 antibody comprises one or more heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 66 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 66. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 66 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 66. In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 66 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 66.In some cases, the anti-Notch2 antibody consists of three heavy chain CDR amino acid sequences from the VH domain of SEQ ID NO: 66 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VH domain of SEQ ID NO: 66. [000160] In some cases, an anti-Notch2 antibody comprises one or more light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 65 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 65. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 65 and a framework, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 65. In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 65 and a framework with at least 95% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 65.In some cases, the anti-Notch2 antibody consists of three light chain CDR amino acid sequences from the VL domain of SEQ ID NO: 65 and a framework with at least 98% sequence similarity to the framework amino acid sequence from the VL domain of SEQ ID NO: 65. [000161] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 66, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 65. In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 66. In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 65. [000162] In some cases, the anti-Notch2 antibody comprises a (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64; (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61, and a VH domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 66, and a VL domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to an amino acid sequence of SEQ ID NO: 65. wherein the antibody specifically binds to Notch2. In some cases, the VH domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 66.In some cases, the VL domain has at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 65. In some cases, the antibody binds to Notch2 with a dissociation constant (KD) that is at most a 10-fold decrease or at most a 10-fold increase compared to the dissociation constant (KD) of an antibody comprising a VH sequence of SEQ ID NO: 66 and a VL sequence of SEQ ID NO: 65. [000163]In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to the amino acid sequence of SEQ ID NO: 66. In some cases, an anti-Notch2 antibody comprises a heavy chain variable domain (VH) sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 66. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 66 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).Optionally, the anti-Notch2 antibody comprises the VH sequence of SEQ ID NO: 66, including post-translational modifications of this sequence. In a particular embodiment, the VH comprises one, two or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO: 62, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO: 63, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO: 64. In some cases, an anti-Notch2 antibody is provided, wherein the antibody comprises a variable light chain (VL) domain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence similarity to the amino acid sequence of SEQ ID NO: 65. In some cases, an anti-Notch2 antibody comprises a variable light chain (VHL) domain sequence having at least 95% sequence similarity to the amino acid sequence of SEQ ID NO: 65.In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Notch2 antibody comprising that sequence retains the ability to bind to Notch2. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 65 are substituted, inserted, and / or deleted. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-Notch2 antibody comprises the VL sequence of SEQ ID NO: 65, including post-translational modifications of this sequence. In a particular embodiment, the VL comprises one, two or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO: 59, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO: 60, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO: 61. [000164]In some embodiments, an anti-Notch2 antibody is provided, wherein the antibody comprises a VH sequence as set forth above, and a VL sequence as set forth above. In some embodiments, the antibody comprises the VH and VL sequences of SEQ ID NO: 66 and SEQ ID NO: 65, respectively, including post-translational modifications of these sequences. [000165] In another aspect, the invention provides an antibody that binds to the same epitope as an anti-Notch2 antibody provided herein. For example, in certain embodiments, an antibody is provided that binds to the same epitope as an anti-Notch2 antibody and is comprised of a VH sequence of SEQ ID NO: 32 and a VL sequence of SEQ ID NO: 31. In some embodiments, an anti-Notch2 antibody is provided that binds to an epitope within the EGF7 repeat of Notch2. In some embodiments, an anti-Notch2 antibody is provided that binds to an epitope within amino acids 260-296 of Notch 2 (SEQ ID NO: 70). In some embodiments, an anti-Notch2 antibody is provided that binds to an epitope within amino acids 260-296 of Notch 2 (SEQ ID NO: 70). [000166]In another aspect, the invention provides an antibody that competes for binding to Notch2 with an anti-Notch2 antibody provided herein. For example, in certain embodiments, an antibody is provided that competes for binding to Notch2 with an anti-Notch2 antibody and comprises a VH sequence having SEQ ID NO: 32 and a VL sequence having SEQ ID NO: 31. [000167] In another aspect of the invention, an anti-Notch2 antibody according to any of the above is a monoclonal antibody, including a chimeric, humanized, or human antibody. In some aspects, an anti-Notch2 antibody is an antibody fragment, e.g., an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In some aspects, the antibody is a full-length antibody, e.g., an intact IgG1, IgG2, IgG3, or IgG4 antibody, or another class or isotype of antibody as defined herein. [000168] In another embodiment, an anti-Notch2 antibody according to any of the above may, singly or in combination, comprise any of the features described in sections 1-8 below: 1. Antibody affinity [000169]In certain embodiments, an antibody provided herein has a dissociation constant (KD) of ≤ 1μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10-8 M or less, e.g., from 10-8 M to 10-13 M, e.g., from 10-9 M to 10-13 M). [000170] In some cases, KD was measured using a BIACORE® surface plasmon resonance assay. For example, an assay was performed using a BIACORE®-2000 or a BIACORE®-3000 (Biacore Institute, Piscataway, NJ) at 25°C with CM5 antigen-immobilized chips at ~10 response units (RU). In some cases, carboxymethylated dextran biosensor chips (CM5, Biacore Institute) were activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the manufacturer's or supplier's instructions. Before injection at a flow rate of 5 μl / min, the antigen was diluted with 10 mM sodium acetate, pH 4.8 to 5 μg / ml (~0.2 μM) to obtain approximately 10 response units (RU) of coupled protein. After antigen injection, 1 M ethanolamine was injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) in PBS and 0.05% polysorbate 20 (Tween-20TM) surfactant (PBST) were injected at 25°C at a flow rate of approximately 25 μl / min.The binding rates (kon) and dissociation rates (koff) were calculated using a simple one-to-one Langmuir (1:1) binding model (BIACORE® Evaluation Software version 3.2) and by simultaneous fitting of the binding and dissociation sensorgrams. The equilibrium dissociation constant (KD) was calculated as the ratio koff / kon. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). [000171]In another exemplary assay using the BIAcore™ T200 instrument, for example, antibodies with human IgG1 constant regions were captured on a protein A chip to yield approximately 300 RU. In some such samples, serial dilutions of purified antigen were injected with 3 mM CaCl2 in excess HBS-P buffer at 37°C at a flow rate of 100 μL / min. Binding rates (ka) and dissociation rates (kd) were calculated using a 1:1 Langmuir binding model (e.g., BIAcore™ T200 Evaluation Software Version 2.0). The equilibrium dissociation constant (KD) may be calculated as the ratio kd / ka. [000172] If the binding rate exceeds 106M--1s--1 as assessed by a surface plasmon resonance assay, then the binding rate can be determined using a fluorescence quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm bandpass) of a 20 nM anti-antigen antibody (Fab form) at 25°C in PBS, pH 7.2, in the presence of increasing concentrations of antigen in a spectrometer, for example a stop-flow equipped with a spectrophotometer (Avio Instruments) or a SLM-AMINCOTM Series 8000 spectrophotometer (ThermoScientific) equipped with a stirred coater. [000173] In another method, the KD is measured by a radioactively labeled antigen binding assay (RIA). In some cases, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, the binding affinity of solution Fabs for antigen is measured by equilibrating the Fab with a minimal concentration of (125I)-labeled antigen in the presence of a titration series of unlabeled antigen and then trapping the bound antigen on a plate coated with anti-Fab antibody (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)). To establish assay conditions, Microtiter® multiwell plates (Thermo Scientific) were coated overnight with 5 μg / mL of an anti-Fab capture antibody (Coppel Laboratories) in 50 mM sodium carbonate (pH 6.9) and then blocked with 2% (w / v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C).In a non-absorbent plate (Nunc #269620), 100 picomolar or 26 picomolar of [125I] antigen were mixed with serial dilutions of a Fab of interest (e.g., as evaluated for anti-VEGF antibody, Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest was then incubated overnight; however, longer incubations may be required (e.g., about 65 hours) to ensure equilibration. The mixtures were then transferred to the trap plate for incubation at room temperature (e.g., for one hour). The solution was then discarded and the plate was washed eight times with 0.1% polysorbate 20 (Tween-20®) in PBS. Once the plates were dry, 150 μl / well of scintillator (MICROSCINT-20TM; Packard) was added and the plates were counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each Fab that gave less than or equal to 20% of maximum binding were selected for use in competitive binding assays. 2. Antibody fragments [000174] In certain embodiments, the antibody provided herein is an antibody fragment. [000175] In some cases, the antibody fragment is a Fab, Fab', Fab'-SH, or F(ab')2 fragment, particularly a Fab fragment. Papain digestion of intact antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each containing heavy and light chain variable domains (VH and VL, respectively), as well as a light chain constant domain (CL) and the first constant domain of the heavy chain (CH1). The term "Fab fragment" therefore refers to an antibody fragment consisting of a light chain containing a VL domain and a CL domain, and a heavy chain fragment containing a VH domain and a CH1 domain. "Fab' fragments" differ from Fab fragments by having several additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the hinge region of the antibody. Fab'-SH are Fab' fragments in which the cysteine ​​residue(s) of the constant domains carry a free thiol group. Pepsin treatment generates an F(ab')2 fragment that has two antigen-binding sites (two Fab fragments) and a portion of the Fc region.For a discussion of Fab and F(ab')2 fragments that contain salvage receptor-binding epitope residues and have an increased in vivo half-life, see U.S. Patent No. 5,869,046. [000176] In some cases, the antibody fragment is a diabody, a triabody, or a tetrabody. "Diabodies" are antibody fragments with two antigen-binding sites that may be bivalent or dual, capable of binding to two antigens. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). [000177] In another embodiment, the antibody fragment is a single-chain Fab fragment. A "single-chain Fab fragment" or "scFab" is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL), and a linker, wherein said antibody domains and said linker have one of the following sequences in the N-terminus to C-terminus direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL. In particular, said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids in length. Said single chain Fab fragments are stabilized by a natural disulfide bond between the CL domain and the CH1 domain. In addition, these single chain Fab fragments may be further stabilized by generating interchain disulfide bonds through the addition of cysteine ​​residues (for example, position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering). [000178] In some cases, the antibody fragment is a single-chain variable fragment (scFv). A "single-chain variable fragment" or "scFv" is a fusion protein of the variable domains of the light (VL) and heavy (VH) chains of an antibody joined by a linker. In particular, the linker is a short polypeptide of 10 to 25 amino acids and is typically rich in glycine for flexibility and rich in serine and threonine for solubility, and can connect the N-terminus of the VH to the C-terminus of the VL or vice versa. The protein retains the specificity of the original antibody despite the removal of the constant regions and the insertion of the linker. For a review of scFv antibody fragments, see, for example, Plückthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (SPRinger-Verlag, New York), pp. 269-315 (1994); see also WO 93 / 16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. [000179]In some cases, the antibody fragment is a single-domain antibody. "Single-domain antibodies" are antibody fragments that consist of all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain cases, a single-domain antibody is a human single-domain antibody (Domantis Institute, Waltham, Massachusetts; see, for example, U.S. Patent No. 6,248,516 B1). [000180] Antibody fragments can be produced by various methods including, but not limited to, proteolytic digestion of an intact antibody as well as recombinant production by recombinant host cells (e.g., Escherichia coli), as described herein. 3. Chimeric and humanized antibodies [000181] In certain embodiments, the antibody provided herein is a chimeric antibody. Specific chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody is composed of a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In another example, a chimeric antibody is a "class-switch" antibody in which the class or subclass of the parent or original antibody has been changed. Chimeric antibodies also include antigen-binding fragments thereof. [000182]In some specific cases, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity in humans, while retaining the specificity and affinity of the parent or original non-human antibody. Generally, a humanized antibody is composed of one or more variable domains in which the CDRs (or portions thereof) are derived from a non-human antibody and the FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally also comprises at least a portion of a human constant region. In some cases, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., an antibody from which the CDR residues were derived) to, for example, restore or improve the specificity or affinity of the antibody. [000183]Humanized antibodies and methods for making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) binding); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "regeneration"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the "guided selection" approach to FR shuffling) are further described. [000184] Human framework regions that may be used for humanization include, but are not limited to: framework regions selected using a "best fit" approach (see, for example, Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies for a specific subgroup of light or heavy chain variable regions (see, for example, Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature framework regions (that have undergone somatic mutation) or human germline framework regions (see, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions obtained from screening FR libraries (see, for example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). 4. Human antibodies [000185]In certain embodiments, the antibody provided herein is a human antibody. Human antibodies can be produced using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008). [000186]Human antibodies may be produced by injecting an immunogen into a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. These animals typically have all or part of the human immunoglobulin loci replaced by endogenous immunoglobulin loci, either extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are typically inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005).See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSETM technology; U.S. Patent No. 5,770,429 describing HuMab® technology; U.S. Patent No. 7,041,870 describing KM MOUSE® technology; and U.S. Patent Application Publication No. US 2007 / 0061900 describing VelociMouse® technology.) Human variable regions derived from intact or complete antibodies produced by these animals may be further modified or altered, for example, by fusion with a different human constant region. [000187] Human antibodies can also be produced by hybridoma-based methods. Human myeloma and murine-human heteromyeloma cell lines have been described for the production of human monoclonal antibodies. (See, for example, Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies produced by human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103: 3557-3562 (2006). Other methods include, for example, those described in U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridoma).Human hybridoma technology (trioma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005). [000188] Human antibodies can also be produced by isolating selected variable domain sequences from human-derived phage display libraries. These variable domain sequences can then be combined with a desired or desired human constant domain. Methods for selecting human antibodies from antibody libraries are described below. 5. Antibodies obtained or derived from the library [000189] In certain embodiments, the antibody provided herein is obtained from a library. Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies having the activity or activities of interest. Methods for screening combinatorial libraries are reviewed, for example, in Lerner et al. in Nature Reviews 16:498-508 (2016). For example, various methods are known in the art for generating phage display libraries and screening these libraries for antibodies having desired or desirable binding properties. Such methods are described, for example, in Frenzel et al. mAbs 8:1177-1194 (2016); Bazan et al. in Human Vaccines and Immunotherapeutics 8:1817-1828 (2012); and Zhao et al. In Critical Reviews in Biotechnology 36:276-289 (2016) and also in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and in Marks and Bradbury in Methods in Molecular Biology 248:161-175 (Lo, ed.)., Human Press, Totowa, NJ, 2003) have been reviewed. [000190] In some specific phage display methods, VH and VL gene lists are individually cloned by polymerase chain reaction (PCR) and random recombination into phage libraries, which can then be screened for antigen-binding phage as described in Winter et al. in Annual Review of Immunology 12: 433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv fragments (scFv) or as Fab fragments. Libraries derived from immunized sources generate antibodies with high affinity for the immunogen without the need for hybridoma construction. Alternatively, the virgin repertoire can be cloned (for example, from humans) to produce a single source of antibodies to a wide range of non-self antigens as well as self antigens, without any immunization, as described by Griffiths et al. in EMBO Journal 12: 725-734 (1993).In addition, pristine libraries can be generated artificially or synthetically by cloning unrearranged V-gene segments from stem cells using PCR primers with random sequences to encode highly variable CDR3 regions and performing in vitro rearrangement, as described by Hoogenboom and Winter in Journal of Molecular Biology 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Patent Nos. 5,750,373; 7,985,840; 7,785,903 and 8,679,490 are also U.S. Patent Publication Nos. 2005 / 0079574, 2007 / 0117126, 2007 / 0237764, and 2007 / 0292936. [000191] Other examples of methods known in the art for screening combinatorial libraries for antibodies with an activity or activities of interest include ribosomal display and mRNA display, as well as methods of antibody display and selection based on bacteria, mammalian cells, insect cells, or yeast cells. Methods for display on the surface of yeast are reviewed, for example, in Scholler et al. in Methods in Molecular Biology 503:135-56 (2012) and in Cherf et al. in Methods in Molecular biology 1319:155-175 (2015), as well as in Zhao et al. in Methods in Molecular Biology 889:73-84 (2012). Methods for display on the ribosome are reviewed, for example, in He et al. in Nucleic Acids Research 25:5132-5134 (1997) and in Hanes et al. in PNAS 94:4937-4942 (1997). [000192]Herein, antibodies or antibody fragments isolated from human antibody libraries are also considered to be human antibodies or human antibody fragments. 6. Multiple antibodies with the ability to bind to multiple antigens [000193]In some specific cases, an antibody provided herein is a multi-antigen binding antibody, e.g., a dual antibody binding to two antigens. "Multi-antigen binding antibodies" are monoclonal antibodies that exhibit binding specificity for at least two different sites, i.e., different epitopes on different antigens or different epitopes on the same antigen. In some specific cases, a multi-antigen binding antibody has three or more binding specificities. In some specific cases, one of the binding specificities is for Notch2 and the other specificity is for each different antigen. In some specific cases, dual antibodies with dual antigen binding capability may bind to two (or more) different Notch2 epitopes.Multiple antibodies with the ability to bind to multiple antigens (e.g., dual antibodies with the ability to bind to two antigens) can be used to localize cells or cytotoxic agents to cells expressing Notch2. Multiple antibodies with the ability to bind to multiple antigens may be prepared as full-length antibodies or antibody fragments. [000194] Techniques for making multiple antibodies with multi-antigen binding capability include, but are not limited to, recombinant co-expression of two immunoglobulin light chain-heavy chain pairs with different specificities (see, e.g., Milstein and Cuello, Nature 305: 537 (1983)) and "protrusion-in-cavity" engineering (see, e.g., U.S. Patent No. 5,731,168, and Atwell et al., J. Mol. Biol. 270:26 (1997)). Multiple antibodies with multi-antigen binding capability can also be made by engineering electrostatic guidance effects to create Fc-heterodimeric antibody molecules (see, e.g., WO 2009 / 089004); Cross-linking two or more antibodies or antibody fragments (see, for example, U.S. Patent No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to generate dual antibodies capable of binding to two antigens (see, for example, Kostelny et al., J. Immunol., 148(5):1547-1553 (1992) and WO 2011 / 034605); using conventional light chain technology to circumvent the problem of light chain mispairing (see, for example, WO 98 / 50431); using "diabody" technology to construct dual antibody fragments capable of binding to two antigens (see, for example, Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, for example, Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trivalent antibodies capable of binding to three antigens, as described, for example, in Tutt et al. J. Immunol. 147: 60 (1991) described, produced. [000195] Engineered antibodies with three or more antigen-binding sites, including, for example, "octopus antibodies" or DVD-Ig, are also included herein (see, for example, WO 2001 / 77342 and WO 2008 / 024715). Other examples of multi-antigen-binding antibodies with three or more antigen-binding sites can be found in WO 2010 / 115589, WO 2010 / 112193, WO 2010 / 136172, WO 2010 / 145792, and WO 2013 / 026831. A dual antibody capable of binding to two antigens or a resulting antigen-binding fragment also includes a "bifunctional FAb" or "DAF" that includes an antigen-binding site that binds to Notch2 as well as another different antigen or two different epitopes of Notch2 (see, for example, US 2008 / 0069820 and WO 2015 / 095539). [000196]Multiple antibodies with multi-antigen binding capability may also be prepared asymmetrically with a domain crossover in one or more binding arms with similar antigen specificity, i.e., by exchanging VH / VL domains (see, for example, WO 2009 / 080252 and WO 2015 / 150447), CH1 / CL domains (see, for example, WO 2009 / 080253) or complete Fab arms (see, for example, WO 2009 / 080251, WO 2016 / 016299, see also Schaefer et al, PNAS, 108 (2011) 1187-1191, and Klein at al., MAbs 8 (2016) 1010-20). In some cases, a multi-antigen-binding antibody is composed of a cross-Fab fragment. The term "cross-Fab fragment" or "xFab fragment" or "crossover Fab fragment" refers to a Fab fragment in which the variable regions or constant regions of the heavy and light chains have been swapped.A cross-Fab fragment consists of a polypeptide chain consisting of a light chain variable region (VL) and a heavy chain constant region 1 (CH1), and a polypeptide chain consisting of a heavy chain variable region (VH) and a light chain constant region (CL). Asymmetric Fab arms can be engineered by introducing charged or uncharged amino acid mutations at the interface of the domains to direct correct Fab pairing. See, for example, WO 2016 / 172485. [000197] Various other molecular forms for multiple antibodies capable of binding to multiple antigens are known in the art and are provided herein (see, for example, Spiess et al., Mol Immunol 67 (2015) 95-106). [000198] A particular type of multi-antigen binding antibody provided herein is a dual-antigen binding antibody that simultaneously binds to a surface antigen on a target cell, e.g., a tumor cell, and to an activating invariant component of the T cell receptor (TCR) complex, such as CD3, to direct the T cells to kill the target cells. Thus, in certain embodiments, an antibody provided herein is a multi-antigen binding antibody, particularly a dual-antigen binding antibody, wherein one of the specificities is for Notch2 and the other is for CD3. [000199] Examples of dual antibody formats capable of binding to two antigens that may be useful for this purpose include, but are not limited to, so-called “BiTE” (dual T cell engaging dual antigen) molecules in which two scFv molecules are fused together by a flexible linker (see, for example, WO 2004 / 106381, WO 2005 / 061547, WO 2007 / 042261, and WO 2008 / 119567, Nagorsen and Bäuerle, Exp Cell Res 317, 1255-1260 (2011)); Diabodies (Holliger et al., Prot Eng 9, 299-305 (1996)) and their derivatives such as tandem diabodies (“TandAb”; Kipriyanov et al., J Mol Biol 293, 41-56 (1999)); “DART” (dual affinity targeting) molecules based on the diabody shape but with a disulfide bridge at the C-terminus for greater stability (Johnson et al., J Mol Biol 399, 436-449 (2010)), and so-called triomabs, which are mouse / rat IgG hybrid molecules (see Seimetz et al., Cancer Treat Rev 36, 458-467 (2010) for more information).Specific dual antibody formats capable of binding to two T cell antigens included herein are described in WO 2013 / 026833, WO 2013 / 026839, WO 2016 / 020309; Bacac et al., Oncoimmunology 5(8) (2016) e1203498. 7. Antibody variants [000200]In certain embodiments, amino acid sequence variants of the provided antibodies are contemplated. For example, it may be desirable to alter the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody can be prepared by making appropriate changes to the nucleotide sequence encoding the antibody, or by peptide synthesis. Such changes include, for example, deletions from and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletions, insertions, and substitutions can be made to achieve the final structure, provided that the final structure has the desired properties, e.g., antigen binding. a) Substitution, insertion, and deletion variants [000201] In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and FRs. Conservative substitutions are shown in Table 1 under the heading “Preferred Substitutions.” More substantial changes are shown in Table 1 under the heading “Exemplary Substitutions,” and as further described below with reference to amino acid side chain classes. Amino acid substitutions can be made to confer a desired activity, for example, to maintain / improve antigen binding, reduce immunogenicity, or improve ADCC or CDC to the antibody of interest and screened products. Table 1 Main Residue Typical Substitutions Preferred Substitutions Alanine (A) Valine; Leucine; Isoleucine Valine Arginine (R) Lysine; Glutamine; Asparagine Lysine Asparagine (N) Glutamine; Histidine; Aspartic Acid, Lysine; Arginine Glutamine Aspartic Acid (D) Glutamic Acid; Asparagine Glutamic Acid Cysteine ​​(C) Serine; Alanine Serine Glutamine (Q) Asparagine; Glutamic Acid Asparagine Glutamic Acid (E) Aspartic Acid; Glutamine Aspartic Acid Glycine (G) Alanine Alanine Histidine (H) Asparagine; Glutamine; Lysine; Arginine Arginine Isoleucine (I) Leucine; Valine; Methionine; Alanine; Phenylalanine; Norleucine Leucine Leucine (L) Norleucine; Isoleucine; Valine; Methionine; Alanine; Phenylalanine Isoleucine Lysine (K) Arginine; Glutamine; Asparagine Arginine Methionine (M) Leucine; Phenylalanine; Isoleucine Leucine Phenylalanine (F) Tryptophan; Leucine; Valine; Isoleucine; Alanine; Tyrosine Tyrosine Proline (P) Alanine Alanine Serine (S) Threonine Threonine Threonine (T) Valine; Serine Serine Tryptophan (W) Tyrosine; Phenylalanine Tyrosine Tyrosine (Y) Tryptophan; Phenylalanine; Threonine; Serine PhenylalanineValine (V) Isoleucine; Leucine; Methionine; Phenylalanine; Alanine; Norleucine Leucine [000202]Amino acids can be grouped based on general side chain characteristics: (1) Hydrophobic: norleucine, methionine, alanine, valine, leucine, isoleucine; (2) Neutral hydrophilic: cysteine, serine, threonine, asparagine, glutamine; (3) Acidic: aspartic acid, glutamic acid; (4) Match: histidine, lysine, arginine; (5) Residues that affect chain orientation: glycine, proline; (6) Aromatic: tryptophan, tyrosine, phenylalanine. [000203] Non-conservative substitutions involve replacing a member of one of these classes with a member of another class. [000204] One type of substitution variant involves the substitution of one or more residues of the variable region of a parent or parent antibody (e.g., a humanized or humanized antibody). Generally, the resulting variant(s) selected for further study have alterations (e.g., improvements) in certain biological properties (e.g., increased affinity, decreased immunogenicity) relative to the parent or parent antibody and / or generally retain certain biological properties of the parent or parent antibody. One example of a substitution variant is an affinity matured antibody, which may be readily produced, for example, using phage display-based affinity maturation techniques, such as those described herein. Briefly, one or more. CDR residues were mutated and variant or altered antibodies were displayed on phage and screened for a specific biological activity (e.g., binding affinity). [000205] Alterations (e.g., substitutions) can be made in the CDRs, for example, to improve the affinity of the antibody. Such alterations can be made in CDR "hot spots," that is, residues encoded by codons that mutate frequently during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and / or residues that are in contact with the antigen and the resulting VH or VL variants are tested for binding affinity. Affinity maturation by construction and reselection from a secondary library has been previously described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some cases of hybrid affinity maturation, diversity was introduced into the variable genes selected for maturation by any of several methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis). A secondary library was then created.This library is then screened to identify each antibody variant with the desired affinity. Another approach to generating diversity involves CDR targeting methods in which multiple CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified, for example, by modeling or alanine scanning mutagenesis. In particular, CDR-H3 and CDR-L3 are most often targeted. [000206] In certain embodiments, substitutions, additions, or deletions may be made in one or more CDRs, provided that the changes do not significantly reduce the ability of the antibody to bind to antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not require a significant reduction in binding affinity may be made in the CDRs. Such changes may, for example, be made outside of the residues in the CDRs that are in contact with the antigen. In some of the variant VH and VL sequences provided above, each CDR is either unchanged or contains no more than one, two, or three amino acid substitutions. [000207] A useful method for identifying residues or regions of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a target residue or group of residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid) is identified and replaced with a negatively charged or neutral amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Additional substitutions may be introduced at amino acid positions that indicate functional sensitivity to the initial substitutions. Alternatively, or in addition, a crystal structure of an antigen-antibody complex may also be used to identify the contact points between the antibody and antigen. These contact residues and adjacent residues may be targeted or deleted as candidates for substitution.Variants may be screened to determine whether they contain desired or desirable characteristics. [000208]Amino acid sequence fusions include amino-terminal and / or carboxyl-terminal linkages ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intra-sequence fusions with one or more amino acid residues. Examples of terminal fusions include an antibody with an N-terminal methionyl residue. Other fusion variants of the antibody molecule include the attachment or fusion to the N-terminus or C-terminus of an antibody with an enzyme (e.g., for ADEPT (Antibody Receptor Targeted Enzyme Prodrug Therapy)) or a polypeptide that increases the serum half-life of the antibody. b) Glycosylation variants [000209] In certain embodiments, an antibody provided herein has been modified to increase or decrease the extent of glycosylation of the antibody. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or deleted. [000210] Where an antibody is composed of an Fc region, the oligosaccharides attached to it can be modified. Native antibodies produced by mammalian cells typically consist of a branched, bifurcated oligosaccharide, usually linked by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32 (1997). This oligosaccharide may contain various carbohydrates, for example, mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to a GlcNAc in the "stem" of the bifurcated oligosaccharide structure. In some cases, modifications may be made to the oligosaccharide of an antibody of the invention to create antibody variants with specific improved properties. [000211] In some cases, the antibody variants provided have a non-fucosylated oligosaccharide, i.e., an oligosaccharide structure that lacks fucose attached (directly or indirectly) to an Fc region. Such a non-fucosylated oligosaccharide (also referred to as a "non-fucosylated" oligosaccharide) is particularly an N-linked oligosaccharide that lacks a fucose residue attached to the first GlcNAc in the stem of the bifurcated oligosaccharide structure. In some cases, the antibody variants provided have an increased proportion of non-fucosylated oligosaccharides in the Fc region compared to the parent or pristine antibody. For example, the proportion of non-fucosylated oligosaccharides may be at least about 20%, at least about 40%, at least about 60%, at least about 80%, or even about 100% (in other words, there are no non-fucosylated oligosaccharides).The percentage of non-fucosylated oligosaccharides is the (average) amount of oligosaccharides lacking fucose residues, relative to the sum of all oligosaccharides bound to Asn 297 (e.g., complex, hybrid, and high-mannose structures), as measured by MALDI-TOF mass spectrometry and described, for example, in WO 2006 / 082515. Asn297 refers to the asparagine residue located at approximately position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may be located approximately ± 3 amino acids upstream or downstream of position 297, i.e. between positions 294 and 300, due to small sequence differences in antibodies. Such antibodies having an increased proportion of non-fucosylated oligosaccharides in the Fc region may exhibit improved effector function and / or improved FcγRIIIa receptor binding function, particularly improved ADCC function. See, for example, US 2003 / 0157108; US 2004 / 0093621. [000212] Examples of cell lines capable of producing antibodies with reduced fucosylation include Lec13 CHO cells defective in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US 2003 / 0157108; and WO 2004 / 056312, especially in Example 11) and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614-622 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003 / 085107). see), or cells with reduced or absent activity of a transporter protein or GDP-fucose synthase (see, for example, US2004259150, US2005031613, US2004132140, US2004110282). [000213] In another embodiment, the antibody variants provided comprise truncated oligosaccharides; for example, those in which a branched oligosaccharide attached to the Fc region of the antibody is truncated with GlcNAc. As described above, these antibody variants may have reduced fucosylation and / or improved ADCC activity as described above. Examples of these antibody variants are described, for example, in Umana et al., Nat Biotechnol 17, 176-180 (1999); Ferrara et al., Biotechn Bioeng 93, 851-861 (2006); WO 99 / 54342; WO 2004 / 065540, WO 2003 / 011878. [000214] Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. These antibody variants may have improved CDC function. These antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764. c) Fc region variants [000215] In certain embodiments, one or more changes can be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may consist of a human Fc region sequence (e.g., an Fc region from human IgG1, IgG2, IgG3, or IgG4) that contains an amino acid change (e.g., a substitution) at one or more amino acid positions. [000216]In certain embodiments, the invention contemplates an antibody variant that has some but not all of the effector functions, making it a good candidate for applications in which the in vivo half-life of the antibody is important but where certain effector functions (such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)) are unnecessary or detrimental. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduction / abolition of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks binding to FcγR (and thus likely lacks ADCC activity), but still has the ability to bind to FcRn. The main cells for mediating ADCC, NK cells, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol.9:457-492 (1991). Non-limiting examples of in vitro assays for assessing the ADCC activity of a molecule of interest are described in U.S. Patent Nos. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see, e.g., Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be utilized (see, for example, the ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (Cell Technology Institute, Mountain View, CA; and the CytoTox 96® Non-Radioactive Cytotoxicity Assays (Promega, Madison, WI). Useful effector cells for these assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively, or in addition, the ADCC activity of the molecule of interest can be measured in vivo, for example, in an animal model such as those disclosed in Clynes et al. Proc. Nat'l Acad. Sci.USA 95:652-656 (1998). C1q binding assays can be additionally performed to confirm that the antibody is capable of binding to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006); WO 2013 / 120929). [000217] Antibodies with reduced effector function include those in which there is a substitution of one or more of the Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including Fc mutants with substitutions at residues 265 and 297 with alanine, also referred to as "DANA" (U.S. Patent No. 7,332,581). [000218] Certain antibody variants have been described that have improved or reduced binding to FcRs. (See, for example, U.S. Patent No. 6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).) [000219] In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions, for example, substitutions at positions 298, 333 and / or 334 of the Fc region, that improve ADCC (EU residue numbering). [000220] In some specific cases, an antibody variant comprises an Fc region with one or more amino acid substitutions, e.g., substitutions at positions 234 and 235 of the Fc region that reduce FcγR binding (EU numbering for residues). In some cases, the substitutions include L234A and L235A (LALA). In some specific cases, the antibody variant also comprises D265A and / or P329G in an Fc region derived from a human IgG1Fc region. In some cases, the substitutions include L234A, L235A, and P329G (LALA-PG) in an Fc region derived from a human IgG1Fc region. (See, e.g., WO 2012 / 130831). In some cases, these substitutions include L234A, L235A, and D265A (LALA-DA) in an Fc region derived from a human IgG1Fc region. [000221] In some cases, modifications have been made to the Fc region that alter (i.e., enhance or reduce) binding to C1q and / or complement-dependent cytotoxicity (CDC), for example, as described in U.S. Patent No. 6,194,551, WO 99 / 51642 and Idusogie et al. J. Immunol. 164: 4178-4184 (2000). [000222]Antibodies with increased half-lives and improved binding to nascent or neonatal Fc receptors (FcRn), which are responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005 / 0014934 (Hinton et al.). These antibodies consist of an Fc region with one or more substitutions that improve binding of the Fc region to FcRn. These Fc variants include those that have the following substitutions at one or more of the Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424 or 434, such as, substitution at residue 434 of the Fc region (see, for example, U.S. Patent No. 7,371,826; Dall'Acqua, WF, et al. J. Biol. Chem. 281 (2006) 23514-23524). [000223]Fc region residues critical for murine FcRn-murine Fc interaction have been identified by site-directed mutagenesis (see, for example, Dall'Acqua, WF, et al. J. Immunol 169 (2002) 5171-5180). Residues I253, H310, H433, N434, and H435 (EU index numbering) are involved in this interaction (Medesan, C., et al., Eur. J. Immunol. 26 (1996) 2533; Firan, M., et al., Int. Immunol. 13 (2001) 993; Kim, JK, et al., Eur. J. Immunol. 24 (1994) 542). Residues I253, H310, and H435 have been shown to be critical for the interaction of human Fc with mouse FcRn (Kim, JK, et al., Eur. J. Immunol. 29 (1999) 2819). Studies on the human FcRn-human Fc complex have shown that residues I253, S254, H435, and Y436 are essential for this interaction (Firan, M., et al., Int. Immunol. 13 (2001) 993; Shields, RL, et al., J. Biol. Chem. 276 (2001) 6591-6604). In Yeung, YA, et al. (J. Immunol.182 (2009) 7667-7671) Various mutants of residues 248 to 259, 301 to 317, 376 to 382, ​​and 424 to 437 have been reported and investigated. [000224]In some specific cases, an antibody variant comprises an Fc region with one or more amino acid substitutions, e.g., substitutions at positions 253, and / or 310, and / or 435 of the Fc region that reduce FcRn binding (EU residue numbering). In some specific cases, the antibody variant comprises an Fc region with amino acid substitutions at positions 253, 310, and 435. In some cases, the substitutions include I253A, H310A, and H435A in an Fc region derived from a human IgG1 Fc region. See, e.g., Grevys, A., et al., J. Immunol. 194 (2015) 5497-5508. [000225]In some specific cases, an antibody variant comprises an Fc region with one or more amino acid substitutions, for example substitutions at positions 310, and / or 433, and / or 436 of the Fc region that reduce FcRn binding (EU residue numbering). In some specific cases, the antibody variant comprises an Fc region with amino acid substitutions at positions 310, 433, and 436. In some cases, the substitutions include H310A, H433A, and Y436A in an Fc region derived from a human IgG1 Fc region. (See, for example, WO 2014 / 177460 A1). [000226] In some specific cases, an antibody variant comprises an Fc region with one or more amino acid substitutions, for example substitutions at positions 252, and / or 254, and / or 256 of the Fc region that enhance FcRn binding (EU residue numbering). In some specific cases, the antibody variant comprises an Fc region with amino acid substitutions at positions 252, 254, and 256. In some cases, the substitutions include M252Y, S254T, and T256E in an Fc region derived from a human IgG1Fc region. See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; See U.S. Patent No. 5,624,821; and WO 94 / 29351. [000227] The C-terminus of the heavy chain of the antibody reported herein can be a complete C-terminus terminated with PGK amino acid residues. The C-terminus of the heavy chain can be a truncated C-terminus in which one or two C-terminal amino acid residues are deleted. In a preferred embodiment, the C-terminus of the heavy chain is a truncated C-terminus terminated with PG. In some of the embodiments reported herein, an antibody is comprised of a heavy chain comprising a C-terminal CH3 domain as defined herein, which contains a C-terminal glycine-lysine dipeptide (G446 and K447, EU Index numbering of amino acid positions). In some of the cases reported herein, an antibody is composed of a heavy chain comprising a C-terminal CH3 domain as defined herein, which contains a C-terminal glycine residue (G446 EU Index numbering of amino acid positions). d) Cysteine ​​engineered antibody variants [000228] In certain cases, it may be preferable to generate cysteine ​​engineered antibodies, for example, THIOMAB™ antibodies in which one or more residues of an antibody have been replaced with cysteine ​​residues. In particular cases, the substituted residues appear at accessible sites on the antibody. By replacing these residues with cysteine, active thiol groups are placed at accessible sites on the antibody and may be used to conjugate the antibody to other moieties, including drug moieties or drug-interface moieties, to generate an immunoconjugate, as further described herein. Cysteine ​​engineered antibodies can be produced as described in U.S. Patent Nos. 7,521,541, 8,30,930, 7,855,275, 9,000,130, or WO 2016040856. 8. Immunoconjugates [000229] The invention also provides immunoconjugates comprising an anti-Notch2 antibody provided herein conjugated (chemically linked) to one or more therapeutic agents such as cytotoxic agents, chemotherapeutic agents, drugs, growth inhibitory agents, toxicants (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant or animal origin or fragments thereof), or radioactive isotopes. [000230]In some cases, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is coupled or conjugated to one or more of the therapeutic agents listed above. The antibody is typically attached to one or more of the therapeutic agents using linkers. A review of ADC technology, including examples of therapeutic agents and drugs and linkers, is provided in Pharmacol Review 68:3-19 (2016). [000231] In some cases, an immunoconjugate is made from an antibody described herein conjugated to an enzymatically active toxin or fragments thereof, including but not limited to diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (derived from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modacin A chain, alpha-sarcin, Aleurites fordii proteins, Phytolacca americana proteins (PAPI, PAPII and PAP-S), Momordica charantia inhibitor, corcin, quercetin, Saponaria officinalis inhibitor, glunin, mitogelin, restrictocin, phenomycin, enomycin and trichothecenes. [000232] In some cases, an immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. These include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and the radioactive isotopes of Lu. When a radioconjugate is used for detection, for scintigraphy studies, the radioconjugate may consist of a radioactive atom, for example Tc99m or I123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron. [000233] Conjugates of an antibody and a cytotoxic agent can be prepared using a range of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-functional fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriamine pentaacetic acid (MX-DTPA) is an example of a chelating agent for conjugating radionucleotides to antibodies.See WO 94 / 11026. The linker may be a "cleavable linker" that facilitates the release of the cytotoxic drug into the cell. For example, an acid-labile linker, peptidase-labile linker, photolabile linker, dimethyl linker, or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be employed. [000234] Immunoconjugates or ADCs discussed herein include, but are not limited to, conjugates prepared with crosslinking reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Rockford, Illinois, USA). B. Recombinant formulations or compositions and methods [000235]Antibodies can be produced using recombinant compositions or formulations and methods described, for example, in US 4,816,567. For these methods, one or more isolated nucleic acid(s) encoding an antibody are provided. [000236] In the case of a native antibody or a fragment of a native antibody, two nucleic acids are required, one for the light chain or a fragment thereof and one for the heavy chain or a fragment thereof. These nucleic acid(s) encode an amino acid sequence comprising the VL and / or an amino acid sequence comprising the VH of the antibody (e.g., the heavy and / or light chain(s) of the antibody). These nucleic acids can be on the same expression vector or on different expression vectors. [000237] In the case of a dual antibody capable of binding to two antigens with heterodimeric heavy chains, four nucleic acids are required, one for the first light chain, one for the first heavy chain containing the first heteromonomeric Fc region polypeptide, one for the second light chain, and one for the second heavy chain containing the second heteromonomeric Fc region polypeptide. The four nucleic acids can be included in one or more nucleic acid molecules or expression vectors. The nucleic acid(s) encode an amino acid sequence comprising a first VL and / or an amino acid sequence comprising a first VH containing the first heteromonomeric Fc region and / or an amino acid sequence comprising a second VL and / or an amino acid sequence comprising a second VH containing the second heteromonomeric Fc region of the antibody (e.g., the first and / or second light chains and / or the first and / or second heavy chains of the antibody). These nucleic acids can be located on one expression vector or different expression vectors, usually these nucleic acids are located on two or three expression vectors, meaning that one vector can contain more than one of these nucleic acids.Examples of such dual antibodies capable of binding to two antigens include CrossMabs (see, for example, Schaefer, W. et al, PNAS, 108 (2011) 11187-1191). For example, one heteromonomeric heavy chain contains so-called "bump mutations" (T366W and optionally one of S354C or Y349C) and the other contains so-called "hole mutations" (T366S, L368A and Y407V and optionally Y349C or S354C) (see, for example, Carter, P. et al., Immunotechnol. 2 (1996) 73) based on the European Union index numbering. [000238]In some instances, isolated nucleic acids encoding an antibody used in the methods reported herein are provided. [000239] In some cases, a method of making an anti-Notch2 antibody is provided, wherein the method comprises culturing a host cell containing nucleic acid(s) encoding the antibody provided above under conditions suitable for expression of the antibody and optionally isolating the antibody from the host cell (or host cell culture medium). [000240] To recombinantly produce an anti-Notch2 antibody, nucleic acids encoding an antibody, for example, as described above, are isolated and inserted into one or more vectors for cloning and / or further expression in a host cell. These nucleic acids may be readily isolated and sequenced using conventional methods (for example, using oligonucleotide probes capable of specifically binding to the genes encoding the light and heavy chains of the antibody) or may be produced by recombinant methods or obtained by chemical synthesis. [000241] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic and eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, US 5,648,237 , US 5,789,199 , and US 5,840,523 . (See also Charlton, KA, In: Methods in Molecular Biology, Vol. 248, Lo, BKC (ed.), Humana Press, Totowa, NJ (2003), pp. 245-254, describing expression of antibody fragments in E. coli.) The antibody, after expression, may be isolated from the bacterial cell pulp in a soluble fraction and further purified. [000242] In addition to prokaryotes, eukaryotic microbes such as yeast or filamentous fungi are suitable cloning or expression hosts for antibody-encoding vectors, including yeast or fungal strains whose glycosylation pathway has been "humanized," resulting in the production of a polypeptide with a partially or fully humanized glycosylation pattern. See Gerngross, TU, Nat. Biotech. 22 (2004) 1409-1414, and Li, H. et al., Nat. Biotech. 24 (2006) 210-215. [000243] Suitable host cells for expressing (glycosylated) antibodies have also been obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. A large number of baculovirus strains have been identified that can be used with insect cells, particularly for transfection of Spodoptera frugiperda cells, a type of moth. [000244] Plant cell cultures can also be used as hosts. See, for example, US 5,959,177, US 6,040,498, US 6,420,548, US 7,125,978, and US 6,417,429 (describing PLANTIBODIESTM technology for producing antibodies in transgenic plants). [000245]Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension can be useful. Other examples of useful mammalian host cell lines include monkey kidney CV1 line transformed with SV40 (COS-7); human fetal kidney line (293 or 293T cells, described, for example, in Graham, FL et al., J. Gen Virol. 36 (1977) 59-74); baby hamster kidney (BHK) cells; mouse Sertoli cells (TM4 cells, described, for example, in Mather, JP, Biol. Reprod. 23 (1980) 243-252); monkey kidney (CV1) cells; African green monkey kidney (VERO-76) cells; Human cervical cancer cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells (described, for example, in Mather, JP et al., Annals NY Acad. Sci. 383 (1982) 44-68); MRC 5 cells; and FS4 cells.Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub, G. et al., Proc. Natl. Acad. Sci. USA 77 (1980) 4216-4220); and myeloma cell lines, such as Y0, NS0, and Sp2 / 0. For a review of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki, P. and Wu, A.M., Methods in Molecular Biology, Vol. 248, Lo, BKC (ed.), Humana Press, Totowa, NJ (2004), pp. 255-268. [000246]In some cases, the host cell is eukaryotic, for example, a Chinese hamster ovary (CHO) cell or lymphoid cell (for example, Y0, NS0, Sp20 cell). C. Measurements [000247] The physical / chemical properties and / or biological activities of the anti-Notch2 antibodies provided herein can be identified, screened, or characterized using various assay methods known in the art. 1. Connectivity and other measurements [000248] In some cases, an antibody of the invention is tested for its antigen binding activity, for example, using known methods such as ELISA, Western blot, etc. [000249] In some cases, competition assays can be used to identify an antibody that competes with one or more of the rat 1B2 antibodies or a humanized version thereof, rat.3107, rb.2338, rb.2430, and / or rb.2621 provided herein for binding to Notch2. In certain cases, the competing antibody binds to the same epitope (e.g., a linear or structural epitope) that rat.1B2 or a humanized version thereof, rat.3107, rb.2338, rb.2430, and / or rb.2621, binds to. Detailed, exemplary, and precise methods for mapping an epitope to which an antibody binds are provided in Morris (1996) “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). [000250] In an exemplary competition assay, immobilized Notch2 is incubated in a solution containing a first labeled antibody that binds to Notch2 (e.g., rat.1B2 or a humanized version thereof, i.e., rat.3107, rb.2338, rb.2430, or rb.2621) and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to Notch2. The second antibody may be present in the supernatant or supernatant of the hybridoma. Immobilized Notch2, as a control, is incubated in a solution containing the first labeled antibody and not the second unlabeled antibody. After incubation under conditions suitable for binding of the first antibody to Notch2, excess unbound antibody was removed and the amount of label bound to the immobilized Notch2 was measured. If the amount of label bound to the immobilized Notch2 in the test sample was significantly reduced compared to the control sample, then it was determined that the second antibody was competing with the first antibody for binding to Notch2.See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Harbor Laboratory, Cold Harbor, NY). [000251]In an exemplary epitope classification assay, surface plasmon resonance was used to determine competition between antibodies. For example, a first antibody (e.g., rat.1B2 or its humanized derivative, rat.3107, rb.2338, rb.2430, or rb.2621) was immobilized on a CMD 200M SensorPrism SPR chip using amino coupling. The analyte was injected for 4 minutes, e.g., 50 nM, and then the second antibody was injected for 4 minutes, e.g., 10 µg / mL. The assay may be performed at 25°C in a HBS-T running buffer (0.01 M Heps, pH 7.4, 0.15 M NaCl, 0.05% P20 surfactant, 25 mM CaCl). The classification data may be processed using the Wasatch Classification Software Tool, Epitope (Cartera USA). 2. Activity Measurements [000252]In some instances, assays are provided for identifying anti-Notch2 antibodies that have a specific biological activity. For example, assays are provided for identifying anti-Notch2 antibodies that inhibit Jagged1-mediated signaling but leave DLL1-mediated signaling substantially intact. Assays are also provided for identifying anti-Notch2 antibodies that reduce the number of secretory cells in vitro and in vivo. [000253] An exemplary non-limiting assay for identifying anti-Notch2 antibodies that inhibit Jagged1-mediated signaling but leave DLL1-mediated signaling substantially unchanged is described in Example 5. Generally, in some examples, a test antibody was added to a culture medium of human cells expressing human Notch2, such as the U87-MG cell line. The culture medium was then contacted with cells expressing Jagged1 or DLL1. Ligand-dependent activation of Notch2 results in the translocation of Notch2-ICD in Notch2-expressing cells. Following incubation, the cultured cells were simultaneously fixed and permeabilized, and then contacted with an anti-Notch2 ICD antibody. After removal of unbound anti-Notch2 ICD antibody, bound antibodies were detected, for example, using a labeled anti-Ig antibody.If the anti-Notch2 antibody tested inhibits Jagged1-mediated signaling but not DLL1-mediated signaling, then coculture with DLL1-expressing cells will produce significantly more signal than coculture with Jagged1-expressing cells. [000254]In some examples, an anti-Notch2 antibody was assayed to determine whether it reduced the number of secretory cells. An exemplary non-limiting assay for selecting antibodies with this activity is described in Example 8. Generally, in some examples, an air-liquid interface (ALI) culture of primary human bronchial epithelial cells (HBECs) was established and cultured for several weeks until they were fully differentiated, as indicated, for example, by the cilia visibly vibrating. The test anti-Notch2 antibody was added to the culture medium of the lower chamber of the ALI culture. After about 7 days, the ALI cultures were analyzed. RNA was extracted from a sample of the culture and assessed for the expression of genes related to secretory cells, such as Muc5b, Muc5ac, and Scgb1a1. Cultures can also be analyzed histologically by fixing the cultures and embedding them in paraffin. Sections were stained with antibodies for markers of secretory cells, such as Muc5b, and ciliated cells, such as tubulin.Cultures incubated with and without the test anti-Notch2 antibody were compared to identify anti-Notch2 antibodies that reduce the number of secretory cells such as goblet cells. D. Methods and compositions or formulations for detection and identification [000255]In certain embodiments, any of the anti-Notch2 antibodies provided herein are useful for detecting the presence of Notch2 in a biological sample. The term "detection" as used herein includes both quantitative and qualitative aspects thereof. In certain embodiments, a biological sample comprises a biological fluid, cell, or tissue, such as sputum, secretory cells, airway epithelial cells, immune cells, lung cells or tissue, or bronchial cells or tissue. [000256]In some embodiments, an anti-Notch2 antibody is provided for use in a method for diagnosing or identifying a disease. In another embodiment, a method for detecting the presence of Notch2 in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an anti-Notch2 antibody as described herein under conditions that permit binding of the anti-Notch2 antibody to Notch2, and determining whether a complex is formed between the anti-Notch2 antibody and Notch2. The method may be an in vitro or in vivo method. In some cases, an anti-Notch2 antibody has been used to select study subjects eligible for treatment with an anti-Notch2 antibody, for example in cases where Notch2 serves as a biomarker for patient selection. [000257] In certain embodiments, labeled or labeled anti-Notch2 antibodies are provided. Labels include, but are not limited to, labels or moieties that are directly recognized (e.g., fluorescent, chromophore, electron-dense, chemiluminescent, and radioactive labels), as well as moieties such as enzymes or ligands that are indirectly recognized, e.g., via an enzymatic reaction or molecular interaction.Examples of labels include, but are not limited to, 32P, 14C, 125I, 3H and 131I radioisotopes, fluorophores such as rare earth chelators or fluoresceins and their derivatives, rhodamine and its derivatives, dansyl, amblyferone, luciferases, e.g., firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazine diones, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases, e.g., glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase, Coupled with an enzyme that uses hydrogen peroxide to oxidize a colored precursor such as HRP, lactoperoxidase or microperoxidase, biotin / avidin, spin labels, bacteriophage labels, stable free radicals, and the like. E. Pharmaceutical compounds or formulations [000258] In another embodiment, pharmaceutical compositions or formulations comprising any of the antibodies provided herein are provided, for example, for use in any of the following therapeutic methods. In some embodiments, a pharmaceutical composition or formulation comprises any of the antibodies provided herein and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition or formulation comprises any of the antibodies provided herein and at least one other therapeutic agent, for example, as described below. [000259] Pharmaceutical formulations of an anti-Notch2 antibody described herein are prepared by mixing the antibody, which has the desired purity, with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the doses and concentrations employed and include, but are not limited to, buffers such as histidine, phosphate, citrate acetate and other organic acids; antioxidants such as ascorbic acid and methionine; Preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamthonium chloride, benzalkonium chloride, benzthonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine,glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates containing glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; self-forming counterions such as sodium; metal complexes (e.g. zinc-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Examples of acceptable pharmaceutically acceptable carriers referred to herein include intermediate drug dispersion agents, including neutrally active hyaluronidase soluble glycoproteins (sHASEGP), e.g., human soluble hyaluronidase PH-20 glycoproteins such as rHuPH20 (Hylenex®, Halozyme Institute). Some specific examples of sHASEGPs and methods of using them, including rHuPH20, are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In some cases, a sHASEGP is combined with one or more other glycosaminoglycans, such as chondroitinases. [000260]Examples of lyophilized antibody formulations or compositions are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations or compositions include those described in U.S. Patent No. 6,171,586 and WO 2006 / 044908, the latter formulations or compositions also comprising a histidine-acetate buffer. [000261]The pharmaceutical composition or formulation disclosed herein can, if desired, also contain more than one active ingredient for treating a particular symptom, preferably combinations with complementary activities that do not adversely affect each other. For example, it may be desirable to provide an additional agent that can reduce the viscoelasticity of mucus. In some embodiments, an additional therapeutic agent is selected from hypertonic saline, mannitol, palmozyme, N-acetylcysteine, cysteamine, and a bronchodilator. These active ingredients are preferably present in the composition in amounts that are effective for the intended purpose. [000262] Active ingredients can be entrapped in microcapsules prepared, for example, by co-aggregation techniques or by interfacial polymerization such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres or microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, respectively. These techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). [000263]Sustained release formulations or compositions may be prepared. Suitable examples of sustained release compositions include semipermeable matrices of solid hydrophobic polymers containing the antibody, where the matrices are in the form of shaped particles, e.g., films or microcapsules. [000264] Pharmaceutical compositions or formulations intended for intrathecal administration are generally sterile. Sterilization may be conveniently accomplished, for example, by filtration through sterile filtration membranes. F. Treatment methods and administration methods [000265]Any of the anti-Notch2 antibodies provided herein can be used in therapeutic methods. [000266]In some embodiments, an anti-Notch2 antibody is provided for use as a medicament. In other embodiments, an anti-Notch2 antibody is provided for use in treating a mucocutaneous obstructive pulmonary disease. In certain embodiments, an anti-Notch2 antibody is provided for use in a method of treatment. In certain embodiments, the invention provides an anti-Notch2 antibody for use in a method of treating a subject suffering from a mucocutaneous obstructive pulmonary disease, comprising administering to the subject an effective amount of the anti-Notch2 antibody. In such an embodiment, the method also comprises administering an effective amount of at least one other therapeutic agent (e.g., one, two, three, four, five, or six other therapeutic agents), e.g., as described below. In other instances, the invention provides an anti-Notch2 antibody for use in reducing the number of secretory cells, such as goblet cells, in an individual, e.g., in the lungs of an individual.In some cases, the invention provides an anti-Notch2 antibody for use in a method of reducing the number of secretory cells, such as goblet cells, in an individual, e.g., in the lungs of an individual, comprising administering to the individual an effective amount of an anti-Notch2 antibody to reduce the number of secretory cells, such as goblet cells, in an individual, e.g., in the lungs of an individual. By reducing the number of secretory cells, such as goblet cells, in the lungs, mucus production in the lungs is reduced and / or mucus clearance is increased, thereby improving one or more symptoms, e.g., of a mucus obstructive lung disease. In some instances, treatment with an anti-Notch2 antibody provided herein improves FEV1 (forced expiratory volume in one second), and / or reduces cough in a study subject with obstructive pulmonary disease. [000267] In another aspect, the invention provides for the use of an anti-Notch2 antibody in the manufacture or preparation of a medicament. In some aspects, the medicament is for the treatment of a mucocutaneous obstructive pulmonary disease. In another aspect, the medicament is for use in a method of treating a mucocutaneous obstructive pulmonary disease comprising administering an effective amount of the medicament to a subject having a mucocutaneous obstructive pulmonary disease. In such an aspect, the method further comprises administering to the subject an effective amount of at least one other therapeutic agent, for example, as set forth below. In another aspect, the medicament is for reducing the number of secretory cells, such as goblet cells, in a subject, for example, in the lungs of a subject. In another embodiment, the medicament is for use in a method of reducing the number of secretory cells, such as goblet cells, in a subject, e.g., in the lungs of a subject, comprising administering an effective amount of the medicament to reduce the number of secretory cells, such as goblet cells, in a subject, e.g., in the lungs of a subject. [000268] In another aspect, the invention provides a method for treating a mucocutaneous obstructive pulmonary disease. In some aspects, the method comprises administering to a subject suffering from mucocutaneous obstructive pulmonary disease an effective amount of an anti-Notch2 antibody. In such an aspect, the method further comprises administering to the subject an effective amount of at least one other therapeutic agent, as described below. [000269] In another aspect, the invention provides a method for reducing the number of secretory cells, such as goblet cells, in an individual, such as in the lungs of an individual. In some aspects, the method comprises administering to the individual an effective amount of an anti-Notch2 antibody to reduce the number of secretory cells, such as goblet cells, in an individual, such as in the lungs of an individual. In some aspects, the "individual" is a human. [000270] Non-limiting examples of mucosal obstructive lung diseases that may be treated with the anti-Notch2 antibodies provided herein include chronic obstructive pulmonary disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis. [000271] In accordance with any of the above, an "individual" or "subject" may be a human being. [000272] In another aspect, the invention provides pharmaceutical formulations comprising any of the anti-Notch2 antibodies provided herein, for example, for use in any of the above therapeutic methods. In some instances, a pharmaceutical composition or formulation comprises any of the anti-Notch2 antibodies provided herein and a pharmaceutically acceptable carrier. In some instances, a pharmaceutical composition or formulation comprises any of the anti-Notch2 antibodies provided herein and at least one other therapeutic agent, for example, as described below. [000273] The antibodies of the invention can be used alone or in a combination therapy. For example, the combination therapy comprises administering an antibody of the invention and administering at least one other therapeutic agent (e.g., one, two, three, four, five, or six other therapeutic agents). In certain embodiments, the combination therapy comprises administering an antibody of the invention and administering at least one other therapeutic agent, such as an agent that reduces the viscoelasticity of mucus. In some embodiments, the additional therapeutic agent is selected from hypertonic saline, mannitol, palmozyme, N-acetylcysteine, cysteamine, and a bronchodilator. [000274] Such combination therapies as mentioned above include combined administration (where two or more therapeutic agents are included in a single pharmaceutical formulation or multiple separate formulations) and separate administration, in which case the administration of the antibody of the invention can occur before, simultaneously with, and / or after the administration of the other therapeutic agent and / or agents. In some cases, the administration of the anti-Notch2 antibody and the administration of the other therapeutic agent are administered within about a month, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days of each other. In some cases, the antibody and additional therapeutic agent are administered to the patient on day 1 of treatment. [000275] An antibody of the invention (and any additional therapeutic agent) can be administered by any suitable route, including parenterally or by injection, intrapulmonarily, and, if desired for local treatment, intranasally. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The dosage administered can be selected by any suitable route, for example, by injection, e.g., intravenous or subcutaneous injection, or intrapulmonary (e.g., inhalation) or intranasal delivery, depending on whether the drug is administered as a single dose or continuously to the patient. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple doses over different time periods, bolus administration, and drip or pulsed or pulsatile infusion. [000276] The antibodies of the invention can be formulated, dosed, and administered in a manner consistent with appropriate medical practices. Factors to be considered in this context include the particular disorder to be treated, the mammal being treated, the clinical condition of the patient, the cause of the disorder, the site to be reached by the agent, the route of administration, the timing of administration, and other factors known to those skilled in the art. Although not required, the antibody is optionally formulated with one or more additional agents currently used to prevent or treat the disorder of interest. The effective amount of such additional agents will depend on the amount of antibody present in the pharmaceutical composition or formulation, the type of disorder or treatment, and other factors previously noted. These have typically been used at the same doses and by the same administration routes described herein, or at approximately 1 to 99% of the doses described herein, or at whatever doses and routes are empirically / clinically appropriate. [000277] For the prevention or treatment of disease, the appropriate dosage of an antibody of the invention (when used alone or in combination with one or more other therapeutic agents) will depend on the type of disease being treated, the type of antibody, the severity and duration of the disease, whether the antibody is being administered for prophylactic or therapeutic purposes, prior or concomitant therapeutic interventions, the patient's clinical history and response to the antibody, and the discretion of the attending physician. The antibody is administered to the patient in its entirety, either as a single dose or over a course of treatment. These doses can be administered intermittently, for example, every week or every three weeks (e.g., such that the patient receives from about two to about twenty or, for example, about six doses of the antibody). A higher initial loading dose, followed by one or more lower doses, may be administered. However, other dosage regimens may be useful. The progress of this treatment can be easily monitored through conventional techniques and assays. G.Manufactured products [000278] In some embodiments of the invention, a product of manufacture is provided comprising materials useful for treating, preventing and / or diagnosing the disorders described above. The product of manufacture comprises a container and a label or packaging material on or with the container. Suitable containers include, for example, bottles, vials, syringes, intravenous solution bags, etc. The containers may be made of a variety of materials, such as glass or plastic. The container contains a composition or formulation that is effective, by itself or in combination with another material, in treating, preventing and / or diagnosing a condition and may also have a sterile access route (for example, the container may be an intravenous solution bag or a vial having a closure that can be penetrated by a hypodermic needle). At least one active agent in the composition or formulation is an antibody of the invention. The label or package contents indicate that this compound or formulation is used to treat the condition in question.In addition, the product of manufacture may comprise (a) a first container with the composition or formulation contained therein, wherein the formulation comprises an antibody of the invention; and may comprise (b) a second container with the composition or formulation contained therein, wherein the formulation comprises a cytotoxic agent or other therapeutic agent. The product of manufacture in this aspect of the invention may also comprise packaging material indicating that the compositions or formulations can be used to treat a particular condition. Alternatively, or in addition, the product of manufacture may also comprise a second (or third) container containing a pharmaceutically acceptable buffer, for example, bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may also include other materials that are desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes. III. Examples [000279] The following are examples of methods and compositions or formulations of the invention. It is understood that various other embodiments may be practiced based on the above description. Example 1: Production of rabbit and rat anti-Notch2 antibodies [000280]New Zealand White rabbits were simultaneously immunized with human and murine extracellular domain (ECD) constructs containing 6-10 EGF Notch2 repeats (huNotch2-EGF6-10 and muNotch2-EGF6-10), and single B cells were isolated using a modified protocol based on Offner et al. PLoS ONE 9(2), 2014. The modified procedure involved direct isolation of IgG+huNotch2+ B cells by FACS in a single well. B cell culture supernatants were assayed for binding to human Notch2 and an unrelated control protein by ELISA. Notch2-specific B cells were lysed and immediately stored at -80°C until molecular cloning. The variable regions (VH and VL) of each monoclonal antibody derived from rabbit B cells were cloned into expression vectors with human constant regions containing the N297G mutation from mRNA extracted as previously described (Offner et al. PLoS ONE 9(2), 2014). Each of the recombinant chimeric rabbit / human antibodies was expressed in Expi293 cells and then purified with protein A.The analyzed anti-Notch2 antibodies were then subjected to functional activity assays and kinetic screening as described herein. [000281] Rats were either immunized with a combination of MBP-huNotch2 EGF6-10 + MBP-huNotch2 EGF7-9 or primed with MBP-huNotch2 EGF6-10 and boosted with huNotch2-EGF6-10, and hybridomas were generated using a modified fusion primer (Price et al. J Immunol Methods 2009). Various conditions were optimized to allow isolation of each IgG+ huNotch2+ hybridoma into individual wells and subsequent further culture after isolation. The resulting hybridoma supernatants were assayed by ELISA, and positive samples were purified using protein A for functional and kinetic characterization. Some rat monoclonal antibodies were sequenced and cloned into a constant region with the N297G mutation. Each of the recombinant chimeric rat / human antibodies was expressed in Expi293 cells and then purified with protein A. The purified anti-Notch2 antibodies were then subjected to functional activity assays and kinetic screening as described herein. Example 2: Kinetic analysis and epitope classification using array-based surface plasmon resonance [000282] An array-based SPR imaging system (Cartera, USA) was used to classify the epitope of a panel of five monoclonal antibodies produced in Example 1 (rat.1B2, rat.3107, rb.2338, rb.2430, and rb.2621) as well as the anti-Notch 2 / 3 antibody OMP-59R5 (tarxtumab, see U.S. Patent No. 8,226,943 B2). The purified antibodies were diluted to 10 µg / mL in 10 mM sodium acetate buffer, pH 4.5. Using amine coupling, antibodies were immobilized directly onto a CMD 200M SensorPrism SPR chip (Zantec Bioanalytics, Germany) using a continuous flow Microspotter (Cartera, USA) to form an array of antibodies. For analysis, an IBIS MX96 SPRi (Cartera, USA) was used to assess the analytes binding to the immobilized ligands. For kinetic analyses, human Notch2 was injected from 0 to 300 nM at 3-fold dilutions over 3 min, followed by a 10 min separation period.For epitope classification, a 4-min injection of 50 nM human Notch2 was performed first, followed by a second 4-min injection of each monoclonal antibody at 10 µg / ml. Between cycles, the surface was reconstituted with 10 mM glycine pH 1.5. The assay was performed at 25°C in HBS-T running buffer (0.01 M Hepes, pH 7.4, 0.15 M NaCl, 0.05% surfactant P20, 25 mM CaCl). Classification data were processed using the Wasatch Epitope Classification software tool (Cartera, USA). [000283]The results are shown in Figure 4. The antibodies rat.1B2, rat.3107, rb.2338, rb.2430, and rb.2621 were found to be in a different epitope class than the anti-Notch 2 / 3 antibody OMP-59R5. Example 3: Humanization of rat anti-Notch2 antibodies [000284] Rat monoclonal antibodies 1B2 and 3107 were humanized as described below. Residue numbers are based on Kabat et al., Sequences of proteins of immunological interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, Md. (1991). [000285] The variants generated during humanization of 1B2 and 3107 were evaluated as human IgG. The hypervariable regions taken from each antibody (positions 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the VL domain, and 26-35 (H1), 50-65 (H2) and 95-102 (H3) in the VH domain) were grafted into the human acceptor framework. For rat 1B2, the VL CDRs were grafted into KV1-12*01 and the VH CDRs were grafted into HV3-73*01. In addition, a glycosylation site in CDR-H2 Asn54-Phe55-Ser56 was mutated to Asp54-Phe55-Ser56. For rat 3107, the VL CDRs were grafted into KV2-30*02 and the VH CDRs were grafted into HV1-2*01. All VL and VH vernier positions derived from the parental antibodies were also grafted into their respective human germline frameworks. The linkages to all rat amino acids at the vernier positions are referred to as L1H1 (hu.1B2.L1H1 and hhu.3107.L1H1). [000286] The binding affinity of the hu.1B2.L1H1 antibody was compared to its chimeric parental clone. The rat Vernier positions of the L1H1 version antibodies were re-humanized to assess the role of each rat Vernier position in the binding affinity to huNOTCH2. Four additional light chain Vernier variants, L2-L5, and eight additional heavy chain Vernier variants, H2-H9, were constructed. Ser43 and Tyr71 on the light chain (L7), and Val24, Ala49, Ser76, and Leu78 on the light chain (H14) were determined to be the main rabbit Vernier residues based on the binding affinity evaluation of the variant antibodies described above (data not shown). Binding affinity was determined as discussed further in Example 6. Chimeric 1B2 binds with a molar KD5 / 21E-9, while hu1B2.L7H14 binds with a KD6 / 13E-9. [000287] The binding affinity of the hhu.3107.L1H1 antibody was compared with its chimeric parent clone. The rat Vernier positions of the L1H1 version antibodies were re-humanized to assess the role of each rat Vernier position in the binding affinity to huNOTCH2. An additional light chain variant (L2) and ten additional heavy chain variants H2-H11 were constructed. [000288]To increase the affinity of the 3107-based humanized anti-Notch2 antibodies, sequence variants of 4 heavy chains were constructed based on the evaluation of the binding affinity and HCS potency of the humanized antibodies (data not shown): H12 in HV1-2*01 with P45, T48, A67, V71, S75 and T76, H13 in HV1-2*01 with P45, T48, A67, V71, T76; H14 and H15, with Vernier residues similar to H12 and H13 in HV5-51*01, respectively. For the light chain, the KV4-1*1 parental line was used for CDR (L7) linkage. In addition, V2 and F36 on the light chain were identified as Vernier residues that retained potency in the HCS assay and were grafted into the KV4-1*01 (L6) parental line. The HCS assays were performed essentially as described in Example 5. Example 4: Improving the affinity of humanized 1B2 antibodies [000289]To increase the potency of the 1B2-based humanized anti-Notch2 antibodies, 560 single-point mutation variants were generated using L7H10 as a template. The resulting antibodies were screened by surface plasmon resonance and ranked according to their dissociation rates. There were five mutations in the heavy chain (A50G, S51Q, I57R, S96H, and R98F) and three mutations in the light chain (S31V, Q55H, and L96I) that resulted in a slower dissociation rate. To identify good combinations of mutations, 80 variants were generated with a set of single and combined mutations and evaluated by surface plasmon resonance characterization. S51Q was identified as the mutation that improved the dissociation rate. [000290]To further improve the affinity of 1B2, L1H1 with S51Q and N54D mutations was used as a template for affinity maturation of phage display. Briefly, a total of four phage libraries were constructed and displayed as monovalent Fab on the surface of bacteriophage M13. The first set of libraries contained two NNK walk CDRs (one for CDR-H1, H2, and H3, and one for CDR-L1, L2, and L3) in which one site in each of the three CDRs was simultaneously randomized. The second set contained two stringent randomization libraries in which either the entire CDR-L3 or CDR-H3 was mutated. [000291] To select for improved affinity, phage libraries were subjected to four rounds of solution sorting with increasing stringency and cold human Notch2 EGF6-10 as competitors. Enrichment was observed for the stringent randomized CDR-H3 library. After comparing the parental sequence with the enriched clones, several CDR-H3 mutations were identified. A total of 54 hybrid variants were reformatted to human IgG1 for antibody production and further analysis of BIAcore binding kinetics and HCS assays. HCS assays were performed essentially as described in Example 5. hu1B2.v2, hu1B2.v4, hu1B2.v9, and hu1B2.v8 were identified as the most improved in both affinity and potency in the HCS assay. The CDR-H3 of these four variants was grafted to the Vernier-humanized spliced ​​variant L7H14 to generate hu1B2.v101, hu1B2.v102, hu1B2.v103, and hu1B2.v104, respectively. Binding affinities were determined as discussed in Example 6 below. hu1B2.L7H14 has a combined affinity of 6.13E-9 molar for hu.Notch2, while hu1B2.v101, hu1B2.v102, hu1B2.v103, and hu1B2.v014 have affinities of 2.84E-09, 3.37E-09, 3.08E-09, and 3.09E-09, respectively. None of the variants showed binding to human Notch1, human Notch3, or human Notch4 by surface plasmon resonance. Nonspecific binding of each anti-Notch2 variant was measured in an ELISA using baculovirus particles (Hotzel et al. MAbs 2012). Hu‎1B2.v102 and hu‎1B2.v104 were screened for molecular assessment problems using AAPH thermal stress and oxidative stress assays (see Dion et al. J. Pharm. Sci 2018, 107(2), 550). No problems were identified. Example 5: High-content screening (HCS) assay to identify antibodies that block Jagged1 signaling but not DLL1 signaling [000292]The human cell line U87-MG, which endogenously expresses high levels of huNotch2 (N2), was harvested and seeded at 4000 cells per well in 384-well UltraCrycell plates (PerkinElmer, Waltham, MA). The plates were incubated in a 37°C CO2 incubator for 2–5 h, during which time antibody (Ab) samples were tested with initial dilutions manually followed by a 10-point series of 3- to 3.5-fold serial dilutions using a Bravo automated liquid handler (Agilent, Santa Clara, CA). The diluted antibody samples were transferred to a duplicate set of plates containing U-87-MG cells. After adding diluted antibodies, 3T3-Jag1 or OP9-DLL1 cells were harvested and each ligand cell line was seeded at 4,000 cells / well on top of Ab-treated U-87-MG cells and incubated to induce ligand-dependent Notch-2 activation and N2-ICD translocation in U-87-MG cells. [000293]After 16 to 22 hours of incubation, each coculture of receptor and ligand-expressing cells was fixed with 4% paraformaldehyde for 10 minutes, the plates were washed with PBS, and then the cells were permeabilized with 0.05% saponin (Sigma-Aldrich, St. Louis, MO) in PBS+0.05% BSA buffer for 1 hour. After permeabilization, the plates were washed, and rabbit anti-N2-ICD mAb D76A6 (Cell Signaling Technology, Danvers, MA) diluted with 0.05% saponin in PBS / BSA buffer was added to the plates and incubated overnight at 4°C. [000294]The next day, the plates were washed and stained with buffer containing anti-rabbit detection antibody conjugated to AF-647 (Jackson Immunoresearch, West Grove, PA) and Hoechst-33342 dye (ThermoFisher Scientific, Waltham, MA) and then incubated for 2 hours at room temperature with gentle shaking. After staining the cells, the plates were washed with wash buffer and then PBS was added to each well and the plates were imaged. [000295] Six images from each well were captured using a 20X water-immersion objective on an Opera Phoenix high-content imaging system (Perkin Elmer, Waltham, MA). Analysis was performed using Columbus Imaging Analysis Software (Perkin Elmer, Waltham, MA), and the nuclear and annular regions around the nuclei were identified and signal intensities were calculated. A threshold was obtained from the maximal inhibitory control samples to calculate the N2-ICD positive nuclear translocation population. The results from the Columbus analysis were loaded into the Genedata Screener application (Legsinkton, MA), where a normalization process was performed using the percent translocation from the neutral controls subtracted from the maximal inhibitory control, and IC50 values ​​were calculated. [000296] Data analysis from 3T3-Jag1 and OP9-DLL1 co-cultures was compared and used to discover Notch2 antibodies that block Jagged1-mediated activation but spare DLL1-mediated activation, and to optimize humanized versions of these antibodies. Exemplary results are shown in Figures 5A-5F. All antibodies tested blocked Jagged1-mediated activation but spare DLL1-mediated activation. Table 2 summarizes the IC50s of each antibody for blocking Jagged1-mediated signaling. Table 2: Jagged1 IC50 of anti-Notch2 antibodies Compound ID Jagged1 IC50 [molar] Chimeric 1B2 1 / 253E-8 hu1B2.L1H1.DFS 7 / 896E-9 hu1B2.v101 3 / 017E-9 hu1B2.v102 1 / 591E-9 hu1B2.v103 1 / 801E-9 hu1B2.v104 2 / 485E-9 3107 Rat 2 / 101E-9 2621 Rabbit 6 / 671E-10 2338 Rabbit 3 / 530E-9 2430 Rabbit 1 / 027E-9 [000297]In a separate experiment, rat antibody 3107 and humanized versions of 3107 were tested in the HCS assay as described above. All antibodies tested in this experiment contained human IgG1 with an N297G mutation. 3107 and the humanized variants all blocked Jagged1-mediated activation but spared DLL1-mediated activation (data not shown). Table 3 summarizes the IC50s of each antibody for blocking Jagged1-mediated signaling. Table 3: Jagged1 IC50 of the anti-Notch2 antibody 3107 and humanized variants Compound ID Jagged1 IC50 [molar] 3107 4 / 88E-09 hu. Notch-3107.L1H15 6 / 08E-09 hu. Notch-3107.L7H12 1 / 10E-08 hu. Notch-3107.L7H13 5 / 94E-09 hu. Notch-3107.L7H14 1 / 05E-08 hu. Notch-3107.L6H12 4 / 71E-09 hu. Notch-3107.L6H13 6 / 42E-09 hu. Notch-3107.L7H15 9 / 16E-09 hu. Notch-3107.L6H14 6 / 65E-09 hu.Notch-3107.L1H12 7 / 85E-09 hu.Notch-3107.L1H13 4 / 92E-09 hu.Notch-3107.L1H14 6 / 95E-09 hu.Notch-3107.L6H15 8 / 03E-09 Example 6: Kinetic analysis using BIAcore™ [000298]The binding affinities of the antibodies were determined by a BIAcore™ T200 instrument. Rabbit antibodies with rabbit variable domains and human constant domains were expressed as chimeric antibodies. Rat antibodies with rat variable domains and human constant regions were expressed as chimeric antibodies. The humanized antibodies were expressed in a human IgG1 substrate. For kinetic measurements, antibodies were captured on a research-grade protein A chip (GE Healthcare) to yield approximately 300 units of response. Ten-fold serial dilutions of huNotch2-EGF6-10 were injected in HBS-P buffer with 3 mM CaCl2 added at 37°C at a flow rate of 100 μL / min. The binding rates (ka) and dissociation rates (kd) were calculated using a 1:1 Langmuir binding model (BIAcore™ T200 assay software version 2.0). The equilibrium dissociation constant (KD) was calculated as the ratio kd / ka. The results are shown in Table 4. Table 4. Binding properties of rat.3107, rat.1B2 and some humanized variants, and rb.2338, rb.2430, and rb.2621 to huNotch2-EGF6-10 (n=3) Sample ka (1 / molar second) kd (1 / second) KD (molar) ‎1B2-ret 1 / 81E+05 9 / 43E-04 5 / 21E-09 ‎hu‎1B2.L1H1.DFS 2 / 26E+05 1 / 16E-03 5 / 15E-09 ‎hu‎1B2.L7H10 4 / 18E+05 4 / 15E-03 9 / 94E-09 ‎hu‎1B2.L7H14 2 / 19E+05 1 / 34E-03 6 / 13E-09 ‎hu‎1B2.v101 2 / 86E+05 8 / 13E-04 2 / 84E-09 ‎hu‎1B2.v102 3 / 87E+05 1 / 31E-03 3 / 37E-09 ‎hu‎1B2.v103 2 / 65E+05 8 / 17E-04 3 / 08E-09 ‎hu‎1B2.v104 3 / 57E+05 1 / 10E-03 3 / 09E-09 3107 Rat 3 / 63E+05 1 / 82E-03 5 / 00E-09 2338 Rabbit 5 / 33E+05 6 / 01E-03 11 / 3E-09 2430 Rabbit 2 / 19E+06 3 / 07E-02 14 / 0E-09 2621 Rabbit 2 / 48E+06 3 / 05E-02 12 / 3E-09 [000299] In a separate experiment, the binding affinity of humanized versions of the rat 3107 antibody was determined as described above. The results are shown in Table 5. Table 5. Binding properties of rat.3107 and some humanized variants Sample ka (1 / molar second) kd (1 / second) KD (molar) ‎rat.3107 3 / 42E+05 3 / 12E-03 9 / 12E-09 ‎hhu.3107.L1H12 3 / 80E+05 5 / 42E-03 1 / 43E-08 ‎hhu.3107.L1H13 3 / 79E+05 5 / 87E-03 1 / 55E-08 ‎hhu.3107.L1H14 3 / 60E+05 6 / 31E-03 1 / 75E-08 ‎hhu.3107.L1H15 3 / 55E+05 6 / 34E-03 1 / 79E-08 ‎hhu.3107.L6H12 4 / 13E+05 hhu.3107.L6H15 3 / 96E+05 3 / 65E-03 9 / 23E-09 hhu.3107.L7H12 3 / 84E+05 3 / 67E-03 9 / 54E-09 hhu.3107.L7H13 3 / 55E+05 3 / 53E-03 9 / 94E-09 hhu.3107.L7H14 3 / 46E+05 3 / 59E-03 1 / 04E-08 hhu.3107.L7H15 3 / 50E+05 4 / 07E-03 1 / 16E-08 [000300]The binding of anti-Notch2 antibodies to Notch2 from other species and to constructs containing different EGF repeat regions was assessed by BIAcore™. For this assay, antibodies with human constant regions were captured on a Protein A chip to achieve approximately 200 RU. Ten-fold serial dilutions of the various antigens were injected in HBS-P buffer with 3 mM CaCl2 added at 37°C at a flow rate of 100 μL / min. The results of this assay are summarized in Table 6. Table 6: Binding of rat.3107, some humanized versions of rat.1B2, and rb.2338, rb.2430, and rb.2621 to various Notch2, human NotCH1, and human NotCH3 constructs ‎‎hu.‎1B2.v102 ‎hu‎1B2.v104 ‎rat.3107 ‎rb.2338 ‎rb.2430 Rb.2621 ‎‎hu‎‎‎Not‎ch2-EGF6-10 + + + + + + ‎hu‎‎‎Not‎ch2-EGF4-7 + + + nt nt nt ‎hu‎‎‎Not‎ch2-EGF5-8 + + + nt nt nt hu Notch2-EGF7-9 + + + nt nt nt huNotch2-EGF6-12-R268K - - - + / - + / - + / - muNotch2-EGF6-10 - - - - - - muNotch2-EGF6-12-K268R + + + + + gpNotch2-EGF6-12 + + + + + + rat Notch2-EGF6-10 - - - nt nt nt hu Not CH1 - - - nt nt nt hu Not CH3 - - - - - - nt = not tested. [000301] Other humanized versions of 1B2 (hu.1B2.L1H1.DFS, hu.1B2.v4L7, hu.1B2.v8L7, hu.1B2.v9L7, hu.1B2.DFS.H14L7) showed similar binding profiles as hu.1B2.v102 and hu.1B2.v104 in Table 4, above. Based on the binding properties of the anti-Notch2 antibodies shown in Table 4, rat.3107, rat.1B2, rb.2338, rb.2430, and rb.2621 humanized versions bind to an epitope within Notch2 of human EGF7. Furthermore, all antibodies tested showed little or no binding to huNotch2-EGF6-12.R268K or to muNotch2-EGF6-10, but did bind to huNotch2-EGF6-10 and muNotch2-EGF6-12.K268R, indicating that these antibodies bind to the arginine at position 268 of human Notch2. Example 7: Inhibition of Jagged1 and DLL1 signaling with anti-Notch2 Fabs [000302] Some of the anti-Notch2 antibodies were reformulated as monovalent Fabs and evaluated for inhibition of Jagged1 and DLL1 signaling using the HCS assay described in Example 5. [000303] The results of the data analysis from the 3T3-Jag1 and OP9-DLL1 co-cultures were used to calculate the Jagged1 IC50 and determine the percentage of maximal inhibition of Jagged1 and DLL1 signaling by the Fabs. Table 7 shows the maximal inhibition of Jagged1 and DLL1 signaling observed for each Fab. Table 7: Maximal inhibition by anti-Notch2 Fabs Fab Maximum Inhibition Jagged1 Maximum Inhibition DLL1 hu1B2.v8 100% 50% hu1B2.v104 100% 60% [000304] Interestingly, although both hu1B2.v8 and hu1B2.v104 were selective for inhibiting Jagged1 signaling in a bivalent antibody format, when reformatted as monovalent Fabs, both hu1B2.v8 and hu1B2.v104 inhibited DLL1 signaling, although the maximal inhibition was reduced compared to inhibition of Jagged1 signaling. In contrast, the monovalent Fab-formatted hu1B2.v1.DFS, hu1B2.v101, and hu1B2.v103 retained Jagged1-specific signaling inhibition activity and did not inhibit DLL1 (data not shown). Without being bound by a particular theory, this difference in selectivity between Fab-formatted hu1B2.v8 and hu1B2.v104 and Fab-formatted hu1B2.v1.DFS, hu1B2.v101, and hu1B2.v103 can be attributed to differences in the CDR-H3 sequences. Hu1B2.v8 and hu1B2.v104 share the CDR-H3 sequence DGGKLALDA (SEQ ID NO: 11), while hu1B2.v1.DFS, hu1B2.v101, and hu1B2.v103, have the CDR-H3 sequences DSGRWGLDA (SEQ ID NO: 8), DGGRWGLDA (SEQ ID NO: 9), and DGGKWGLDA (SEQ ID NO: 12), respectively. Example 8: Reduction of secretory cell numbers with anti-Notch2 antibodies [000305] Air-liquid interface (ALI) cultures: Primary human bronchial epithelial cells (HBECs) were plated on 0.4 μm pore PET transwell plates (Corning #7369) and cultured under submerged conditions until confluent in Pneumacult Ex-Plus medium (Stem Cell Technologies #05040). Once confluent, the medium was removed from the upper chamber and the HBECs were exposed to air, and the medium in the lower chamber was replaced with Pneumacult ALI basal medium (Stem Cell Technologies #05001). Cells were cultured for 3-4 weeks and were fully differentiated when cilia began to visibly vibrate. [000306]Antibody treatment and sample analysis: Antibodies were added to the basal culture media at a concentration of 50 mg / ml. Antibody was added again when the culture media in the lower chamber was replaced (3 times in one week). On day 7, ALI cultures were harvested for RNA and histological analysis. For RNA analysis, RNA was extracted using the Qiagen RNA Extraction Kit (#74106). After cDNA synthesis using the iScript cDNA Synthesis (Biorad #1708891), gene expression analysis was performed for the Muc5b, Muc5ac, and Scgb1a1 genes (Tekman assays). For histological analysis, transwells were formalin-fixed and paraffin-embedded. Samples were sectioned and stained for anti-Muc5b (goblet cells), anti-acetylated a-tubulin (ciliated cells), and DAPI (nuclear staining). [000307] As shown in Figures 6A-6D, treatment with the anti-Notch2 antibody 1B2 reduced the expression of Muc5b, Muc5ac, and Scgb1a1 mRNA in ALI HBEC cultures. Treatment with the anti-Notch2 antibody 1B2 also reduced the appearance of goblet cells as detected by immunofluorescence using anti-Muc5b antibodies. These results indicate that inhibition of Jagged-Notch2 signaling is sufficient to significantly reduce goblet secretory cells in culture. [000308]Although the invention has been described in some detail with the aid of illustrations and examples to be sufficiently clear and understandable, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all scientific literature and patent certificates cited herein are expressly incorporated by reference in their entirety. IV. Table of some specific sequences Sequence ID Number Sequence Description 1 ‎‎CDR-L1 from ‎rat‎1B2, ‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 QTSEDIYSGLA 2 ‎‎CDR-L2 from ‎rat‎1B2, ‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 GASRLQD 3 ‎‎CDR-L3 from ‎rat‎1B2, ‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎hu‎1B2.v101, ‎hu‎1B2.v102, hu1B2.v103, hu1B2.v104 QQGFKYPLT 4 CDR-H1 of rat1B2, hu.1B2.v1.DFS.H1, hu.1B2.H10, hu.1B2.DFS.H14, hu.1B2.H1.N54D.S51Q, hu.1B2.v2, hu.1B2.v4, hu.1B2.v8, hu.1B2.v9, hu1B2.v101, hu1B2.v102, hu1B2.v103, hu1B2.v104 DFYME 5 CDR-H2 from rat1B2 ASRNKANNFSIVYSASVKD 6 CDR-H2 From hu.1B2.v1.DFS.H1, hu.1B2.H10, hu.1B2.DFS.H14 ASRNKANDFSIVYSASVKD 7 CDR-H2 from hu.1B2.H1.N54D.S51Q, hu.1B2.v2, hu.1B2.v4 ‎‎hu.‎1B2.v8, ‎‎hu.‎1B2.v9, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 AQRNKANDFSIVYSASVKD 8 ‎‎CDR-H3 from rat‎1B2, ‎hu.‎1B2.‎v1.DFS.H1, hu.1B2.H10, ‎‎hu.‎1B2.DFS.H14, ‎‎hu.‎1B2.H1.N54D.S51Q DSGRWGLDA9 ‎‎CDR-H3 AZ ‎‎hu.‎1B2.v2, ‎hu‎1B2.v101 DGGRWGLDA 10 ‎‎CDR-H3 AZ ‎‎hu.‎1B2.v4, ‎hu‎1B2.v102 DGGRLALDA 11 ‎‎CDR-H3 AZ ‎‎hu.‎1B2.v8, ‎hu‎1B2.v104 DGGKLALDA 12 ‎‎CDR-H3 از ‎‎hu.‎1B2.v9, ‎hu‎1B2.v103 DGGKWGLDA 87 ‎LC-FR1 از ‎‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎‎hu.‎1B2.v101, ‎‎hu.‎1B2.v102, ‎‎hu.‎1B2.v103 ‎‎hu.‎1B2.v104 DIQMTQSPSS VSASVGDRVT ITC 88 ‎LC-FR2 AZ ‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎‎hu.‎1B2.v101, ‎‎hu.‎1B2.v102, ‎‎hu.‎1B2.v103, ‎‎hu.‎1B2.v104 WYQQKP GKSPKLLIY 89 ‎LC-FR3 AZ ‎hu‎1B2.L1 GVPS RFSGSGSGTD YTLTISSLQP EDFATYFC 90 ‎LC-FR3 AZ ‎hu‎1B2.L7, ‎‎hu.‎1B2.v101, ‎‎hu.‎1B2.v102, ‎‎hu.‎1B2.v103, ‎‎hu.‎1B2.v104 PSGV RFSGSGSGTD YTLTISSLQP EDFATYYC 91 ‎LC-FR4 AZ ‎hu‎1B2.L1, ‎hu‎1B2.L7, ‎‎hu.‎1B2.v101, ‎‎hu.‎1B2.v102, ‎‎hu.‎1B2.v103, ‎‎hu.‎1B2.v104 FGG GTKVEIK 92 ‎HC-FR1 from ‎hu.‎1B2.v1.DFS.H1, ‎‎hu.‎1B2.H10, ‎‎hu.‎1B2.DFS.H14, ‎‎hu.‎1B2.H1.N54D.S51Q, ‎‎hu.‎1B2.v2, ‎‎hu.‎1B2.v4, ‎‎hu.‎1B2.v8, ‎‎hu.‎1B2.v9, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 EVQLVESGGG LVQPGGSLKL SCAVSGFTFS 93 ‎HC-FR2From ‎hu.‎1B2.‎v1.DFS.H1, ‎‎hu.‎1B2.H1.N54D.S51Q, ‎‎hu.‎1B2.v2, ‎‎hu.‎1B2.v4, ‎‎hu.‎1B2.v8, ‎‎hu.‎1B2.v9, WIRQA SGKGLEWIA 94 ‎HC-FR2 from ‎‎hu.‎1B2.H10, ‎‎hu.‎1B2.DFS.H14, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 WVRQA SGKGLEWVA 95 HC-FR3 of ‎‎hu.‎1B2.‎v1.DFS.H1, hu.1B2.H1.N54D.S51Q, ‎‎hu.‎1B2.v2, ‎‎hu.‎1B2.v4, ‎‎hu.‎1B2.v8, ‎‎hu.‎1B2.v9 RF TISRDTSKST LYLQMNSLKT EDTAVYYCSR 107 ‎HC-FR3 from ‎‎hu.‎1B2.H10 RF TISRDDSKST AYLQMNSLKT EDTAVYYCSR 96 ‎HC-FR3 from ‎‎hu.‎1B2.DFS.H14, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 RF TISRDDSKST LYLQMNSLKT EDTAVYYCSR 97 ‎HC-FR4 from ‎‎hu.‎1B2.v1.DFS.H1, ‎‎hu.‎1B2.H10, ‎‎hu.‎1B2.DFS.H14, ‎‎hu.‎1B2.H1.N54D.S51Q, ‎‎hu.‎1B2.v2, ‎‎hu.‎1B2.v4, ‎‎hu.‎1B2.v8, ‎‎hu.‎1B2.v9, ‎hu‎1B2.v101, ‎hu‎1B2.v102, ‎hu‎1B2.v103, ‎hu‎1B2.v104 W GQGTLVTVSS 13 Light chain variable region (VL) ‎rat.‎1B2 DIQMTQSPAS LSASLGETVT IQCQTSEDIY SGLAWYHQKP GKSPQLLIYG ASRLQDGVPS RFTGSGSGTQ YSLKISSMQT EDEGVYFCQQ GFKYPLTFGS GTKLEIK 14 Heavy chain variable region (VH) ‎rat.‎1B2EVKLVDYGGG LVQPGASLRL SCEVSGFTFS DFYMEWIRQA PGKGLEWIAA SRNKANNFSI VYSASVKDRF TISRDTYKSI LYLQMSTLKP EDTAVYYCSR DSGRWGLDAW GQGTSVIVSS 15 hu.1B2.L1 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKP GKSPKLLIYG ASRLQDGVPS RFSGSGSGTD YTLTISSLQP EDFATYFCQQ GFKYPLTFGG GTKVEIK 16 hu.1B2.L7 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKP GKSPKLLIYG ASRLQDGVPS RFSGSGSGTD YTLTISSLQP EDFATYYCQQ GFKYPLTFGG GTKVEIK 17 hu.‎1B2.‎v1.DFS.H1 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWIRQA SGKGLEWIAA SRNKANDFSI VYSASVKDRF TISRDTSKST LYLQMNSLKT EDTAVYYCSR 19 DSGRWGLDAW GQGTLVTVSS hu.‎1B2.DFS.H14 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWVRQA SGKGLEWVAA SRNKANDFSI VYSASVKDRF TISRDDSKST LYLQMNSLKT EDTAVYYCSR DSGRWGLDAW GQGTLVTVSS 20 hu.‎1B2.H1.N54D.S51Q VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWIRQA SGKGLEWIAA QRNKANDFSI VYSASVKDRF TISRDTSKST LYLQMNSLKTEDTAVYYCSR DSGRWGLDAW GQGTLVTVSS 21 hu.1B2.v2 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWIRQA SGKGLEWIAA QRNKANDFSI VYSASVKDRF TISRDTSKST LYLQMNSLKT EDTAVYYCSR DGGRWGLDAW GQGTLVTVSS 22 hu.1B2.v4 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWIRQA SGKGLEWIAA QRNKANDFSI VYSASVKDRF TISRDTSKST LYLQMNSLKT EDTAVYYCSR DGGRLALDAW GQGTLVTVSS 23 hu.1B2.v8 VH LVQPGGSLKL SCAVSGFTFS EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWIRQA SGKGLEWIAA QRNKANDFSI VYSASVKDRF TISRDTSKST LYLQMNSLKT EDTAVYYCSR DGGKWGLDAW GQGTLVTVSS 25 hu.1B2.v101 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKP GKSPKLLIYG ASRLQDGVPS RFSGSGSGTD YTLTISSLQP EDFATYYCQQ GFKYPLTFGG GTKVEIK 26 hu.1B2.v101 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWVRQA SGKGLEWVAA QRNKANDFSI VYSASVKDRF TISRDDSKST LYLQMNSLKT EDTAVYYCSR DGGRWGLDAW GQGTLVTVSS 27 hu.1B2.v102 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKPGKSPKLLIYG ASRLQDGVPS RFSGSGSGTD YTLTISSLQP EDFATYYCQQ GFKYPLTFGG GTKVEIK 28 ‎hu.‎1B2.v102 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWKVRQVARGWASGWSI VYSASVKDRF TISRDDSKST LYLQMNSLKT EDTAVYYCSR DGGRLALDAW GQGTLVTVSS 29 ‎hu.‎hu.‎1B2.v103 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKP GKSPKLLISGGGVGGPS ASRFQLLISGPS YTLTISSLQP EDFATYYCQQ GFKYPLTFGG GTKVEIK 30 ‎hu.‎1B2.v103 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWVRQA SGKGLEWVAA QRNKANDFSI VYSASVKDSKMSQMSKLYTSLY EDTAVYYCSR DGGKWGLDAW GQGTLVTVSS 31 ‎hu.‎hu.‎1B2.v104 VL DIQMTQSPSS VSASVGDRVT ITCQTSEDIY SGLAWYQQKP GKSPKLLIYG ASRLQDGVPS RFSGSGSGTD YTLTISSLQATGGFYGGTFQYGDFQQ GTKVEIK 32 ‎hu.‎1B2.v104 VH EVQLVESGGG LVQPGGSLKL SCAVSGFTFS DFYMEWVRQA SGKGLEWVAA QRNKANDFSI VYSASVKDRF TISRDDSKST LYLQMNSLKT EDTAVYCLADSSRDDSKST LYLQMNSLKT EDTAVYKLADSS G3GVGQGTVTL rat.3107 CDR-L1, hhu.3107.L1, hhu.3107.L6, and hhu.3107.L7 RSSQSLVHSDGNTYLH 34 rat.3107 CDR-L2, hhu.3107.L1, 0.36, and h. ‎hhu.3107.L7 RISNRFS 35 ‎rat.3107 ‎CDR-L3,‎hhu.3107.L1, ‎hhu.3107.L6, and ‎hhu.3107.L7 LQSTHFPDT 36 ‎rat.3107 ‎CDR-H1, ‎hu.3107.V1-2.H1, ‎hu.3107.H12, ‎hu.31, 7.H13 hu.3107.V5-51.H1, ‎hu.3107.H14, and ‎hu.3107.H15 NYVIH 37 ‎rat.3107 ‎CDR-H2, ‎hu.3107.V1-2.H1, ‎hu.3107.H12, ‎hu.31, 7.H13 hu.3107.V5-51.H1, ‎hu.3107.H14, and ‎hu.3107.H15 YIIPGSGGTKFNEKFKG 38 ‎rat.3107 ‎CDR-H3, ‎hu.3107.V1-2.H1, ‎hu.3107.V1-2.H1, ‎hu.3107.V1-2.H1, ‎hu.3107.H13, 7.H131. hu.3107.V5-51.H1, ‎hu.3107.H14, and ‎hu.3107.H15 DGAGSFTY 39 ‎rat.3107 VL DVLMTQTPVS LPVSLGGQVS ISCRSSQSLV HSDGNTYLHW FLQKPGQRFSQLIDRFS SRVEPEDLGV YYCLQSTHFP DTFGGGTKVE IK 40 ‎rat.3107 VH QVQLQQSGAE LAKSGSVKI SCKASGYTFS NYVIHWIKQT TGQAPEWTGY IIPGSGGTKF NEKFKGKATL TVDKSSTTAY MQLSVTQ AGAGSYFTYG TLVTVSS 98 ‎hhu.3107.L1 VL DVVMTQSPLS LPVTLGQPAS ISCRSSQSLV HSDGNTYLHW FQQRPGQ‎SPR LLIYRISNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCLQSTHFP DTFGGGKVL9639. VL DVVMTQSPDS LAVSLGERAT INCRSSQSLV HSDGNTYLHW FQQKPGQPPK LLIYRISNRF SGVPDRFSGS GSGTDFTLTI SSLQAEDVAV YYCLQSTHFPDTFGGGTKVE IK 100 hhu.3107.L7 VL DIVMTQSPDS LAVSLGERAT INCRSSQSLV HSDGNTYLHW YQQKPGQPPK LLIYRISNRF SGVPDRFSGS GSGTDFTLTI SSLQAEDVAV YYCLQSTHFP DTFGGGTKVE IK 101 hu.3107.V1-2.H1 VH EVQLVQSGAE VKKPGASVKV SCKASGYTFS NYVIHWIRQA PGQGPEWTGY IIPGSGGTKF NEKFKGRATL TVDKSSTTAY MELSRLRSDD TVVYYCARDG AGSFTYWGQG TLVTVSS 102 hu.3107.H12 VH EVQLVQSGAE VKKPGASVKV SCKASGYTFS NYVIHWVRQA PGQGPEWTGY IIPGSGGTKF NEKFKGRATS TVDTSSTTAY MELSRLRSDD TVVYYCARDG AGSFTYWGQG TLVTVSS 103 hu.3107.H13 VH EVQLVQSGAE VKKPGASVKV SCKASGYTFS NYVIHWVRQA PGQGPEWTGY IIPGSGGTKF NEKFKGRATS TVDTSITTAY MELSRLRSDD TVVYYCARDG AGSFTYWGQG TLVTVSS 104 hu.3107.V5-51.H1 VH EVQLVQSGAE VKKPGESLKI SCKASGYTFS NYVIHWIRQM PGKGPEWTGY IIPGSGGTKF NEKFKGQATL SVDKSSTTAY LQWSSLKASD TAMYYCARDG AGSFTYWGQG TLVTVSS 105 ‎hu.3107.H14 VH EVQLVQSGAE VKKPGESLKI SCKGSGYTFS NYVIHWVRQM PGKGPEWTGY IIPGSGGTKF NEKFKGQATI SVDKSSSTTAY LQWSSLKASD TAMYYCARDG AGSFTYWGQG TLVTVSS 106 hu.3107.H15 VH EVQLVQSGAE VKKPGESLKI SCKGSGYTFS NYVIHWVRQM PGKGPEWTGY IIPGSGGTKFNEKFKGQATI SVDKSITTAY LQWSSLKASD TAMYYCARDG AGSFTYWGQG TLVTVSS 41 ‎rb.2338 ‎CDR-L1 QASQSISSYLA 42 ‎rb.2338 ‎CDR-L2 RASKLAS 43 ‎rb.23C3-33‎ QSNSYGNNWVGG 44 ‎rb.2338 ‎CDR-H1 SGYDMC 45 ‎rb.2338 ‎CDR-H2 CIYAGSEGFTYYASWAK 46 ‎rb.2338 ‎CDR-H3 WTDSDGSNL 47 38‎rb. VEAAVGGTVT IKCQASQSIS SYLAWYQQKP GQPPKLLIYR ASKLASGVPS RFSGRGSGTQ FTLTISDLEC ADAATYYCQS NSYGNNWVGG FGGGTKVEIK 48 ‎rb.2338 VH QSLEEASSGGDL VKASPGSSGDL VKASPGSSGFWMCWMCW PGKGLEWIAC IYAGSEGFTY YASWAKGRFT ISKSSSTTVT LQMTSLTVAD TATYFCARWT DSDGSNLWGP GTLVTVSS 49 ‎rb.2430, ‎rb.2430.C95dS ‎CDR-L1 QASQSVVNNRLA 50 rb.24 30, ‎rb.2430.C95dS ‎CDR-L2 GASTLES 51 ‎rb.2430 ‎CDR-L3 QGEFLCSSGDCVA 52 ‎rb.2430.C95dS ‎‎CDR-L3 QGEFLCSSGDSVA 53 ‎rb.2403, ‎dS. ‎CDR-H1 SYDMS 54 ‎rb.2430, ‎rb.2430.C95dS ‎CDR-H2 IIQAGSNTLFYASWA 55 ‎rb.2430, ‎rb.2430.C95dS ‎‎CDR-H3 GGVIGHF N524 V524 V.L. AQVLTQTASS VSAAVGGTVT INCQASQSVV NNRLAWYQQK PGQPPKLLMY GASTLESGVS SRFKGSGSGT QFTLTISGVQ CDDAATYYCQ GEFLCSSGDC VAFGGGTKVE IK 57rb.2430.C95dS VL AQVLTQTASS VSAAVGGTVT INCQASQSVV NNRLAWYQQK PGQPPKLLMY GASTLESGVS SRFKGSGSGT QFTLTISGVQ CDDAATYYCQ GEFLCSSGDS VAFGGGTKVE IK 58 rb.2430 VH QSVEESGGRL Rb.2621 CDR-L2 RASTLAS 61 rb.2621 CDR-L3 QQTYSGAGVDNL 62 rb.2621 CDR-H1 SGYDMC 63 rb.2621 CDR-H2 CIVTVSGNTYYASWAK 64 rb.2621 CDR-H3 DGGFTDTWYFHL 65 rb.2621 VL AYDMTQTPAS VEVAVGGTVT IKCQASESIG SYLAWYQQKP GQPPKLLIYR ASTLASGVPS RFKGSGSGTE FTLTISGVQC DDAATYYCQQ TYSGAGVDNL FGGGTKVEIK 66 rb.2621 VH QSLEESGGGL VQPGASLTLT CTASGFSFSS GYDMCWVRQA PGKGLEWIAC IVTVSGNTYY ASWAKGRFTI SKTSSTTVTL QMTSLTAADT ATYFCARDGG FTDTWYFHLW GPGTLVTVSS 67 MBP-‎hu‎‎‎Not‎ch2 EGF6-10 AGSMGKIEEG KLVIWINGDK GYNGLAEVGK KFEKDTGIKV TVEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSGL LAEITPDKAF QDKLYPFTWD AVRYNGKLIA YPIAVEALSL IYNKDLLPNP PKTWEEIPAL DKELKAKGKS ALMFNLQEPY FTWPLIAADG GYAFKYENGKYDIKDVGVDN AGAKAGLTFL VDLIKNKHMN ADTDYSIAEA AFNKGETAMT INGPWAWSNI DTSKVNYGVT VLPTFKGQPS KPFVGVLSAG INAASPNKEL AKEFLENYLL TDEGLEAVNK DKPLGAVALK SYEEELAKDP RIAATMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TNSSSNNNNN NNNNNGENLY FQGSDSLYVP CAPSPCVNGG TCRQTGDFTF ECNCLPGFEG STCERNIDDC PNHRCQNGGV CVDGVNTYNC RCPPQWTGQF CTEDVDECLL QPNACQNGGT CANRNGGYGC VCVNGWSGDD CSENIDDCAF ASCTPGSTCI DRVASFSCMC PEGKAGLLCH LDACISNPC HKGALCDTNP LNGQYICTCP QGYKGADCTE DVDEGNSHHH HHHHH 68 MBP-‎hu‎‎Not‎ch2 ‎EGF7-9 AGSMGKIEEG KLVIWINGDK GYNGLAEVGK KFEKDTGIKV TVEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSGL LAEITPDKAF QDKLYPFTWD AVRYNGKLIA YPIAVEALSL IYNKDLLPNP PKTWEEIPAL DKELKAKGKS ALMFNLQEPY FTWPLIAADG GYAFKYENGK YDIKDVGVDN AGAKAGLTFL VDLIKNKHMN ADTDYSIAEA AFNKGETAMT INGPWAWSNI DTSKVNYGVT VLPTFKGQPS KPFVGVLSAG INAASPNKEL AKEFLENYLL TDEGLEAVNK DKPLGAVALK SYEEELAKDP RIAATMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDEALKDAQ TNSSSNNNNN NNNNNGENLY FQGSERNIDD CPNHRCQNGG VCVDGVNTYN CRCPPQWTGQ FCTEDVDECL LQPNACQNGGTCANRNGGYG CVCVNGWSGD DCSENIDDCA FASCTPGSTC IDRVASFSCM CPEGKAGLLC HLDDAGNSHHH HHHHHH 69 huNotch2 EGF7 (amino acids 260-296), cynoNotch2 EGF7 (amino acids 260-296) Notch2 EGF7 guinea pig (amino acids 244-280) N IDDCPNHRCQ NGGVCVDGVN TYNCRCPPQW TGQFCT 70 Human Notch2, with signal sequence (amino acids 1-25) MPALRPALLW ALLALWLCCA APAHALQCRD GYEPCVNEGM CVTYHNGTGY CKCPEGFLGE YCQHRDPCEK NRCQNGGTCV AQAMLGKATC RCASGFTGED CQYSTSHPCF VSRPCLNGGT CHMLSRDTYE CTCQVGFTGK ECQWTDACLS HPCANGSTCT TVANQFSKKC LTGFTGQKCE TDVNECDIPG HCQHGGTCLN LPGSYQCQCP QGFTGQYCDS LYVPCAPSPC VNGGTCRQTG DFTFECNCLP GFEGSTCERN IDDCPNHRCQ NGGVCVDGVN TYNCRCPPQW TGQFCTEDVD ECLLQPNACQ NGGTCANRNG GYGCVCVNGW SGDDCSENID DCAFASCTPG STCIDRVASF SCMCPEGKAG LLCHLDDACI SNPCHKGALC DTNPLNGQYI CTCPQGYKGA DCTEDVDECA MANSNPCEHA GKCVNTDGAF HCECLKGYAG PRCEMDINEC HSDPCQNDAT CLDKIGGFTC LCMPGFKGVH CELEINECQS NPCVNNGQCV DKVNRFQCLC PPGFTGPVCQ IDIDDCSSTP CLNGAKCIDH PNGYECQCAT GFTGVLCCEEN IDNCDPDPCH HGQCQDGIDS YTCICNPGYM GAICSDQIDECYSSPCLNDG RCIDLVNGYQ CNCQPGTSGV NCEINFDDCA SNPCIHGICM DGINRYSCVC SPGFTGQRCN IDIDECASNP CRKGATCING VNGFRCICPE GPHHPSCYSQ VNECLSNPCI HGNCTGGLSG YKCLCDAGWV GINCEVDKNE CLSNPCQNGG TCDNLVNGYR CTCKKGFKGY NCQVNIDECA SNPCLNQGTC FDDISGYTCH CVLPYTGKNC QTVLAPCSPN PCENAAVCKE SPNFESYTCL CAPGWQGQRC TIDIDECISK PCMNHGLCHN TQGSYMCECP PGFSGMDCEE DIDDCLANPC QNGGSCMDGV NTFSCLCLPG FTGDKCQTDM NECLSEPCKN GGTCSDYVNS YTCKCQAGFD GVHCENNINE CTESSCFNGG TCVDGINSFS CLCPVGFTGS FCLHEINECS SHPCLNEGTC VDGLGTYRCS CPLGYTGKNC QTLVNLCSRS PCKNKGTCVQ KKAESQCLCP SGWAGAYCDV PNVSCDIAAS RRGVLVEHLC QHSGVCINAG NTHYCQCPLG YTGSYCEEQL DECASNPCQH GATCSDFIGG YRCECVPGYQ GVNCEYEVDE CQNQPCQNGG TCIDLVNHFK CSCPPGTRGL LCEENIDDCA RGPHCLNGGQ CMDRIGGYSC RCLPGFAGER CEGDINECLS NPCSSEGSLD CIQLTNDYLC VCRSAFTGRH CETFVDVCPQ MPCLNGGTCA VASNMPDGFI CRCPPGFSGA RCQSSCGQVK CRKGEQCVHT ASGPRCFCPS PRDCESGCAS SPCQHGGSCH PQRQPPYYSC QCAPPFSGSR CELYTAPPST PPATCLSQYC ADKARDGVCD EACNSHACQW DGGDCSLTME NPWANCSSPL PCWDYINNQC DELCNTVECL FDNFECQGNS KTCKYDKYCA DHFKDNHCDQGCNSEECGWD GLDCAADQPE NLAEGTLVIV VLMPPEQLLQ DARSFLRALG TLLHTNLRIK RDSQGELMVY PYYGEKSAAM KKQRMTRRSL PGEQEQEVAG SKVFLEIDNR QCVQDSDHCF KNTDAAAALL ASHAIQGTLS YPLVSVVSES LTPERTQLLY LLAVAVVIIL FIILLGVIMA KRKRKHGSLW LPEGFTLRRD ASNHKRREPV GQDAVGLKNL SVQVSEANLI GTGTSEHWVD DEGPQPKKVK AEDEALLSEE DDPIDRRPWT QQHLEAADIR RTPSLALTPP QAEQEVDVLD VNVRGPDGCT PLMLASLRGG SSDLSDEDED AEDSSANIIT DLVYQGASLQ AQTDRTGEMA LHLAARYSRA DAAKRLLDAG ADANAQDNMG RCPLHAAVAA DAQGVFQILI RNRVTDLDAR MNDGTTPLIL AARLAVEGMV AELINCQADV NAVDDHGKSA LHWAAAVNNV EATLLLLKNG ANRDMQDNKE ETPLFLAARE GSYEAAKILL DHFANRDITD HMDRLPRDVA RDRMHHDIVR LLDEYNVTPS PPGTVLTSAL SPVICGPNRS FLSLKHTPMG KKSRRPSAKS TMPTSLPNLA KEAKDAKGSR RKKSLSEKVQ LSESSVTLSP VDSLESPHTY VSDTTSSPMI TSPGILQASP NPMLATAAPP APVHAQHALS FSNLHEMQPL AHGASTVLPS VSQLLSHHHI VSPGSGSAGS LSRLHPVPVP ADWMNRMEVN ETQYNEMFGM VLAPAEGTHP GIAPQSRPPE GKHITTPREP LPPIVTFQLI PKGSIAQPAG APQPQSTCPP AVAGPLPTMY QIPEMARLPS VAFPTAMMPQ QDGQVAQTIL PAYHPFPASV GKYPTPPSQH SYASSNAAER TPSHSGHLQG EHPYLTPSPE SPDQWSSSSPHSASDWSDVT TSPTPGGAGG GQRGPGTHMS EPPHNNMQVY A 71 Notch2 cynomolgus monkey, with signal sequence (amino acids 1-25 M PALRPALLWA LLALWLCRAA PARALQCRDG YEPCVNEGMC VTYHNGTGYC KCPEGFLGEY CQHRDPCEKN RCQNGGTCVA QAMLGKATCR CASGFTGEDC QYSTSHPCFV SRPCLNGGTC HMLSRDTYEC TCQVGFTGKE CQWTDACLSH PCANGSTCTT VANQFSCKCL TGFTGQKCET DVNECDIPGH CQHGGTCLNL PGSYQCQCPQ GFTGQHCDSL YVPCAPSPCV NGGTCRQTGD FTFECNCLPG FEGSTCERNI DDCPNHRCQN GGVCVDVNT YNCRCPPQWT GQFCTEDVDE CLLQPNACQN GGTCANRNGG YGCVCVNGWS GDDCSENIDD CAFASCTPGS TCIDRVASFS CMCPEGKAGL LCHLDDACIS NPCHKGALCD TNPLNGQYIC TCPQGYKGAD CTEDVDECAM ANSNPCEHAG KVCNTDGAFH CECLKGYAGP RCEMDINECH SDPCQNDATC LDKIGGFTCL CMPGFKGVHC ELEINECQSN PCVNNGQCVD KVNRFQCLCP PGFTGPVCQI DIDDCSSTPC LNGAKCIDHP NGYECQCATG FTGVLCEENI DNCDPDPCHH GQCQDGIDSY TCICNPGYMG AICSDQIDEC YSSPCLNDGR CIDLVNGYQC NCQPGTSGVN CEINFDDCAS NPCIHGICMD GINRYSCVCS PGFTGQRCNI DIDECASNPC RKGATCINGV NGFRCICPEG PHHPSCYSQV NECLSNPCIH GNCTGGLSGY KCLCDAGWVG INCEVDKNEC LSNPCQNGGT CDNLVNGYRC TCKKGFKGYN CQVNIDECASNPCLNQGTCF DDISGYTCHC VLPYTGKNCQ TVLAPCSPNP CENAAVCKES PNFESYTCLC APGWQGQRCT IDIDECISKP CMNHGLCHNT QGSYMCECPP GFSGMDCEED IDDCLANPCQ NGGSCVDGVN TFSCLCLPGF TGDKCQTDMN ECLSEPCKNG GTCSDYVNSY TCKCQAGFDG VHCENNIDEC TESSCFNGGT CVDGINSFSC LCPVGFTGLF CLHEINECSS HPCLNEGTCV DGLGTYHCSC PLGYTGKNCQ TLVNLCSRSP CKNKGTCIQD KAESRCRCPS GWAGAYCDVP NVSCDIAASR RGVLVEHLCQ HSGVCINAGN THYCQCPLGY TGSYCEEQLD ECASNPCQHG ATCSDFIGGY RCECVPGYQG VNCEYEVDEC QNQPCQNGGT CIDLVNHFKC SCPPGTRGLL CEENIDDCAR GPHCLNGGQC VDRIGGYSCR CLPGFAGERC EGDINECLSN PCSSEGSLDC IQLTNDYLCV CRSAFTGRHC ETFVDVCPQM PCLNGGTCAV ASNMPDGFIC RCPPGFSGAR CQSSCGQVKC RKGEQCVHTA SGPRCFCPNP RDCESGCASS PCQHGGSCHP QRQPPYYSCQ CAPPFWGSRC ELYTAPPSTP PATCLSQYCA DKARDGVCDE ACNSHACQWD GGDCSLTMEN PWANSSPLP CWDYINNQCD ELCNTAECLF DNFECQGNSK TCKYDKYCAD HFKDNHCDQG CNSEECGWDG LDCAADQPEN LAEGTLVIVV LMPPEQLLQD ARSFLRALGT LLHTNLRIKR DSQGELMVYP YYGEKSAAMK KQRMTRRSIP GEQEQEVAGS KVFLEIDNRQ CVQDSDHCFK NTDAAAALLA SHAIQGTLSY PLVSVVSESL TPERTQLLYL LAVAVVIILF IILLGVIMAK RKRKHGSLWLPEGFTLRRDA SNHKRREPVG QDAVGLKNLS VQVSEANLIG SGTSEHWVDD EGPQPKKVKA EDEALLSEED DPIDRRPWTQ QHLEAADIRR TPSLALTPPQ AEQEVDVLDV NVRGPDGCTP LMLASLRGGS SDLSDEDEDA EDSSANIITD LVYQGASLQA QTDRTGEMAL HLAARYSRAD AAKRLLDAGA DANAQDNMGR CPLHAAVAAD AQGVFQILIR NRVTDLDARM NDGTTPLILA ARLAVEGMVA ELINCQADVN AVDDHGKSAL HWAAAVNNVE ATLLLLKNGA NRDMQDNKEE TPLFLAAREG SYEAAKILLD HFANRDITDH MDRLPRDVAR DRMHHDIVRL LDEYNVTPSP PGTVLTSALS PVICGPNRSF LSLKHTPMGK KSRRPSAKNT MPTSLPNLAK EAKDAKGSRR KKSLSEKVQL SESSVTLSPV DSLESPHTYV SDTTSSPMIT SPGILQASPN PMLATAAPPA SVHAQHALSF SNLHEMQPLA HGASTVLPSV SQLLSHHIV PPSSGSAGSL SRLHPVPVPA DWMNRMEVNE TQYNEMFGMV LAPAEGTHPS IAPQSRPPEG KHITTPREPL PPIVTFQLIP KGSIAQPAGA PQPQSTCPPA VTGPLPTMYQ IPEMARLPSV AFPTAMMPQQ DGQVAQTILP AYHPFPASVG KYPTPPSQHS YASSNAAERT PSHSGHLQGE HPYLTPSPES PDQWSSSSPH SASDWSDVTT SPTPGGAGGG QRGPGTHMSE PPHNNMQVYA 72 Guinea pig Notch2, with signal sequence (amino acids 1-9) MYLFCFVLAL QCRDDYEPCV NEGICVTYHN GTGYCKCPEG FLGEYCQHRD PCEKNRCQNG GTCVAQAMLG RATCRCALGF TGEDCQYSTSHPCFVNPPCQ NGGTCHMLSW DTYECTCQVG FTGKLCQWID ACLSQPCANG STCTTVANQF SCKCLAGFTG QKCETDVNEC DIPGQCQNGG TCLNLPGSYQ CQCSQGFTGQ HCDNPYVPCA PSPCVNGGTC RQTGDFTFEC SCLPGFEGST CERNIDDCPN HRCQNGGVCV DGVNTYNCRC PPQWTGQFCT EDVDECLLQP NACQNGGTCT NRNGGYGCVC VNGWSGDDCS ENIDDCAFAS CTPGSTCIDR VASFSCMCPE GKAGLLCHLD DACISNPCHK GALCDTNPLN GHYICTCPQG YKGADCTEDV DECAMTNSNP CEHAGKCVNT DGAFHCECLK GYAGPRCEMD INECHSDPCQ NDATCLDKIG GFTCLCMPGF KGVHCEIEIN ECQSNPCVNN GQCVDKVNRF QCLCPPGFTG PVCQIDIDDC SSTPCLNGAK CIDHPNGYEC QCATGFTGLL CEENIDNCDP DPCHHGQCQD GIDSYTCICN PGYMGAICSD QIDECYSSPC LNEGRCIDLV NGYQCNCQPG TSGVNCEINF DDCASSPCVN GTCVDGISRY SCVCSPGFTG QRCNVDIDEC ASNPCRKGAT CINDVNGFRC ICPEGPHHPS CYSQVNECLS NPCIHGSCIG GLSGYKCLCD AGWVGINCEV DKNECLSNPC QNGGTCDNLV NGYKCTCKKG FKGYNCQVNI DECASNPCLN QGTCFDDVSG YTCQCALPYT GKNCQTVLAP CSPNPCENAA VCKEAPNFES FTCLCAPGWQ GQRCTVDIDE CVSKPCMNHG LCHNTQGSYM CECPPGFSGM DCEEDINDCL ANPCQNGGSC VDGVNTFSCM CLPGFIGDKC QTDMNECLSE PCKNGGTCSD YVNSYTCKCQ AGFDGVHCEN NIDECTDSSC FNGGTCVDGI NSFSCLCPVGFTGPFCLHEI NECSSHPCLN EGTCVDGLGT YRCTCPLGYT GKNCQTLVNL CSQSPCKNKG TCIQEKAESR CLCPSGWTGA YCDVPNVSCD VAALNKGVLA KNLCKNSGAC ​​INAGNTHHCQ CPLGYTGSYC EQQLDECATDGTCVGTCVGTCVIGGTC PGYQGVNCEY EVDECQNQPC RNGGTCVDLV NHFKCSCPPG TRGLFCEENI DDCAGGPHCL NGGQCVDRIG GYSCRCLPGF AGERCEGDIN ECLSNPCNSE GSLDCIQLTN NYQCVCRSTF TGRHCETFVD VCPQKPSNPPCLNG FGTCVASCGCGCGCGCGCGC GQVKCRKGEQ CVHTAAGPRC FCPSPQDCES GCASSPCQHG GSCYPQRQPP YYSCHCSVPF GGNHCQFYMA PTSIPSDICA SQYCADKARD GVCDEVCNSH ACQWDGGDCS LTMEDPWANC SSPLPCWNYI NNQCDELCNT AENFCFQDCKTGCY KYCADHFKDN HCDQGCNSEE CGWDGLDCAA DQPENLAEGT LVIVVLMPPE QLLQDARSFL RALGTLLHTN LRIKLDSQGL PMVYPYYGEK SAAMKKQKLS RRSLPDEQEQ EVAGSQVFLE IDNRQCVQDS EQCFALKLSHA QUESTION VSESLSPKPT PLLYLLAVAV VFILFIILLG VIMAKRKRKH GSLWLPEGFT LRRDSSNHKR REPVGQDAVG LKNLSVQVSE ANLIGSGTSE HWVDDEGPQP KKAKAEDEAL LSEEEDPIDR RPWTQQHLEA ADIRRTPSLA LTPPPQEQLDVCTEVMLDGVCTAVVR LRGGSSDMSD EDEDGEDSSA NIITDLVYQG ASLQAQTDRT GEMALHLAAR YSRADAAKRL LDAGADANAQ DNMGRCPLHA AVAADAQGVFQILIRNRVTD LDARMNDGTT PLILAARLAV EGMVAELINC QADVNAVDDH GKSALHWAAA VNNVEATLLL LKNGANRDMQ DNKEETPLFL AAREGSYEAA KILLDHFANR DITDHMDRLP RDVARDRMHH DIVRLLDEYN VTPSPPGTVL TSALSPVICG PNRSFLSLKH TPMAKKSRRP NAKSTMPTSL PNLAKEAKDA KGSRRKKSLS EKVQLSESSV TLSPVDSLES PHTYVSDTTS SPMITSPGIL QASPNPMLAA AAPQAPVHAQ HALSFPNPHE MQPLAPGAST VLPSVSQLLS HHHIVPPGSS SAGNLSRLHP VTVPADWMNR MEMSDTQYNE MFGMVLTPAE GTHPGIAPQS RPPEGKHVPT PRETLPPIVT FQLIPKGSIA QPAGASQPQS TCPPAVAGPL PTMYQIPEMA RLPGVAFPTA MMPQQDGQVA QTILPAYHPF PASVGKYPTP PSQHSYASSN AAERTPNHSG HLQGEHPYLT PSPDSPDQWS SSSPHSASDW SDVTTSPTPG SGGGGQRGPG THMSEPPHSN MQVYA 73 Mouse Notch2, with signal sequence (amino acids 1-25) MPALRPAALR ALLWLWLCGA GPAHALQCRG GQEPCVNEGT CVTYHNGTGF CRCPEGFLGE YCQHRDPCEK NRCQNGGTCV PQGMLGKATC RCAPGFTGED CQYSTSHPCF VSRPCQNGGT CHMLSRDTYE CTCQVGFTGK QCQWTDACLS HPCENGSTCT SVASQFSCKC PAGLTGQKCE ADINECDIPG RCQHGGTCLN LPGSYRCQCP QGFTGQHCDS PYVPCAPSPC VNGGTCRQTG DFTFECNCLP GFEGSTCERN IDDCPNHKCQ NGGVCVDGVN TYNCRCPPQW TGQFCTEDVD ECLLQPNACQNGGTCTNRNG GYGCVCVNGW SGDDCSENID DCAYASCTPG STCIDRVASF SCLCPEGKAG LLCHLDDACI SNPCHKGALC DTNPLNGQYI CTCPQGYKGA DCTEDVDECA MANSNPCEHA GKCVNTDGAF HCECLKGYAG PRCEMDINEC HSDPCQNDAT CLDKIGGFTC LCMPGFKGVH CELEVNECQS NPCVNNGQCV DKVNRFQCLC PPGFTGPVCQ IDIDDCSSTP CLNGAKCIDH PNGYECQCAT GFTGILCDEN IDNCDPDPCH HGQCQDGIDS YTCICNPGYM GAICSDQIDE CYSSPCLNDG RCIDLVNGYQ CNCQPGTSGL NCEINFDDCA SNPCMHGVCV DGINRYSCVC SPGFTGQRCN IDIDECASNP CRKGATCIND VNGFRCICPE GPHHPSCYSQ VNECLSNPCI HGNCTGGLSG YKCLCDAGWV GVNCEVDKNE CLSNPCQNGG TCNNLVNGYR CTCKKGFKGY NCQVNIDECA SNPCLNQGTC FDDVSGYTCH CMLPYTGKNC QTVLAPCSPN PCENAAVCKE APNFESFSCL CAPGWQGKRC TVDVDECISK PCMNNGVCHN TQGSYVCECP PGFSGMDCEE DINDCLANPC QNGGSCVDHV NTFSCQCHPG FIGDKCQTDM NECLSEPCKN GGTCSDYVNS YTCTCPAGFH GVHCENNIDE CTESSCFNGG TCVDGINSFS CLCPVGFTGP FCLHDINECS SNPCLNAGTC VDGLGTYRCI CPLGYTGKNC QTLVNLCSRS PCKNKGTCVQ EKARPHCLCP PGWDGAYCDV LNVSCKAAAL QKGVPVEHLC QHSGICINAG NTHHCQCPLG YTGSYCEEQL DECASNPCQH GATCNDFIGG YRCECVPGYQ GVNCEYEVDE CQNQPCQNGG TCIDLVNHFK CSCPPGTRGLLCEENIDECA GGPHCLNGGQ CVDRIGGYTC RCLPGFAGER CEGDINECLS NPCSSEGSLD CVQLKNNYNC ICRSAFTGRH CETFLDVCPQ KPCLNGGTCA VASNMPDGFI CRCPPGFSGA RCQSSCGQVK CRRGEQCIHT DSGPRCFCLN PKDCESGCAS NPCQHGGTCY PQRQPPHYSC RCPPSFGGSH CELYTAPTST PPATCQSQYC ADKARDGICD EACNSHACQW DGGDCSLTME DPWANCTSTL RCWEYINNQC DEQCNTAECL FDNFECQRNS KTCKYDKYCA DHFKDNHCDQ GCNSEECGWD GLDCASDQPE NLAEGTLIIV VLLPPEQLLQ DSRSFLRALG TLLHTNLRIK QDSQGALMVY PYFGEKSAAAM KKQKMTRRSL PEEQEQEQEV IGSKIFLEID NRQCVQDSDQ CFKNTDAAAA LLASHAIQGT LSYPLVSVFS ELESP‎RNAQL LYLLAVAVVI ILFFILLGVI MAKRKRKHGF LWLPEGFTLR RDSSNHKRRE PVGQDAVGLK NLSVQVSEAN LIGSGTSEHW VDDEGPQPKK AKAEDEALLS EDDPIDRRPW TQQHLEAADI RHTPSLALTP PQAEQEVDVL DVNVRGPDGC TPLMLASLRG GSSDLSDEDE DAEDSSANII TDLVYQGASL QAQTDRTGEM ALHLAARYSR ADAAKRLLDA GADANAQDNM GRCPLHAAVA ADAQGVFQIL IRNRVTDLDA RMNDGTTPLI LAARLAVEGM VAELINCQAD VNAVDDHGKS ALHWAAAVNN VEATLLLLKN GANRDMQDNK EETPLFLAAR EGSYEAAKIL LDHFANRDIT DHMDRLPRDV ARDRMHHDIV RLLDEYNVTP SPPGTVLTSA LSPVLCGPNR SFLSLKHTPM GKKARRPNTK STMPTSLPNLAKEAKDAKGS RRKKCLNEKV QLSESSVTLS PVDSLESPHT YVSDATSSPM ITSPGILQAS PTPLLAAAAP AAPVHTQHAL SFSNLHDMQP LAPGASTVLP SVSQLLSHHH IAPPGSSSAG SLGRLHPVPV PADWMNRVEM NETQYSEMFG MVLAPAEGAH PGIAAPQSRP PEGKHMSTQR EPLPPIVTFQ LIPKGSIAQA AGAPQTQSSC PPAVAGPLPS MYQIPEMPRL PSVAFPPTMM PQQEGQVAQT IVPTYHPFPA SVGKYPTPPS QHSYASSNAA ERTPSHGGHL QGEHPYLTPS PESPDQWSSS SPHSASDWSD VTSPTPGGG GGGQRGPGTH MSEPPHSNMQ VYA 74 ‎‎hu‎‎‎Not‎ch2-EGF6-10 AGSDSLYVPC APSPCVNGGT CRQTGDFTFE CNCLPGFEGS TCERNIDDCP NHRCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC ANRNGGYGCV CVNGWSGDDC SENIDDCAFA SCTPGSTCID RVASFSCMCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGQYICTCPQ GYKGADCTED VDEGNSHHHH HH 75 mu‎‎‎Not‎ch2-EGF6-10 AGSDSPYVPC APSPVCNGGT CRQTGDFTFE CNCLPGFEGS TCERNIDDCP NHKCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC TNRNGGYGCV CVNGWSGDDC SENIDDCAYA SCTPGSTCID RVASFSCLCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGQYICTPQ GYKGADCTED VDEGNSGLND IFEAQKIEWH ENLYFQGHHH HHHHH 76 gp‎‎‎Not‎‎ch2-EGF6-12 AGSDNPYVPC APSPCVNGGT CRQTGDFTFE CSCLPGFEGSTCERNIDDCP NHRCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC TNRNGGYGCV CVNGWSGDDC SENIDDCAFA SCTPGSTCID RVASFSCMCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGHYICTCPQ GYKGADCTED VDECAMTNSN PCEHAGKCVN TDGAFHCECL KGYAGPRCEM DINECHSDPC QNDATCLDKI GGFTCLCMPG FKGVHCEIEI NEGNSGLNDI FEAQKIEWHE NLYFQGHHHH HHHH 77 huNotch2-EGF6-12.R268K AGSDSLYVPC APSPCVNGGT CRQTGDFTFE CNCLPGFEGS TCERNIDDCP NHKCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC ANRNGGYGCV CVNGWSGDDC SENIDDCAFA SCTPGSTCID RVASFSCMCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGQYICTCPQ GYKGADCTED VDECAMANSN PCEHAGKCVN TDGAFHCECL KGYAGPRCEM DINECHSDPC QNDATCLDKI GGFTCLMPG FKGVHCEGNS GLNDIFEAQK IEWHENLYFQ GHHHHHHHH 78 mu‎‎‎‎Not‎ch2-EGF6-12.K268R AGSDSPYVPC APSPCVNGGT CRQTGDFTFE CNCLPGFEGS TCERNIDDCP NHRCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC TNRNGGYGCV CVNGWSGDDC SENIDDCAYA SCTPGSTCID RVASFSCLCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGQYICTCPQ GYKGADCTED VDECAMANSN PCEHAGKCVN TDGAFHCECL KGYAGPRCEM DINECHSDPC QNDATCLDKI GGFTCLCMPGFKGVHCELEV NEGNSGLNDI FEAQKIEWHE NLYFQGHHHH HHHH 79 rat‎‎‎Not‎ch2-EGF6-10 AGSDSPYVPC APSPCVNGGT CRQTGDFTSE CHCLPGFEGS NCERNIDDCP NHKCQNGGVC VDGVNTYNCR CPPQWTGQFC TEDVDECLLQ PNACQNGGTC TNRNGGYGCV CVNGWSGDDC SENIDDACAFA SCTPGSTCID RVASFSCLCP EGKAGLLCHL DDACISNPCH KGALCDTNPL NGQYICTCPQ AYKGADCTED VDEGNSGLND IFEAQKIEWH ENLYFQGHHH HHHHH 80 mu‎‎‎Not‎ch2 ‎EGF7 (amino acids 260-296) N IDDCPNHKCQ NGGVCVDGVN TYNCRCPPQW TGQFCT 81 ‎‎Not‎ch2 rat, with signal sequence (amino acids 1-25) MPALRPAALR ALLWLWLCGA GPAHALQCRG GQEPCVNEGT CVTYHNGTGY CRCPEGFLGE YCQHRDPCEK NRCQNGGTCV TQAMLGKATC RCAPGFTGED CQYSTSHPCF VSRPCQNGGT CHMLSWDTYE CTCQVGFTGK QCQWTDVCLS HPCENGSTCS SVANQFSCRC PAGITGQKCD ADINECDIPG RCQHGGTCLN LPGSYRCQCP QRFTGQHCDS PYVPCAPSPC VNGGTCRQTG DFTSEHCLP GFEGSNCERN IDDCPNHKCQ NGGVCVDGVN TYNCRCPPQW TGQFCTEDVD ECLLQPNACQ NGGTCTNRNG GYGCVCVNGW SGDDCSENID DCAFASCTPG STCIDRVASF SCLCPEGKAG LLCHLDDACI SNPCHKGALC DTNPLNGQYI CTCPQAYKGA DCTEDVDECA MANSNPCEHA GKCVNTDGAF HCECLKGYAG PRCEMDINEC HSDPCQNDATCLDKIGGFTC LCMPGFKGVH CELEVNECQS NPCVNNGQCV DKVNRFQCLC PPGFTGPVCQ IDIDDCSSTP CLNGAKCIDH PNGYECQCAT GFTGTLCDEN IDNCDPDPCH HGQCQDGIDS YTCICNPGYM GAICSDQIDE CYSSPCLNDG RCIDLVNGYQ CNCQPGTSGL NCEINFDDCA SNPCLHGACV DGINRYSCVC SPGFTGQRCN IDIDECASNP CRKDATCIND VNGFRCMCPE GPHHPSCYSQ VNECLSSPCI HGNCTGGLSG YKCLCDAGWV GINCEVDKNE CLSNPCQNGG TCNNLVNGYR CTCKKGFKGY NCQVNIDECA SNPCLNQGTC LDDVSGYTCH CMLPYTGKNC QTVLAPCSPN PCENAAVCKE APNFESFTCL CAPGWQGQRC TVDVDECVSK PCMNNGICHN TQGSYMCECP PGFSGMDCEE DINDCLANPC QNGGSCVDKV NTFSCLCLPG FVGDKCQTDM NECLSEPCKN GGTCSDYVNS YTCTCPAGFH GVHCENNIDE CTESSCFNGG TCVDGINSFS CLCPVGFTGP FCLHDINECS SNPCLNSGTC VDGLGTYRCT CPLGYTGKNC QTLVNLCSPS PCKNKGTCAQ EKARPRCLCP PGWDGAYCDV LNVSCKAAAL QKGVPVEHLC QHSGICINAG NTHHCQCPLG YTGSYCEEQL DECASNPCQH GATCSDFIGG YRCECVPGYQ GVNCEYEVDE CQNQPCQNGG TCIDLVNHFK CSCPPGTRGL LCEENIDDCA GAPHCLNGGQ CVDRIGGYSC RCLPGFAGER CEGDINECLS NPCSSEGSLD CIQLKNNYQC VCRSAFTGRH CETFLDVCPQ KPCLNGGTCA VASNVPDGFI CRCPPGFSGA RCQSSCGQVK CRRGEQCVHT ASGPHCFCPN HKDCESGCASNPCQHGGTCY PQRQPPYYSC RCSPPFWGSH CESYTAPTST PPATCLSQYC ADKARDGICD EACNSHACQW DGGDCSLTME DPWANCTSSL RCWEYINNQC DELCNTAECL FDNFECQRNS KTCKYDKYCA DHFKDNHCDK GCNNEECGWD GLDCAADQPE NLAEGILVIV VLLPPEQLLQ DSRSFLRALG TLLHTNLRIK QDSQGALMVY PYYGEKSAAM KKQKVARRSL PDEQEQEIIG SKVFLEIDNR QCVQDSDQCF KNTDAAAALL ASHAIQGTLS YPLVSVVSES EDPRNTPLLY LLAVAVVIIL FLILLGVIMA KRKRKHGFLW LPEGFTLRRD SSNHKRREPV GQDAVGLKNL SVQVSEANLI GSTTSEHWGD DEGPQPKKAK AEDDEALLSE DDPVDRRPWT QQHLEAADIR RTPSLALTPP QAEQEVDVLD VNVRGPDGCT PLMLASLRGG SSDLSDEDED AEDSSANIIT DLVYQGASLQ AQTDRTGEMA LHLAARYSRA DAAKRLLDAG ADANAQDNMG RCPLHAAVAA DAQGVFQILI RNRVTDLDAR MNDGTTPLIL AARLAVEGMV AELINCQADV NAVDDHGKSA LHWAAAVNNV EATLLLLKNG ANRDMQDNKE ETPLFLAARE GSYEAAKILL DHFANRDITD HMDRLPRDVA RDRMHHDIVR LLDEYNVTPS PPGTVLTSAL SPVLCGPNRS FLSLKHTPMG KKARRPNTKS TMPTSLPNLA KEAKDVKGSR RKKCLNEKVQ LSESSVTLSP VDSLESPHTY VSDATSSPMI TSPGILQASP TPLLAAAPAA PVHAQHALSF SNLHEMQPLR PGASTVLPSV SQLLSHHHIV PPGSGSAGSL GRLHSVPVPS DWMNRVEMSE TQYSEMFGMV LAPAEGTHPG MAAPQSRAPEGKPIPTQREP LPPIVTFQLI PKGSLAQAAG APQTQSGCPP AVAGPLPSMY QIPEMARLPS VAFPPTMMPQ QEGQVAQTIV PTYHPFPASV GKYPTPPSQH SYASSNAAER TPNHGGHLQG EHPYLTPSPE SPDQWSSSSP HSASDWSDVT TSPTPGGGGG GQRGPGTHMS EPPHSNMQVY A 82 ‎hu‎‎‎Not‎ch2-EGF4-7 GSQWTDACLS HPCANGSTCT TVANQFSKKC LTGFTGQKCE TDVNECDIPG HCQHGGTCLN LPGSYQCQCL QGFTGQYCDS LYVPCAPSPC VNGGTCRQTG DFTFECNCLP GFEGSTCERN IDDCPNHRCQ NGGVCVDGVN TYNCRCPPQW TGQFCTEDVD EGNSGLNDIF EAQKIEWHEN LYFQGHHHHH HHH 83 ‎hu‎‎Not‎ch2-EGF5-8 GSETDVNECD IPGHCQHGGT CLNLPGSYQC QCLQGFTGQY CDSLYVPCAP SPCVNGGTCR QTGDFTFFECN CLPGFEGSTC ERNIDDCPNH RCQNGGVCVD GVNTYNCRCP PQWTGQFCTE DVDECLLQPN ACQNGGTCAN RNGGYGCVCV NGWSGDDCSE NIDDGNSGLN DIFEAQKIEW HENLYFQGHH HHHHHH 84 ‎hu‎‎‎Not‎ch2-‎EGF7-9 AHHHHHHGEN LYFQGSERNI DDCPNHRCQN GGVCVDGVNT YNCRCPPQWT GQFCTEDVDE CLLQPNACQN GGTCANRNGG YGCVCVNGWS GDDCSENIDD CAFASCTPGS TCIDRVASFS CMCPEGKAGL LCHLDDAGNS 85 hu‎‎Not‎CH1 AGSERPYVPC SPSPCQNGGT CRPTGDVTHE CACLPGFTGQ NCEENIDDCP GNNCKNGGAC VDGVNTYNCR CPPEWTGQYC TEDVDECQLM PNACQNGGTC HNTHGGYNCVCVNGWTGEDC SENIDDCASA ACFHGATCHD RVASFYCECP HGRTGLLCHL NDACISNPCN EGSNCDTNPV NGKAICTCPS GYTGPACSQD VDEGNSGLND IFEAQKIEWH ENLYFQGHHH HHHHH 86 hu‎‎Not‎CH3 GSENPAVPCA PSPCRNGGTC RQSGDLTYDC ACLPGFEGQN CEVNVDDCPG HRCLNGGTCV DGVNTYNCQC PPEWTGQFCT EDVDECQLQP NACHNGGTCF NTLGGHSCVC VNGWTGESCS QNIDDCATAV CFHGATCHDR VASFYCACPM GKTGLLCHLD DACVSNPCHE DAICDTNPVN GRAICTCPPG FTGGACDQDV DECSIGANPC EHLGRCVNTQ GSFLCQCGRG YTGPRCETDV NECLSGPCRN QATCLDRIGQ FTCICMAGFT GTYCEVDIDE GNSGLNDIFE AQKIEWHENL YFQGHHHHHHH HH

Claims

WHAT IS CLAIMED IS:

1. An isolated antibody that binds to human Notch2, wherein the antibody comprises: a) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 7 or 6, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12, 8, 9, 10, or 11, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3; b) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 36, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 37, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 38, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 34, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 35; c) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 41, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 43; d) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 53, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 54, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 55, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 49, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 50, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 51 or 52; or e) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 62, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 64, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61.

2. The isolated antibody of claim 1, wherein the antibody comprises: a) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 30, 17-24, 26, 28, and 32; b) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 29, 15, 16, 25, 27, and 31; c) a VH sequence as defined in (a) and a VL sequence as defined in (b); d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 14; e) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 13; f) a VH sequence as defined in (d) and a VL sequence as defined in (e); g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 40; h) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 39; i) a VH sequence as defined in (g) and a VL sequence as defined in (h); j) a VH sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 102-106; k) a VL sequence having at least 95% sequence identity to an amino acid sequence selected from SEQ ID NOs: 98-100; l) a VH sequence as defined in (j) and a VL sequence as defined in (k); m) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 48; n) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 47; o) a VH sequence as defined in (m) and a VL sequence as defined in (n); p) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 58; q) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 56 or 57; r) a VH sequence as defined in (p) and a VL sequence as defined in (q); s) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 66; t) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 65; u) a VH sequence as defined in (s) and a VL sequence as defined in (t); v) a VH sequence comprising the amino acid sequence of SEQ ID NO: 14; w) a VL sequence comprising the amino acid sequence of SEQ ID NO: 13; x) a VH sequence as defined in (v) and a VL sequence as defined in (w); y) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 17-24, 26, 28, 30, and 32; z) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 15, 16, 25, 27, 29, and 31; aa) a VH sequence as defined in (y) and a VL sequence as defined in (z); bb) a VH sequence comprising the amino acid sequence of SEQ ID NO: 40; cc) a VL sequence comprising the amino acid sequence of SEQ ID NO: 39; dd) a VH sequence as defined in (bb) and a VL sequence as defined in (cc); ee) a VH sequence comprising an amino acid sequence selected from SEQ ID NOs: 101-106; ff) a VL sequence comprising an amino acid sequence selected from SEQ ID NOs: 98-100; gg) a VH sequence as defined in (ee) and a VL sequence as defined in (ff); hh) a VH sequence comprising the amino acid sequence of SEQ ID NO: 48; ii) a VL sequence comprising the amino acid sequence of SEQ ID NO: 47; jj) a VH sequence as defined in (hh) and a VL sequence as defined in (kk); kk) a VH sequence comprising the amino acid sequence of SEQ ID NO: 58; ll) a VL sequence comprising the amino acid sequence of SEQ ID NO: 56 or 57; mm) a VH sequence as defined in (kk) and a VL sequence as defined in (ll); nn) a VH sequence comprising the amino acid sequence of SEQ ID NO: 66; oo) a VL sequence comprising the amino acid sequence of SEQ ID NO: 65; or pp) a VH sequence as defined in (nn) and a VL sequence as defined in (oo).

3. The isolated antibody of claim 1 or claim 2, wherein the antibody comprises a heavy chain variable domain (VH) comprising: (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 7; and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 12, and a light chain variable domain (VL) comprising: (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:

34. The isolated antibody of any one of claims 1-3, wherein the antibody comprises a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 30 and a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 29.

5. The isolated antibody of any one of claims 1-4, wherein the antibody comprises a VH sequence of SEQ ID NO: 30 and a VL sequence of SEQ ID NO: 29.

6. The isolated antibody of any one of claims 1-5, which is a monoclonal antibody.

7. The isolated antibody of any one of claims 1-6, which is a humanized or chimeric antibody.

8. The isolated antibody of any one of claims 1-7, which is an antibody fragment that binds Notch2.

9. The isolated antibody of claim 8, wherein the antibody fragment is selected from Fv, scFv, Fab, Fab', Fab’-SH, and F(ab')2 .

10. The isolated antibody of claim 9, wherein the antibody fragment is a Fab, Fab', or Fab’-SH.

11. The isolated antibody of any one of claims 1-7, which is a full-length antibody.

12. The isolated antibody of claim 11, wherein the antibody is a full-length IgG antibody.

13. The isolated antibody of claim 12, wherein the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody.

14. An isolated antibody that competes for binding to human Notch2 with the antibody of any one of claims 1-13 .

15. The isolated antibody of any one of claims 1-14, wherein the antibody: a) inhibits Jagged1-mediated signaling, but does not inhibit DLL1-mediated signaling; b) inhibits Jagged1-mediated signaling to a greater extent than DLL1-mediated signaling; c) does not inhibit binding of Jagged1 to Notch2; d) does not inhibit binding of DLL1 to Notch2; e) binds an epitope within the EGF7 repeat of Notch2; f) binds an epitope within amino acids 260-296 of Notch2; g) contacts arginine 268 (R268) of human Notch2; h) does not bind a Notch2 comprising lysine 268 (K268); i) binds a polypeptide comprising the amino acid sequence of SEQ ID NO: 74 and does not bind a polypeptide comprising the amino acid sequence of SEQ ID NO: 77; j) binds to human Notch2 and cynomolgus monkey Notch2; k) does not bind to mouse Notch2; l) binds to guinea pig Notch2; and / or m) does not bind to human Notch1 or human Notch3.

16. The isolated antibody of any one of claims 1-15, wherein the antibody: a) binds human Notch2 with an affinity (KD ) of less than 20 nM, less than 15 nM, less than 10 nM, or less than 5 nM, as determined by surface plasmon resonance; and / or b) inhibits Jagged1-mediated signaling with an IC50 of less than 20 nM, less than 15 nM, less than 10 nM, or less than 5 nM, optionally wherein inhibition of Jagged1-mediated signaling is determined using a high-content screening (HCS) assay.

17. An isolated nucleic acid encoding the antibody of any one of claims 1-16.

18. An expression vector comprising the nucleic acid of claim 17.

19. A host cell comprising the nucleic acid of claim 17.

20. A host cell that expresses the antibody of any one of claims 1-16.

21. The host cell of claim 20, wherein the host cell comprises the nucleic acid of claim 17 or the expression vector of claim 18.

22. A method of producing an antibody that binds to human Notch2 comprising culturing the host cell of any one of claims 19, 20, or 21 under conditions suitable for the expression of the antibody.

23. The method of claim 22, further comprising recovering the antibody from the host cell .

24. An antibody produced by the method of claim 22 or claim 23.

25. A pharmaceutical composition comprising the antibody of any one of claims 1-16 and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25, further comprising an additional therapeutic agent.

27. The pharmaceutical composition of claim 26, wherein the additional therapeutic agent is selected from hypertonic saline, mannitol, pulmozyme, N-acetyl cysteine, cysteamine, and a bronchodilator.

28. The antibody of any one of claims 1-16 or the pharmaceutical composition of any one of claims 25-27 for use as a medicament.

29. The antibody of any one of claims 1-16 or the pharmaceutical composition of any one of claims 25-27 for use in treating a muco-obstructive lung disease.

30. The antibody for use of claim 29, wherein the muco-obstructive lung disease is selected from chronic obstructive lung disease (COPD), cystic fibrosis, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, and bronchiolitis.

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