Conjugated Chemically Inducible Degradation Agents and Methods of Use

Abstract

The subject matter described herein relates to antibody-CIDE conjugates (Ab-CIDEs), pharmaceutical compositions containing them, and their use in the treatment of diseases and conditions in which targeted protein degradation is beneficial.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority and benefit to U.S. Provisional Patent Application No. 62 / 749,812, filed on October 24, 2018, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Reference to a Sequence Listing Submitted as a Text File via EFS - WEB The official copy of the Sequence Listing was electronically submitted via EFS - Web as an ASCII - formatted sequence listing having a file named 515668_SEQLIST.TXT, created on October 24, 2018, and having a size of 274 kilobytes, and was submitted simultaneously with the specification. The sequence listing contained in this ASCII - formatted document is part of this specification and is hereby incorporated by reference in its entirety.

[0003] The subject matter described herein generally relates to degrader conjugates comprising antibody - proteolysis targeting chimeric molecules useful for promoting intracellular degradation of target proteins.

Background Art

[0004] Cell maintenance and normal function require the regulated degradation of cellular proteins. For example, the degradation of regulatory proteins triggers events in the cell cycle such as DNA replication, chromosome segregation, etc. Thus, the degradation of such proteins affects cell growth, differentiation, and death.

[0005] Protein inhibitors can block or reduce protein activity within cells, but intracellular proteolysis can also reduce activity or completely remove the target protein. Thus, utilizing the cell's proteolytic pathways can provide a means for reducing or removing protein activity. One of the cell's major degradation pathways is known as the ubiquitin-proteasome system. In this system, proteins are marked for degradation by the proteasome by ubiquitinating the protein. Protein ubiquitination is accomplished by an E3 ubiquitin ligase that binds to the protein and attaches ubiquitin molecules to the protein. The E3 ubiquitin ligase is part of a pathway that includes E1 and E2 ubiquitin ligases, which make ubiquitin available to the E3 ubiquitin ligase for attachment to the protein.

[0006] To utilize this degradation pathway, the molecular construct combines an E3 ubiquitin ligase with the protein to be targeted for degradation and an antibody that targets the protein. To facilitate protein degradation by the proteasome, the molecular construct is composed of a group that binds to the E3 ubiquitin ligase and a group that binds to the protein target for degradation. These groups are typically linked by a linker. This molecular construct can bring the E3 ubiquitin ligase into proximity with the protein, such that the E3 ubiquitin ligase is ubiquitinated and labeled for degradation. However, the relatively large size of the molecular construct can be a problem for targeted delivery.

[0007] In the art, there is a continuing need for enhanced targeted delivery of such molecular constructs to cells containing a protein target. The subject matter described herein addresses this and other deficiencies in the art. SUMMARY OF THE INVENTION

[0008] In one aspect, the subject matter described herein is a covalently linked Ab-CIDE (PAC), and the positions of the covalent bonds linking the components of the Ab-CIDE: Ab, L1 (linker 1), L2 (linker 2), protein binding group, and E3 ligase binding group can be adjusted as desired to prepare an Ab-CIDE having desirable properties such as in vivo pharmacokinetics, stability, and solubility.

[0009] In one aspect, the subject matter described herein is of the following formula: Ab-(L1-D) p wherein D is a CIDE having the structure E3LB-L2-PB; E3LB is covalently linked to L2, and the E3LB is a group that binds an E3 ligase, and the E3 ligase is von Hippel-Lindau (VHL); L2 is a linker covalently linked to E3LB and PB; PB is a protein binding group covalently linked to L2, and the PB is a group that binds BRD4 or ERα, including all its variants, mutations, splice variants, indels, and fusions; Ab is an antibody covalently linked to L1; L1 is a linker covalently linked to Ab and D; and p has a value of from about 1 to about 8, relates to a conjugated chemical degradation inducer ("CIDE") having.

[0010] Another aspect of the subject matter described herein is a pharmaceutical composition comprising an Ab-CIDE and one or more pharmaceutically acceptable excipients.

[0011] Another aspect of the subject matter described herein is the use of an Ab-CIDE in a method of treating a condition and a disease by administering to a subject a pharmaceutical composition comprising the Ab-CIDE.

[0012] Another aspect of the subject matter described herein is a method of making Ab-CIDE.

[0013] Another aspect of the subject matter described herein is a manufactured product comprising a pharmaceutical composition comprising Ab-CIDE, a container, and a package insert or label indicating that the pharmaceutical composition can be used to treat a disease or condition.

Brief Description of the Drawings

[0014]

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Mode for Carrying Out the Invention

[0015] Antibody-chemical inducer of degradation (``CIDE'') conjugates (referred to herein as Ab-CIDE or PAC), useful for targeted protein degradation and for the treatment of related diseases and disorders, are disclosed herein. The subject matter described herein utilizes antibody targeting to direct CIDE to target cells or tissues. As described herein, it has been shown that by linking an antibody to CIDE to form Ab-CIDE, the CIDE is delivered to the target cell or target tissue. Herein, for example as shown in the Examples, cells expressing an antigen can be targeted by an antigen-specific Ab-CIDE, whereby the CIDE portion of the Ab-CIDE is delivered into the target cell. CIDEs comprising antibodies to antigens not found on the cell do not result in significant intracellular delivery of the CIDE to the cell.

[0016] Accordingly, the subject matter described herein relates to Ab-CIDE compositions that effect ubiquitination of a target protein and subsequent protein degradation. The composition comprises an antibody covalently linked to a linker (L1), which is covalently linked at any available attachment point to a CIDE, which CIDE comprises an E3 ubiquitin ligase binding (E3LB) portion that recognizes an E3 ubiquitin ligase protein that is VHL or XIAP and a protein binding portion (PB) that recognizes a target protein that is ERα or BRD4. The subject matter described herein is useful for modulating protein activity and treating diseases and conditions related to protein activity.

[0017] Here, the subject matter disclosed in this specification is described more fully below. However, many modifications and other embodiments of the subject matter disclosed herein will come to mind to those of ordinary skill in the art having the benefit of the teachings presented above. Accordingly, the subject matter disclosed herein should not be limited to the specific embodiments disclosed, but rather modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. If one or more of the incorporated documents, patents, and the like are different from or conflict with this application (including but not limited to defined terms, usage of terms, described techniques, etc.), this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety.

[0018] I. Definitions The term "CIDE" generally refers to a proteolytic targeting chimeric molecule having three components, an E3 ubiquitin ligase binding moiety (E3LB), a linker L2, and a protein binding moiety (PB).

[0019] The terms "residue", "moiety" or "group" refer to a component covalently bonded or linked to another component. By way of example, a residue of a compound has the atom(s) of the compound, such as hydrogen or hydroxy, replaced by a covalent bond, thereby binding the residue to another component of CIDE, L1-CIDE or Ab-CIDE. For example, "a residue of CIDE" refers to CIDE covalently bonded to one or more groups such as linker L2, which itself may be further linked to an antibody if desired.

[0020] The terms "covalently bound" or "covalently linked" refer to a chemical bond formed by the sharing of one or more pairs of electrons.

[0021] As used herein, the term "peptide mimetic" or "PM" means a non-peptide chemical moiety. A peptide is a short chain of amino acid monomers linked by peptide (amide) bonds, which are covalent chemical bonds formed when the carboxyl group of one amino acid reacts with the amino group of another amino acid. The shortest peptides are dipeptides consisting of two amino acids joined by a single peptide bond, followed by tripeptides, tetrapeptides, and so on. Peptide mimetic chemical moieties include non-amino acid chemical moieties. A peptide mimetic chemical moiety may also include one or more amino acids separated by one or more non-amino acid chemical units. A peptide mimetic chemical moiety does not contain two or more adjacent amino acids linked by peptide bonds in any part of its chemical structure.

[0022] The term "antibody" as used herein is used in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments as long as they exhibit the desired biological activity (Miller et al (2003) Jour. of Immunology 170:4854 - 4861). Antibodies may be murine, human, humanized, chimeric, or derived from other species. An antibody is a protein produced by the immune system that can recognize and bind to a specific antigen (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). The target antigen generally has multiple binding sites, also called epitopes, which are recognized by the CDRs (complementary determining regions) of multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen can have more than one corresponding antibody. An antibody includes a full - length immunoglobulin molecule or an immunologically active portion of a full - length immunoglobulin molecule, i.e., a molecule containing an antigen - binding site that immunospecifically binds to the target of interest or an antigenic part thereof, such targets including, but not limited to, cancer cells or cells that produce autoantibodies associated with autoimmune diseases. The immunoglobulins disclosed herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA), subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or type of immunoglobulin molecule. The immunoglobulins can be derived from any species. However, in one aspect, the immunoglobulins are of human, murine, or rabbit origin.

[0023] As used herein, the term "antibody fragment(s)" includes a portion of a full-length antibody, generally the antigen-binding or variable region thereof. Exemplary antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; minibodies (Olafsen et al. (2004) Protein Eng. Design & Sel 17(4):315-323), fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDRs (complementary determining regions), and epitope-binding fragments of any of the above that immunospecifically bind to a cancer cell antigen, viral antigen, or microbial antigen, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0024] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations that contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they can be synthesized without the contamination of other antibodies. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the subject matter described herein may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567; U.S. Patent No. 5,807,715). "Monoclonal antibodies" may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-628; Marks et al. (1991) J. Mol. Biol. 222:581-597.

[0025] As used herein, monoclonal antibodies specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is from a particular species or is identical or homologous to the corresponding sequence in an antibody belonging to a particular antibody class or subclass, while the remainder of the chain(s) is from a different species or is identical or homologous to the corresponding sequence in an antibody belonging to a different antibody class or subclass, and fragments of such antibodies, provided that they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al. (1984), Proc. Natl. Acad. Sci. USA, 81:6851-6855). Chimeric antibodies of interest herein include "primatized" antibodies that include variable domain antigen-binding sequences from non-human primates (e.g., Old World monkeys, apes, etc.) and human constant region sequences.

[0026] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is from a particular source or species and the remainder of the heavy and / or light chain is from a different source or species.

[0027] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. Antibodies are broadly divided into five classes: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0028] As used herein, the term "intact antibody" refers to an antibody that includes VL and VH domains, as well as light chain constant domain (CL) and heavy chain constant domains CH1, CH2, and CH3. The constant domains can be the constant domains of the native sequence (e.g., the constant domains of the native human sequence) or amino acid sequence variants thereof. An intact antibody can have one or more "effector functions," which refer to biological activities that can be attributed to the Fc constant region of the antibody (the Fc region of the native sequence or an amino acid sequence variant of the Fc region). Examples of antibody effector functions include C1q binding, complement-dependent cytotoxicity, Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and downregulation of cell surface receptors such as the B cell receptor and BCR.

[0029] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes the native sequence Fc region and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also referred to as the EU 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.

[0030] As used herein, the terms "framework" or "FR" refer to variable domain residues other than hypervariable region (HVR) residues. The FR of the variable domain generally consists of four FR domains, FR1, FR2, FR3, and FR4. Thus, HVR sequences and FR sequences generally appear in the following sequences in VH (or VL). FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0031] The terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to the native antibody structure or having a heavy chain containing an Fc region as defined herein.

[0032] A "human antibody" has an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell or derived from a non-human source that utilizes the human antibody repertoire, or other human antibody coding sequence. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0033] A "humanized" antibody refers to a chimeric antibody that includes amino acid residues derived from non-human HVRs and amino acid residues derived from human FRs. In certain embodiments, a humanized antibody includes substantially all of at least one, typically two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. The "humanized form" of an antibody refers to an antibody that has been humanized, such as a non-human antibody.

[0034] An "isolated antibody" is an antibody that has been separated from the components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity as determined, for example, by 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", vol. 848, pp. 79-87 (2007).

[0035] An "isolated nucleic acid" refers to a nucleic acid molecule that has been separated from the components of its natural environment. The isolated nucleic acid originally was contained in a cell that contained the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0036] An "isolated nucleic acid encoding an antibody" refers to one or more nucleic acid molecules encoding an antibody heavy chain and light chain (or fragments thereof), including nucleic acid molecules (which may be in a single vector or separate vectors) present at one or more locations within a host cell.

[0037] A "naked antibody" refers to an antibody that is not bound to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. A naked antibody may be present in a pharmaceutical formulation.

[0038] "Natural antibody" refers to naturally occurring immunoglobulin molecules having various structures. For example, natural IgG antibodies are about 150,000 Dalton heterotetrameric glycoproteins consisting of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called the variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called the variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chains of an antibody may be assigned to one of two types called kappa (κ) and lambda (λ) based on the amino acid sequence of their constant domains.

[0039] The "percent amino acid sequence identity (%)" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps if necessary to obtain the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignments for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using known computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One of ordinary skill in the art can determine appropriate parameters for aligning the sequences, including any algorithms necessary to achieve the maximum degree of alignment over the full length of the sequences being compared. However, for the purposes herein, the percent amino acid sequence identity value is generated using the ALIGN-2 sequence comparison computer program. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code is filed in the user documentation of the U.S. Copyright Office (Washington D.C., 20559) and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California), or may be compiled from its source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are set and unchanged by the ALIGN-2 program.

[0040] In situations where ALIGN-2 is employed for amino acid sequence comparison, (or where a given amino acid sequence A can be purchased as a given amino acid sequence having or containing a certain specific amino acid sequence identity % with, or opposite to, sequence B with respect to a given amino acid sequence B), the amino acid sequence identity % of a given amino acid sequence A with respect to, with, or opposite to a given amino acid sequence B is calculated as follows: 100 times the fraction X / Y wherein X is the number of amino acid residues scored as identity matches by the sequence alignment program ALIGN-2 in the alignment of this program for A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % of A with respect to B will not be equal to the amino acid sequence identity % of B with respect to A. Unless otherwise specified, all values of amino acid sequence identity % used herein are obtained as described in the paragraph immediately preceding the use of the ALIGN-2 computer program.

[0041] Depending on the amino acid sequence of the constant domain of the heavy chain, intact antibodies can be assigned different "classes". There are five major classes of intact immunoglobulin antibodies, namely, IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into "subclasses" (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional arrangements of the different classes of immunoglobulins are well known. Ig forms include forms with or without hinge modifications (Roux et al. (1998), "J. Immunol." 161:4083 - 4090; Lund et al. (2000), "Eur. J. Biochem." 267:7246 - 7256; U.S. Patent Application Publication No. 2005 / 0048572; U.S. Patent Application Publication No. 2004 / 0229310).

[0042] As used herein, the term "human consensus framework" refers to a framework that represents the amino acid residues that most commonly occur in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as that in Kabat et al., "Sequences of Proteins of Immunological Interest", 5th Edition, NIH Publication, No. 91-3242, Bethesda, Maryland (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (supra).

[0043] For the purposes of this specification, an "acceptor human framework" is a framework that includes the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework that is derived from a human immunoglobulin framework or a human consensus framework as defined below. An "acceptor human framework" that is "derived from" a human immunoglobulin framework or a human consensus framework may include the same amino acid sequence or may include changes in the amino acid sequence. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

[0044] As used herein, the terms "variable region" or "variable domain" refer to the domain of an antibody heavy or light chain that binds an antigen. The variable domains of the heavy and light chains of a native antibody (VH and VL, respectively) generally have similar structures, and each domain comprises four conserved framework regions (FRs) and three hypervariable regions (HVRs). See, for example, Kindt et al., Kuby Immunology, 6 th , W.H. Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Further, an antibody that binds a particular antigen may be isolated by screening a library of complementary VL or VH domains using the VH or VL domain of the antibody that binds the antigen. See, for example, Portolano et al., "J. Immunol.", Vol. 150, pages 880-887 (1993), Clarkson et al., "Nature", Vol. 352, pages 624-628 (1991).

[0045] The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops") in an array. Generally, native four-chain antibodies contain six HVRs, three in VH (H1, H2, H3) and three in VL (L1, L2, L3). HVRs generally contain amino acid residues derived from hypervariable loops and / or "complementary determining regions" (CDRs), which have the highest sequence variability and / or are involved in antigen recognition. Exemplary hypervariable loops occur 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).) Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3) are present at amino acid residues 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of H2 and 95-102 of H3. (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)) Except for CDR1 in VH, CDRs generally contain amino acid residues that form hypervariable loops. CDRs also include "specificity determining regions", i.e., "SDRs", which are residues that contact the antigen. SDRs are contained within a region of the CDR called the omission-CDR, i.e., a-CDR. Exemplary a-CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2 and a-CDR-H3) are present at amino acid residues 31-34 of L1, 50-55 of L2, 89-96 of L3, 31-35B of H1, 50-58 of H2 and 95-102 of H3. (See Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008).)Unless otherwise specified, HVR residues, and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (supra).

[0046] The term "effector function" refers to biological activities attributable to the Fc region of an antibody that vary with the antibody isotype. Examples of antibody effector functions include the following: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0047] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds.

[0048] "Epitope 4D5" or "4D5 epitope" or "4D5" is the region within the extracellular domain of HER2 to which the antibody 4D5 (ATCC CRL 10463) and trastuzumab bind. This epitope is proximal to the transmembrane domain of HER2 and is within domain IV of HER2. To screen for antibodies that bind to the 4D5 epitope, routine cross-blocking assays such as those described in "Antibodies, A Laboratory Manual" Cold Spring Harbor Laboratory, eds. Harlow and David Lane (1988) can be performed. Alternatively, epitope mapping can be performed to assess whether an antibody binds to the 4D5 epitope of HER2 (any one or more residues within the region derived from approximately residue 550 to approximately residue 610, including HER2 (SEQ ID NO: 39)).

[0049] "Epitope 2C4" or "2C4 epitope" is the region within the extracellular domain of HER2 to which antibody 2C4 binds. To screen for antibodies that bind to the 2C4 epitope, routine cross-blocking assays such as those described in "Antibodies, A Laboratory Manual", Cold Spring Harbor Laboratory, edited by Harlow and David Lane (1988) can be performed. Alternatively, epitope mapping can be performed to evaluate whether an antibody binds to the 2C4 epitope of HER2. Epitope 2C4 contains residues derived from domain II in the extracellular domain of HER2. The 2C4 antibody and pertuzumab bind to the extracellular domain of HER2 at the junction of domains I, II, and III (Franklin et al., "Cancer Cell" 5: 317-328 (2004)).

[0050] "Affinity" refers to the strength of the total 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 specified, as used herein, "binding affinity" refers to the specific binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by methods common in the art, including those described herein. Specific illustrative descriptions and exemplary embodiments for measuring binding affinity are described below. In certain embodiments, the antibodies described herein have a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤5 nM, ≤4 nM, ≤3 nM, ≤2 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M).

[0051] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to the parental antibody without such modifications, and such modifications improve the affinity of the antibody for the antigen.

[0052] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures and vectors incorporated into the genome of a host cell into which the vector has been introduced. Certain vectors can direct the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors".

[0053] As used herein, the term "free cysteine amino acid" refers to a cysteine amino acid residue that has been engineered into the parental antibody, has a thiol functional group (-SH), and is not paired as an intramolecular or intermolecular disulfide bridge. As used herein, the term "amino acid" means glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, lysine, arginine, histidine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine or citrulline.

[0054] As used herein, the terms "linker", "linker unit" or "linkage" mean a chemical moiety comprising a chain of atoms that covalently attaches a CIDE moiety to an antibody, or a chemical moiety comprising a chain of atoms that covalently attaches a component of a CIDE to another component of the CIDE. In various embodiments, the linker is a divalent group specified as L1 or L2.

[0055] "Patient", "individual", or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, horses, etc.), primates (e.g., non-human primates such as humans, monkeys, etc.), rabbits, rodents (e.g., mice, rats, etc.). In certain embodiments, the patient, individual, or subject is a human. In some embodiments, the patient may be a "cancer patient", i.e., one who has or is at risk of having one or more symptoms of cancer.

[0056] "Patient population" refers to a group of cancer patients. Such populations can be used to demonstrate the statistically significant efficacy and / or safety of a drug.

[0057] A "recurrent" patient is one who has signs or symptoms of cancer after remission. Optionally, the patient has recurred after adjuvant or neoadjuvant therapy.

[0058] A cancer or biological sample "showing HER expression, amplification, or activation" is one that, in a diagnostic test, expresses (including overexpresses) the HER receptor, contains an amplified HER gene, and / or demonstrates activation or phosphorylation of other HER receptors.

[0059] As used herein, "neoadjuvant therapy" or "preoperative therapy" refers to therapy that is conducted before surgery. The goal of neoadjuvant therapy is to provide immediate systemic treatment and potentially eradicate micrometastases that would otherwise grow following a standard series of surgery followed by systemic therapy. Neoadjuvant therapy can also help to reduce tumor size, thereby enabling complete resection of initially unresectable tumors or preservation of part of an organ and its function. Additionally, neoadjuvant therapy allows for in vivo evaluation of drug efficacy that can guide the selection of subsequent treatment.

[0060] As used herein, "adjuvant therapy" refers to a treatment method that is performed after radical surgery and that cannot detect evidence of residual disease in order to reduce the risk of disease recurrence. The purpose of adjuvant therapy is to prevent cancer recurrence and thus reduce the likelihood of cancer-related death. Adjuvant therapy as used herein specifically excludes neoadjuvant therapy.

[0061] "Radical surgery" is used as the term is used within the medical community. Radical surgery includes, for example, surgeries or surgical or other procedures that result in the removal or excision of a tumor, including those that result in the removal or excision of all tumors visible to the naked eye. Radical surgery includes, for example, complete or curative resection of the tumor or complete gross resection. Radical surgery includes procedures that occur in one or more stages, including, for example, multi-stage surgical procedures in which one or more surgical or other procedures are performed prior to excision of the tumor. Radical surgery includes procedures for removing or excising a tumor that includes the involved organ, a part of the organ and tissue, and surrounding organs such as lymph nodes, part of an organ or tissue. The removal may be incomplete such that tumor cells may remain despite not being detected.

[0062] "Survival" refers to patients who remain alive and includes disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Survival can be estimated by the Kaplan-Meier method, and differences in survival are calculated using the stratified log-rank test.

[0063] "Progression-free survival" (PFS) is the earlier of the time from the first day of treatment until documented disease progression (including isolated CNS progression) or death from any cause in the study.

[0064] "Disease-free survival (DFS)" refers to patients who have survived without cancer recurrence for a specified period, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., starting from the initiation of treatment or the first diagnosis. In one aspect of the subject matter described herein, DFS is analyzed according to the principle of treatment intent, i.e., the patient is evaluated based on the assigned treatment method. Events used in the analysis of DFS may include local, regional, and distant recurrence of cancer, the occurrence of secondary cancer, and death from any cause in patients without previous events (e.g., breast cancer recurrence or a second primary cancer).

[0065] "Overall survival" refers to patients who have survived for a specified period, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., starting from the initiation of treatment or the first diagnosis.

[0066] "Prolonging survival" means increasing DFS and / or OS in treated patients compared to untreated patients or compared to a control treatment protocol. Survival is monitored for at least about 6 months, or at least about 1 year, or at least about 2 years, or at least about 3 years, or at least about 4 years, or at least about 5 years, or at least about 10 years, etc., after the initiation of treatment or the first diagnosis.

[0067] "Monotherapy" means a treatment regimen that includes only a single therapeutic agent for the treatment of cancer or a tumor during a series of treatment periods.

[0068] "Maintenance therapy" means a treatment regimen administered to reduce the likelihood of disease recurrence or progression. Maintenance therapy can be provided over any length of time, including a long period up to the lifespan of the subject. Maintenance therapy can be provided after initial therapy or in combination with initial therapy or additional treatment methods. The dosage used for maintenance therapy may vary and may include a reduced dosage compared to the dosage used for other types of treatment methods.

[0069] The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to a cell into which exogenous nucleic acid has been introduced, including the progeny of such a cell. Host cells include "transformants" and "transformed cells", including primary transformed cells and progeny derived therefrom regardless of the number of passages. Progeny may not have exactly the same nucleic acid content as the parental cell and may contain mutations. Progeny of mutants having the same function or biological activity as that screened or selected for the originally transformed cell are included in the present invention.

[0070] The terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal typically characterized by unregulated cell growth / proliferation. A "tumor" contains one or more cancer cells. Examples of cancers are provided elsewhere in this specification.

[0071] "HER2-positive" cancer includes cancer cells having higher HER2 than normal levels. Examples of HER2-positive cancers include HER2-positive breast cancer and HER2-positive gastric cancer. Optionally, HER2-positive cancer has an immunohistochemistry (IHC) score of 2+ or 3+ and / or an in situ hybridization (ISH) amplification rate of ≧2.0. The term "HER2-positive cell" refers to a cell that expresses HER2 on its surface.

[0072] The term "early-stage breast cancer (EBC)" or "early breast cancer" is used herein to refer to breast cancer that has not spread beyond the breast or axillary lymph nodes. This includes non-invasive ductal carcinoma as well as stage I, IIA, IIB, and IIIA breast cancers.

[0073] Tumors or cancers as "Stage 0", "Stage I", "Stage II", "Stage III" or "Stage IV", and references to the various sub-stages within this classification, refer to the classification of tumors or cancers using all stage classifications or Roman numeral staging methods known in the art. The actual stage of cancer depends on the type of cancer, but generally, stage 0 cancer is an in situ lesion, stage I cancer is a small localized tumor, stage II and III cancers are locally advanced tumors showing regional lymph node involvement, and stage IV cancer represents metastatic cancer. The specific stage of each type of tumor is known to those skilled in the art.

[0074] The term "metastatic breast cancer" means a state of breast cancer in which cancer cells are transmitted by blood vessels or lymphatic vessels from the original site to one or more sites in other locations in the body, forming one or more secondary tumors in one or more organs other than the breast.

[0075] "Advanced" cancer is cancer that has spread outside the original site or organ, either by local invasion or metastasis. Thus, the term "advanced" cancer includes both locally advanced diseases and metastatic diseases. "Recurrent" cancer is one that has regrown at either the initial site or a distant site after response to initial therapy such as surgery. "Local recurrence" cancer is cancer that recurs at the same location as the previously treated cancer after treatment. "Surgically operable" or "resectable" cancer is limited to the primary organ and is suitable for surgery (resection). "Non-resectable" or "unresectable" cancer cannot be removed (resected) by surgery.

[0076] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or blocks cell function and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P32 , Pb 212 , and Lu radioisotopes); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and their fragments, such as nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins derived from bacteria, fungi, plants or animals (including fragments and / or variants thereof); and various antitumor or anticancer agents disclosed below, but not limited thereto.

[0077] "Chemotherapeutic agent" refers to a chemical substance useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN (registered trademark)); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (especially bratasin and bratasinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL (registered trademark)); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (including synthetic analogs topotecan (HYCAMTIN (registered trademark)), CPT-11 (irinotecan, CAMPTOSAR (registered trademark)), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); podophyllotoxin; podophyllinic acid; teniposide; cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); erythrocin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembucine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (see, for example, calicheamicin, especially calicheamicin γ1I and calicheamicin omega I1 (see, for example, Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)));CDP323, an oral alpha-4 integrin inhibitor; dynemicin including dynemicin A; esperamicin; and neocarzinostatin chromophore and related chromoprotein engimycin antibiotics chromophore), acrasinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, cardinophyllin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®), pegylated liposomal doxorubicin (CAELYX®), and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, for example mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rhodrubicin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites, for example methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone, and 5-fluorouracil (5-FU); folic acid analogs, for example denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, for example fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs, for example ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens, for example calusterone, drostanolone propionate, epitioestanol, mepitiostane, testolactone; antiadrenal agents, for example aminoglutethimide, mitotane, trilostane; folic acid supplements, for example folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid;Eniluracil; Amasakurin; Bestrabucil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diazikuon; Elfornithine; Elliptinium acetate; Epothilone; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids, such as Maytansine and Ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Losoxantrone; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, Oregon); Razoxane; Lysoxine; Sizofiran; Spirogermanium; Tenuazonic acid; Triazikuon; 2,2’,2’-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, Verracurin A, Lolitrem A and Anguizine); Urethane; Vindesine (ELDISINE (registered trademark), FILDESIN (registered trademark)); Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gasitocin; Arabinoside (“Ara-C”); Thiotepa; Taxoids, such as Paclitaxel (TAXOL (registered trademark)), albumin-modified nanoparticle formulation of Paclitaxel (ABRAXANETM), and Docetaxel (TAXOTERE (registered trademark)); Chlorambucil; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum agents, such as Cisplatin, Oxaliplatin (e.g., ELOXATIN (registered trademark)), and Carboplatin; Vincas that prevent tubulin polymerization and microtubule formation, including Vinblastine (VELBAN (registered trademark)), Vincristine (ONCOVIN (registered trademark)), Vindesine (ELDISINE (registered trademark), FILDESIN (registered trademark)), and Vinorelbine (NAVELBINE (registered trademark)); Etoposide (VP-16); Ifosfamide; Mitoxantrone; Leucovorin; Novantrone; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO: difluoromethylornithine);Retinoids, such as retinoic acids including bexarotene (TARGRETIN (registered trademark)); bisphosphonates, such as clodronate (e.g., BONEFOS (registered trademark) or OSTAC (registered trademark)), etidronate (DIDROCAL (registered trademark)), NE-58095, zoledronic acid / zoledronate (ZOMETA (registered trademark)), alendronate (FOSAMAX (registered trademark)), pamidronate (AREDIA (registered trademark)), tiludronate (SKELID (registered trademark)), or risedronate (ACTONEL (registered trademark)); troxacitabine (1,3-dioxolane nucleoside cytosine analogs); antisense oligonucleotides, particularly genes of signal transduction pathways involved in abnormal cell proliferation, such as PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such as the THERATOPE (registered trademark) vaccine and gene therapy vaccines, such as the ALLOVECTIN (registered trademark) vaccine, LEUVECTIN (registered trademark) vaccine, and VAXID (registered trademark) vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN (registered trademark)); rmRH (e.g., ABARELIX (registered trademark)); BAY 43-9006 (sorafenib, Bayer); SU-11248 (sunitinib, SUTENT (registered trademark), Pfizer); perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); bortezomib (VELCADE (registered trademark)); CCI-779; tipifarnib (R11577); olaphenib, ABT510; Bcl-2 inhibitors, such as oblimersen sodium (GENASENSE (registered trademark), antisense oligonucleotide); pixantrone; EGFR inhibitors (see the definition below); tyrosine kinase inhibitors; serine-threonine kinase inhibitors, such as rapamycin (sirolimus, RAPAMUNE (registered trademark)); farnesyltransferase inhibitors, such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids, or derivatives of any of the above;and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), FOLFOX (abbreviation for combination therapy of oxaliplatin (ELOXATINTM) and 5-FU, leucovorin).;

[0078] The chemotherapeutic agents defined herein include "anti-hormonal agents" or "endocrine therapies" that act to modulate, reduce, block, or inhibit the effects of hormones that can promote cancer growth.They may be hormones themselves, including selective estrogen receptor modulators (SERMs) having a mixed agonist / antagonist profile such as tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and SERM3; antiestrogens having no agonist properties such as fulvestrant (FASLODEX®) and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and / or suppress ER levels); aromatase inhibitors including steroidal aromatase inhibitors such as formestane and exemestane (AROMASIN®), and non-steroidal aromatase inhibitors such as anastrozole (ARIMIDEX®), letrozole (FEMARA®), and aminoglutethimide, and other aromatase inhibitors including vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, and 4(5)-imidazole; luteinizing hormone-releasing hormone agonists including leuprolide (LUPRON® and ELIGARD®), goserelin, buserelin, and tripterelin; progestins such as megestrol acetate and medroxyprogesterone acetate, estrogens such as diethylstilbestrol and Premarin, and sex steroids including androgens / retinoids such as fluoxymesterone, all-trans retinoic acid, and fenretinide; onapristone; antiprogesterone; estrogen receptor downregulators (ERDs); antiandrogens such as flutamide, nilutamide, and bicalutamide; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more of the foregoing, but not limited thereto.

[0079] As used herein with respect to adjunctive therapy, the term "immunosuppressant" refers to a substance that acts to suppress or mask the immune system of a mammal being treated herein. This would include substances that suppress cytokine production, downregulate or suppress self-antigen expression, or mask MHC antigens. Examples of such agents include 2-amino-6-aryl-5-substituted pyrimidines (see U.S. Patent No. 4,665,077); non-steroidal anti-inflammatory drugs (NSAIDs); glucocorticoids such as ganciclovir, tacrolimus, cortisol or aldosterone, anti-inflammatory agents such as cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, or leukotriene receptor antagonists; purine antagonists such as azathioprine or mycophenolate mofetil (MMF); alkylating agents such as cyclophosphamide; bromocriptine; danazol; dapsone; glutaraldehyde (which masks MHC antigens as described in U.S. Patent No. 5,290,654; No. 4,120,649); anti-idiotype antibodies to MHC antigens and MHC fragments; cyclosporin A; steroids such as corticosteroids or glucocorticoids or glucocorticoid analogs such as prednisone, methylprednisolone such as SOLU-MEDROL® sodium succinate methylprednisolone and dexamethasone; dihydrofolate reductase inhibitors such as methotrexate (oral or subcutaneous); antimalarial agents such as chloroquine and hydroxy; sulfasalazine; leflunomide; anti-interferon-alpha, -beta, or -gamma antibodies, anti-tumor necrosis factor (TNF)-alpha antibodies (cytokine or cytokine receptor antibodies including infliximab (REMICADE®) or adalimumab), anti-TNF-alpha immunoadhesin (etanercept), anti-TNF-beta antibodies, anti-interleukin-2 (IL-2) antibodies and anti-IL-2 receptor antibodies, and anti-interleukin-6 (IL-6) receptor antibodies and antagonists (such as ACTEMRA™ tocilizumab); anti-LFA-1 antibodies including anti-CD11a and anti-CD18 antibodies; anti-L3T4 antibodies; heterologous anti-lymphocyte globulin;Pan T antibodies, preferably anti-CD3 or anti-CD4 / CD4a antibodies; soluble peptides containing an LFA-3 binding domain (International Publication No. WO90 / 08187, after July 26, 1990); streptokinase; transforming growth factor beta (TGF-beta); streptodornase; host-derived RNA or DNA; FK506; RS-61443; chlorambucil; deoxyspergualin; rapamycin; T cell receptor (Cohen et al., U.S. Patent No. 5,114,721); T cell receptor fragments (Offner et al., "Science" 251:430-432 (1991); International Publication No. WO90 / 11294; Ianeway, "Nature", 341:482 (1989); and International Publication No. WO91 / 01133); BAFF antagonists such as BAFF antibodies and BR3 antibodies and zTNF4 antagonist (for review, see Mackay and Mackay, "Trends Immunol", 23:113-115 (2002), see also the definitions below); biological agents that interfere with T cell helper signals such as anti-CD40 receptor or anti-CD40 ligand (CD154) include CD40-CD40 ligand (e.g., Durie et al., "Science" 261:1328-1330 (1993); Mohan et al., "J. Immunol", 154:1470-1480 (1995)), and CTLA4-Ig (Finck et al., "Science", 265:1225-1227 (1994)); and T cell receptor antibodies (EP340,109), such as T10B9. Some preferred immunosuppressive agents herein include cyclophosphamide, chlorambucil, azathioprine, leflunomide, MMF, or methotrexate.;

[0080] As used herein, "treatment" (and its grammatical variants, e.g., "treating" or "to treat") refers to a clinical intervention in an attempt to alter the natural course in an individual being treated, which can be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include preventing the onset or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, remission or palliation of the condition, and recovery or improved prognosis. In some embodiments, the antibodies of the subject matter described herein are used to delay the onset of a disease or to slow the progression of a disease.

[0081] A drug administered "concurrently" with one or more other drugs is administered on the same treatment day as the one or more other drugs and, if desired, at the same time as the one or more other drugs during the same treatment cycle. For example, in the case of a cancer therapy administered every three weeks, the concurrently administered drugs are each administered on day 1 of the three-week cycle.

[0082] An "effective amount" of a drug, e.g., a pharmaceutical formulation, refers to an amount effective at dosages and for periods of time necessary to achieve a desired therapeutic or prophylactic result. For example, an effective amount of a drug for treating cancer reduces the number of cancer cells, reduces tumor size, inhibits (i.e., delays, preferably stops) infiltration of cancer cells into the underlying organs, inhibits (i.e., delays, preferably stops) tumor metastasis, inhibits tumor growth to some extent, and / or alleviates to some extent one or more of the symptoms associated with the cancer. To the extent the drug can prevent the growth of existing cancer cells and / or kill them, the drug can be cytostatic and / or cytotoxic. An effective amount results in an increased progression-free survival (e.g., as measured by Response Evaluation Criteria in Solid Tumors (RECIST) or CA-125 changes), produces an objective response (partial response (PR) or complete response (CR)), prolongs overall survival, and / or improves one or more symptoms of the cancer (e.g., as evaluated by FOSI).

[0083] As used herein, the term "therapeutically effective amount" means any amount that, as compared to a corresponding subject not receiving such amount, results in treatment of a disease, disorder, or side effect, or a decrease in the rate of progression of a disease or disorder. This term also includes, within its scope, amounts effective to enhance normal physiological functions. For use in therapy, a therapeutically effective amount of Ab-CIDE and its salts can be administered as the raw chemical substance. In addition, the active ingredient can be provided as a pharmaceutical composition.

[0084] As used herein, unless otherwise defined in the claims, the term "optionally" means that the subsequently described event(s) may or may not occur, including both the event(s) that occur and the event(s) that do not occur.

[0085] As used herein, unless otherwise specifically defined, the phrases "optionally substituted", "substituted" or variations thereof indicate substitution as required, including one or more substituents, for example, a multiple degree of substitution of 1, 2 or 3. This phrase should not be construed as overlapping with the substitutions described and illustrated herein.

[0086] The term "pharmaceutical formulation" refers to a preparation in a form in which the biological activity of the active ingredient contained therein is effective and which contains no further constituents that are unacceptably toxic to the subject to which the formulation is administered.

[0087] The term "pharmaceutically acceptable excipient" refers to a component in a pharmaceutical formulation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable excipients include, but are not limited to, buffers, carriers, stabilizers, or preservatives.

[0088] As used herein, the phrase "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic or inorganic salt of a molecule. Representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may contain another molecule, such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Further, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In instances where multiple charged atoms are part of a pharmaceutically acceptable salt, multiple counterions can be present. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0089] Other salts that are not pharmaceutically acceptable may be useful in the preparation of the compounds described herein and are to be considered as forming a further aspect of the subject matter. These salts, such as oxalate or trifluoroacetate salts, are not pharmaceutically acceptable per se but may be useful in the preparation of salts that are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable salts.

[0090] As used herein, the term "plurality" refers to two or more conjugates. Each conjugate may be the same as or different from any other conjugate in the plurality.

[0091] "Small molecule" or "small molecule compound" generally refers to an organic molecule with a size of less than about 5 kilodaltons (Kd). In some embodiments, the small molecule is less than about 4 Kd, 3 Kd, about 2 Kd, or about 1 Kd. In some embodiments, the small molecule is less than about 800 Daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, the small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule is non-polymeric. Small molecules are not proteins, polypeptides, oligopeptides, peptides, polynucleotides, oligonucleotides, polysaccharides, glycoproteins, proteoglycans, etc. A derivative of a small molecule refers to a molecule that shares the same structural core as the original small molecule but can be prepared by a series of chemical reactions from the original small molecule.

[0092] As used herein, the term "alkyl" refers to a carbon atom chain of any length from 1 to 12 (C1-C 12refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical, and the alkyl radical may be independently substituted with one or more substituents described below as needed. In another embodiment, the alkyl radical has 1 to 8 carbon atoms (C1-C8), or 1 to 6 carbon atoms (C1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 1-heptyl, 1-octyl, and the like.

[0093] As used herein, the term "alkylene" refers to a saturated straight-chain or branched-chain divalent hydrocarbon radical having from 1 to 12 carbon atoms (C1 - C 12 ), and the alkylene radical may be independently substituted, if desired, with one or more of the substituents described below. In another embodiment, the alkylene radical has from 1 to 8 carbon atoms (C1 - C8), or from 1 to 6 carbon atoms (C1 - C6). Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), etc.

[0094] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having from 2 to 8 carbon atoms (C2 - C8) with at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond, and the alkenyl radical may be independently substituted, if desired, with one or more of the substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethynylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0095] The term "alkenylene" refers to a straight-chain or branched-chain divalent hydrocarbon radical having from 2 to 8 carbon atoms (C2 - C8) with at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond, and the alkenylene radical may be independently substituted, if desired, with one or more of the substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethynylene or vinylene (-CH=CH-), allyl (-CH2CH=CH-), etc.

[0096] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical of any length from 2 to 8 carbon atoms (C2 - C8) having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. The alkynyl radical may be independently substituted, if desired, with one or more substituents described herein. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CH2C≡CH), etc.

[0097] The term "alkynylene" refers to a straight-chain or branched-chain divalent hydrocarbon radical of any length from 2 to 8 carbon atoms (C2 - C8) having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. The alkynylene radical may be independently substituted, if desired, with one or more substituents described herein. Examples include, but are not limited to, ethynylene (-C≡C-), propynylene (propargylene, -CH2C≡C-), etc.

[0098] The terms "carbocycle", "carbocyclic", "carbocyclic ring", and "cycloalkyl" refer to a monocyclic ring having 3 to 12 carbon atoms (C3 - C 12Or it refers to a monovalent non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicyclic ring. The bicyclic carbocyclic ring having 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, and the bicyclic carbocyclic ring having 9 or 10 atoms can be arranged as a bicyclo[5,6] or [6,6] system, or as a bridged system such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The spiro moiety is also included within the scope of this definition. Examples of monocyclic carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The carbocyclic group is independently substituted, if necessary, with one or more substituents described herein.

[0099] "Aryl" means a monovalent aromatic hydrocarbon radical having 6 to 20 carbon atoms (C6~C 20 ) derived by removing one hydrogen atom from a single carbon atom of the parent aromatic ring system. Some aryl groups are represented as "Ar" in the exemplary structures. Aryl includes bicyclic radicals containing a saturated, partially unsaturated ring, or an aromatic ring fused to an aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzene, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc. The aryl group is independently substituted, if necessary, with one or more substituents described herein.

[0100] "Arylene" means a divalent aromatic hydrocarbon radical of 6 to 20 carbon atoms (C6-C 20 ) derived by removing two hydrogen atoms from two carbon atoms of the parent aromatic ring system. Some arylene groups are represented as "Ar" in exemplary structures. Arylene includes bicyclic radicals containing aromatic rings condensed to saturated, partially unsaturated rings, or aromatic carbocyclic rings. Typical arylene groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzene, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, etc. The arylene group is optionally substituted with one or more substituents described herein.

[0101] The terms "heterocyclic ring", "heterocyclic ring", and "heterocyclic ring system" are used synonymously herein and refer to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) carbocyclic radical of 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, the remaining ring atoms are C, and one or more ring atoms are independently substituted, optionally, with one or more of the substituents described below. The heterocyclic ring is a monocyclic ring of 3 to 7 members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicyclic ring of 7 to 10 members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example, a bicyclo[4,5], [5,5], [5,6], or [6,6] system. The heterocyclic ring is described in Paquette, Leo A; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, since 1950), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclic ring" includes radicals in which the heterocyclic radical is condensed with a saturated, partially unsaturated ring, or an aromatic carbocyclic or heterocyclic ring.Examples of the heterocyclic ring include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolinylimidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl, and N-pyridylurea. The spiro moiety is also included within the scope of this definition. Examples of the heterocyclic group in which two ring atoms are substituted with an oxo (=O) moiety are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic group herein is independently substituted with one or more substituents described herein, as necessary.

[0102] The term "heteroaryl" refers to a monovalent aromatic radical of a 5-, 6-, or 7-membered ring, including a fused ring system of 5 to 20 atoms containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, at least one of which is aromatic. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, 1-methyl-1H-benzo[d]imidazole, [1,2,4]triazolo[1,5-a]pyridine, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The heteroaryl group is independently substituted, if desired, with one or more substituents described herein.

[0103] A complex ring or heteroaryl group may, if possible, be bonded to carbon (carbon-bonded) or nitrogen (nitrogen-bonded). By way of example, but not limitation, a carbon-bonded complex ring or heteroaryl is bonded at the 2, 3, 4, 5, or 6 position of pyridine, the 3, 4, 5, or 6 position of pyridazine, the 2, 4, 5, or 6 position of pyrimidine, the 2, 3, 5, or 6 position of pyrazine, the 2, 3, 4, or 5 position of furan, tetrahydrofuran, thiophene, thienyl, pyrrole, or tetrahydropyrrole, the 2, 4, or 5 position of oxazole, imidazole, or thiazole, the 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, the 2 or 3 position of aziridine, the 2, 3, or 4 position of azetidine, the 2, 3, 4, 5, 6, 7, or 8 position of quinoline, or the 1, 3, 4, 5, 6, 7, or 8 position of isoquinoline.

[0104] By way of example, but not limitation, a nitrogen-bonded complex ring or heteroaryl is bonded at the 1 position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, the 2 position of isoindole or isoindoline, the 4 position of morpholine, and the 9 position of carbazole or β-carboline.

[0105] The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0106] The term "stereoisomer" refers to a compound having the same chemical constitution but differing with respect to the arrangement of atoms or groups in space.

[0107] "Diastereomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as, for example, melting point, boiling point, spectral characteristics, and reactivity. A mixture of diastereomers may be separated under high-resolution analytical procedures such as electrophoresis and chromatography.

[0108] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0109] The stereochemical definitions and conventions used herein generally follow S.P. Parker, ed., "McGraw-Hill Dictionary of Chemical Terms" (1984), McGraw-Hill Book Company (New York) and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds" (1994), John Wiley & Sons, Inc. New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to specify the designation of the rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also sometimes be referred to as an enantiomer, and a mixture of such isomers is often called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and these can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0110] Other terms, definitions, and abbreviations used in this specification include the following: wild type ("WT"); cysteine engineered variant antibody ("thio"); light chain ("LC"); heavy chain ("HC"); 6-maleimidocaproyl ("MC"); maleimidopropanoyl ("MP"); valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("ala-phe"), p-aminobenzyl ("PAB") and p-aminobenzyloxycarbonyl ("PABC"); A118C (EU numbering) = A121C (sequential numbering) = A114C (Kabat numbering) of light chain heavy chain K149C (Kabat numbering). Additional definitions and abbreviations are provided herein.

[0111] II. Chemical decomposition inducing substances A chemical decomposition inducing substance (CIDE) molecule can be conjugated to an antibody to form an "Ab-CIDE" conjugate. The antibody is conjugated to the CIDE ("D") via a linker (L1), and the CIDE includes a ubiquitin E3 ligase binding group ("E3LB"), a linker ("L2"), and a protein binding group ("PB"). The general formula of the Ab-CIDE molecule is as follows: Ab-(L1-D) p wherein D is a CIDE having the structure E3LB-L2-PB; E3LB is an E3 ligase binding group covalently bound to L2; L2 is a linker covalently bound to E3LB and PB; PB is a protein binding group covalently bound to L2; Ab is an antibody covalently bound to L1; L1 is a linker covalently bound to Ab and D; and p has a value of from about 1 to about 50. The variable p reflects that the antibody can be linked to one or more L1-D groups. In one embodiment, p is from 1 to 8. In another embodiment, p is about 2.

[0112] The following sections describe the components that make up Ab-CIDE. To obtain an Ab-CIDE with strong potency and a desirable therapeutic index, the following components are provided.

[0113] 1. Antibody (Ab) As described herein, an antibody, such as a monoclonal antibody (mAb), is used to deliver CIDE to a target cell, e.g., a cell that expresses a specific protein targeted by the antibody. The antibody portion of the Ab-CIDE can target cells that express the antigen, whereby the antigen-specific Ab-CIDE is typically intracellularly delivered to the target cell by endocytosis. Ab-CIDE comprising an antibody against an antigen not found on the cell surface can result in a less specific intracellular delivery of the CIDE portion into the cell, but the Ab-CIDE can still undergo pinocytosis. The Ab-CIDE and methods of using them described herein advantageously utilize cell surface antibody recognition and / or endocytosis of the Ab-CIDE to deliver the intracellular CIDE portion.

[0114] a. Human antibody In certain embodiments, the antibodies provided herein are human antibodies. 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.", Vol. 5: pp. 368-74 (2001) and Lonberg, "Curr. Opin. Immunol.", Vol. 20: pp. 450-459 (2008).

[0115] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to an antigenic challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces the endogenous immunoglobulin locus, or is present extrachromosomally, or is randomly integrated into the chromosomes of the animal. In such transgenic mice, the exogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Patent No. 5,770,429, which describes HuMab® technology; U.S. Patent No. 7,041,870, which describes K-M MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VelociMouse® technology. The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

[0116] Human antibodies can also be produced by methods based on hybridomas. Human myelomas and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, e.g., Kozbor, "J. Immunol.", Vol. 133, p. 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.", Vol. 147, p. 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., "Proc. Natl. Acad. Sci. USA" Vol. 103, pp. 3557-3562 (2006). Further methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, "Xiandai Mianyixue", Vol. 26, No. 4, pp. 265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (triooma technology) is also described in Vollmers and Brandlein, "Histology and Histopathology", Vol. 20, No. 3: pp. 927-937 (2005) and Vollmers and Brandlein, "Methods and Findings in Experimental and Clinical Pharmacology", Vol. 27, No. 3: pp. 185-91 (2005).

[0117] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Subsequently, such variable domain sequences can be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0118] b. Library-derived antibodies Antibodies for use in Ab-CIDE can be isolated by screening a combinatorial library for antibodies having the desired activity(ies). For example, phage display libraries can be generated and various methods for screening such libraries for antibodies possessing the desired binding characteristics are known in the art. Such methods are reviewed, for example, in Hoogenboom et al., "Methods in Molecular Biology" Vol. 178, pp. 1-37 (edited by O'Brien et al., Human Press, Totowa, NJ, 2001), and are further described below: for example, McCafferty et al., "Nature" Vol. 348, pp. 552-554; Clackson et al., "Nature" Vol. 352, pp. 624-628 (1991); Marks et al., "J. Mol. Biol." Vol. 222, pp. 581-597 (1992); Marks and Bradbury, "Methods in Molecular Biology" Vol. 248, pp. 161-175 (Lo et al., Human Press, Totowa, NJ, 2003); Sidhu et al., "J. Mol. Biol." Vol. 338, No. 2, pp. 299-310 (2004); Lee et al., "J. Mol. Biol." Vol. 340, No. 5, pp. 1073-1093 (2004); Fellouse, "Proc. Natl. Acad. Sci. USA" Vol. 101, No. 34, pp. 12467-12472 (2004); and Lee et al., "J. Immunol. Methods" Vol. 284, Nos. 1-2, pp. 119-132 (2004).

[0119] In certain phage display methods, the repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR), randomly recombined in a phage library, and then antigen-binding phages can be screened as described by Winter et al., "Ann. Rev. Immunol.", Vol. 12, pp. 433 - 455 (1994). Phages typically display antibody fragments either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunization sources provide high-affinity antibodies against immunogens without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) as described by Griffiths et al., "EMBO J", Vol. 12: pp. 725 - 734 (1993) to provide a single source of antibodies against a wide range of non-self and self antigens without any immunization. Finally, naive libraries can be synthetically generated by cloning germline V gene segments from stem cells and achieving rearrangement in vitro using PCR primers containing random sequences to encode highly variable CDR3 regions as described by Hoogenboom and Winter, "J. Mol. Biol.", Vol. 227, pp. 381 - 388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373, and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0120] Antibodies or antibody fragments isolated from a human antibody library are considered herein to be human antibodies or human antibody fragments.

[0121] c. Chimeric and Humanized Antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, Vol. 81, pp. 6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, a chimeric antibody is a "class switch" antibody in which the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0122] In certain embodiments, the 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 non-human antibody. Usually, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or a portion thereof), are derived from a non-human antibody and the FRs (or a portion thereof) are derived from human antibody sequences. A humanized antibody optionally also comprises at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

[0123] For humanized antibodies and methods for their production, reviews are available, for example, in Almagro and Fransson, "Front. Biosci.", 13:1619 - 1633 (2008), and are further described below: for example, 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 complementarity - determining region (CDR) grafting); Padlan, "Mol. Immunol.", 28:489 - 498 (1991) (describing "resurfacing"); 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 a "guided selection approach" to FR shuffling).

[0124] Framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best fit" method (see, e.g., Sims et al., "J. Immunol.", Vol. 151: 2296 (1993)); framework regions derived from consensus sequences of human antibodies of specific subgroups of the light or heavy chain variable regions (see, e.g., Carter et al., "Proc. Natl. Acad. Sci. USA", Vol. 89: 4285 (1992); and Presta et al., "J. Immunol.", Vol. 151: 2623 (1993)); human mature (somatic hypermutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, "Front. Biosci.", Vol. 13: 1619 - 1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., "J. Biol. Chem.", Vol. 272: 10678 - 10684 (1997) and Rosok et al., "J. Biol. Chem.", Vol. 271: 22611 - 22618 (1996)).

[0125] d. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, e.g., bispecific antibodies. As used herein, the term "multispecific antibody" encompasses antibodies that have multiple epitope specificities (i.e., can bind to two or more different epitopes on one biological molecule or can bind to epitopes on two or more different molecules) and include antigen - binding domains.

[0126] In some embodiments, the multispecific antibody is a monoclonal antibody having binding specificity for at least two different antigen-binding sites (such as bispecific antibodies). In some embodiments, the first antigen-binding domain and the second antigen-binding domain of the multispecific antibody may bind two epitopes within one and the same molecule (intramolecular binding). For example, the first antigen-binding domain and the second antigen-binding domain of the multispecific antibody may bind two different epitopes on the same protein molecule. In certain embodiments, the two different epitopes to which the multispecific antibody binds are epitopes that are not simultaneously bound by one monospecific antibody (e.g., a conventional antibody, etc.) or one single variable domain of an immunoglobulin. In some embodiments, the first antigen-binding domain and the second antigen-binding domain of the multispecific antibody may bind epitopes located within two separate molecules (intermolecular binding). For example, the first antigen-binding domain of the multispecific antibody may bind to one epitope on one protein molecule, while the second antigen-binding domain of the multispecific antibody may bind to another epitope on a different protein molecule, thereby crosslinking the two molecules.

[0127] In some embodiments, the antigen-binding domains of a multispecific antibody (such as a bispecific antibody) include two VH / VL units, where the first VH / VL unit binds to a first epitope and the second VH / VL unit binds to a second epitope, and each VH / VL unit includes a heavy-chain variable domain (VH) and a light-chain variable domain (VL). Such multispecific antibodies include, but are not limited to, full-length antibodies, antibodies having two or more VL and VH domains, and antibody fragments (such as Fab, Fv, dsFv, scFv, diabody, bispecific diabody, and triabody that are covalently or non-covalently linked). A VH / VL unit that further includes at least a portion of the heavy-chain variable region and / or at least a portion of the light-chain variable region may also be referred to as an "arm" or a "hemimer" or a "half-antibody". In some embodiments, a hemimer includes a portion of the heavy-chain variable region sufficient to allow for the formation of an intramolecular disulfide bond with a second hemimer. In some embodiments, a hemimer includes a knob mutation or a hole mutation that allows for heterodimerization with a second hemimer or half-antibody, such as a second hemimer or half-antibody that includes a complementary hole mutation or knob mutation. Knob mutations and hole mutations are further discussed below.

[0128] In certain embodiments, the multispecific antibodies provided herein can be bispecific antibodies. As used herein, the term "bispecific antibody" refers to a multispecific antibody that can bind to two different epitopes on one molecule or to epitopes on two different molecules, including antigen-binding domains. Bispecific antibodies are also referred to herein as having "bispecificity" or being "bispecific." Exemplary bispecific antibodies can bind to both a protein and any other antigen. In certain embodiments, one of the binding specificities is for a protein and the other is for CD3. See, e.g., U.S. Patent No. 5,821,337. In certain embodiments, a bispecific antibody can bind to two different epitopes of the same protein molecule. In certain embodiments, a bispecific antibody can bind to two different epitopes for two different protein molecules. Bispecific antibodies can also be used to localize a cytotoxic agent to cells expressing a protein. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0129] Techniques for making multispecific antibodies include, but are not limited to, the recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, "Nature" 305:537 (1983), WO 93 / 08829, and Traunecker et al., "EMBO J." 10:3655 (1991)), and "knob-into-hole" engineering (see, e.g., U.S. Patent No. 5,731,168), WO 2009 / 089004, US 2009 / 0182127, US 2011 / 0287009, Marvin and Zhu, "Acta Pharmacol. Sin." (2005) 26(6):649-658, and Kontermann (2005) "Acta Pharmacol. Sin.", 26:1-9). As used herein, the term "knob-into-hole" or "KnH" technology refers to a technique for directing the pairing of two polypeptides in vitro or in vivo by introducing a protrusion (knob) into one polypeptide and a cavity (hole) into the other polypeptide at the interface where they interact. For example, KnH has been introduced at the Fc:Fc binding interface, CL:CH1 interface, or VH / VL interface of an antibody (see, e.g., US 2011 / 0287009, US 2007 / 0178552, WO 96 / 027011, WO 98 / 050431, Zhu et al., 1997, "Protein Science" 6:781-788, and WO 2012 / 106587). In some embodiments, KnH drives the pairing of two different heavy chains during the production of a multispecific antibody. For example, a multispecific antibody having KnH in its Fc regions may further comprise a single variable domain linked to each Fc region, or may further comprise different heavy chain variable domains that pair with similar or different light chain variable domains. The KnH technology can also be used to pair two different receptor extracellular domains together, or any other polypeptide sequence that contains different target recognition sequences (including, e.g., affibodies, peptibodies, and other Fc fusions).

[0130] As used herein, the term "knob mutation" refers to a mutation that introduces a protrusion (knob) into a polypeptide at an interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a hole mutation.

[0131] As used herein, the term "hole mutation" refers to a mutation that introduces a cavity (hole) into a polypeptide at an interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a knob mutation.

[0132] A "protrusion" refers to at least one amino acid side chain that protrudes from the interface of a first polypeptide and can thus be positioned within a compensatory cavity of an adjacent interface (i.e., the interface of a second polypeptide), thereby stabilizing, for example, a heteromultimer and making heteromultimer formation more favorable than homomultimer formation. A protrusion may be present at the original interface or introduced synthetically (e.g., by modifying the nucleic acid encoding the interface). In some embodiments, the nucleic acid encoding the interface of the first polypeptide is changed to encode a protrusion. To achieve this, the nucleic acid encoding at least one "original" amino acid residue at the interface of the first polypeptide is replaced with a nucleic acid encoding at least one "transferred" amino acid residue having a larger side chain volume than the original amino acid residue. It is understood that more than one original residue and corresponding transferred residues may be present. The side chain volumes of various amino residues are shown, for example, in Table 1 of U.S. Patent Application Publication No. 2011 / 0287009. A mutation that introduces a "protrusion" may be referred to as a "knob mutation".

[0133] In some embodiments, the grafting residue for forming the protrusion is a naturally occurring amino acid residue selected from arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W). In some embodiments, the grafting residue is tryptophan or tyrosine. In some embodiments, the original residues for forming the protrusion, such as alanine, asparagine, aspartic acid, glycine, serine, threonine, or valine, have a small side chain volume.

[0134] A "cavity" refers to at least one amino acid side chain that is recessed from the interface of the second polypeptide and thus accommodates a corresponding protrusion on the interface of the adjacent first polypeptide. The cavity may be present in the original interface or introduced synthetically (e.g., by modifying the nucleic acid encoding the interface). In some embodiments, the nucleic acid encoding the interface of the second polypeptide is altered to encode a cavity. To achieve this, the nucleic acid encoding at least one "original" amino acid residue of the interface of the second polypeptide is replaced with DNA encoding at least one "grafting" amino acid residue having a smaller side chain volume than the original amino acid residue. It is understood that more than one original residue and corresponding grafting residue may be present. In some embodiments, the grafting residue for forming the cavity is a naturally occurring amino acid residue selected from alanine (A), serine (S), threonine (T), and valine (V). In some embodiments, the grafting residue is serine, alanine, or threonine. In some embodiments, the original residues for forming the cavity, such as tyrosine, arginine, phenylalanine, or tryptophan, have a large side chain volume. The mutation that introduces a "cavity" may be referred to as a "hole mutation".

[0135] The protrusion is "positionable" within the cavity, which means that the protrusion and the spatial position of the cavity at the interface of the first polypeptide and the second polypeptide, and the size of the protrusion and the cavity, respectively, are such that the protrusion can be positioned within the cavity without significantly disturbing the normal association of the first polypeptide and the second polypeptide at the interface. Protrusions such as Tyr, Phe, and Trp typically do not extend perpendicular to the axis of the interface and do not have a preferred conformation, and the alignment of the protrusion with the corresponding cavity may in some cases depend on modeling the protrusion / cavity pair based on a three-dimensional structure such as that obtained by X-ray crystallography or nuclear magnetic resonance (NMR). This can be achieved using techniques widely accepted in the art.

[0136] In some embodiments, the knob mutation in the IgG1 constant region is T366W (EU numbering). In some embodiments, the hole mutation in the IgG1 constant region comprises one or more mutations selected from T366S, L368A, and Y407V (EU numbering). In some embodiments, the hole mutation in the IgG1 constant region comprises T366S, L368A, and Y407V (EU numbering).

[0137] In some embodiments, the knob mutation in the IgG4 constant region is T366W (EU numbering). In some embodiments, the hole mutation in the IgG4 constant region comprises one or more mutations selected from T366S, L368A, and Y407V (EU numbering). In some embodiments, the hole mutation in the IgG4 constant region comprises T366S, L368A, and Y407V (EU numbering).

[0138] Multispecific antibodies can be made by engineering the electrostatic steering effect to create antibody Fc-heterodimer molecules (WO 2009 / 089004 A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980, and Brennan et al., "Science," 229:81 (1985)); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., "J. Immunol.," 148(5):1547-1553 (1992)); using the "diabody" technology to make bispecific antibody fragments (see, e.g., Hollinger et al., "Proc. Natl. Acad. Sci. USA," 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and can be made, for example, as described in Tutt et al., "J. Immunol." 147:60 (1991).

[0139] Engineered antibodies having three or more functional antigen-binding sites, including "octopus antibodies" or "dual variable domain immunoglobulins" (DVDs), are also included herein (see, e.g., U.S. Patent Application Publication No. 2006 / 0025576 A1, and Wu et al., "Nature Biotechnology" (2007)). Antibodies or fragments herein also include "Dual Acting FAb" or "DAF" that include antigen-binding sites that bind a target protein as well as a different, separate antigen (see, e.g., US2008 / 0069820).

[0140] e. Antibody fragments In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds. (Springer-Verlag, New York), pp. 269-315 (1994); also see U.S. Pat. Nos. 5,571,894 and 5,587,458, and International Publication No. WO93 / 16185. For a description of Fab and F(ab’)2 fragments that include salvage receptor binding epitope residues and have extended in vivo half-lives, see U.S. Pat. No. 5,869,046.

[0141] A diabody is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. See, e.g., European Patent No. 404,097, International Publication No. WO1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003), and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Tri- and tetra-specific antibodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0142] A single domain antibody is an antibody fragment that includes 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 embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 B1).

[0143] Antibody fragments can be made by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phage) as described herein.

[0144] f. Antibody variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of residues within the amino acid sequence of the antibody. Deletions, insertions, and substitutions may be combined arbitrarily to arrive at the final construct, provided that the final construct possesses the desired properties, such as antigen binding.

[0145] g. Recombinant methods and compositions Antibodies may be produced using, for example, the recombinant methods and compositions described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an antibody described herein is provided. Such a nucleic acid can encode an amino acid sequence comprising the VL of the antibody and / or an amino acid sequence comprising the VH (e.g., the light and / or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In such an embodiment, the host cell comprises (e.g., is transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphocyte cell (e.g., Y0, NS0, Sp20 cells). In one embodiment, a method of making an antibody is provided, the method comprising culturing a host cell comprising a nucleic acid encoding the antibody described above under conditions suitable for expression of the antibody and optionally recovering the antibody from the host cell (or the host cell culture medium).

[0146] With regard to the recombinant production of antibodies, for example, a nucleic acid encoding the antibody described above is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such a nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody).

[0147] Host cells suitable for cloning or expressing vectors encoding antibodies include the prokaryotic and eukaryotic cells described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and effector functions are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (Charlton, "Methods in Molecular Biology", 248 (describing the expression of antibody fragments in E. coli, also see B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254). After expression, the antibody can be isolated from the bacterial cell paste in the soluble fraction and further purified.

[0148] In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are suitable hosts for cloning or expressing vectors encoding antibodies, including fungal and yeast strains in which the glycosylation pathway has been "humanized" and produce antibodies with a partially or fully human glycosylation pattern. See Gerngross "Nat. Biotech." 22:1409-1414 (2004), and Li et al. "Nat. Biotech." 24:210-215 (2006).

[0149] Host cells suitable for the expression of glycosylated antibodies can also be obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous baculovirus strains have been identified and can be used in combination with insect cells, particularly for the transfection of Spodoptera frugiperda cells.

[0150] Plant cell cultures can also be used as hosts. See, for example, U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429, which describe the PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0151] Vertebrate cells may also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Non-limiting examples of useful mammalian host cell lines include the simian kidney CV1 cell line transformed by SV40 (COS-7); human fetal kidney cell lines (e.g., 293 or 293 cells described in Graham et al., "J. Gen Virol.", 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells described in Mather, "Biol. Reprod.", 23:243-251 (1980)); simian kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); dog 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, e.g., Mather et al., "Annals N.Y. Acad. Sci" 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., "Proc. Natl. Acad. Sci. USA", Vol. 77:4216 (1980)), 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 and Wu, "Methods in Molecular Biology", 248 (B.K.C. Lo, ed., Human APress, Totowa, N.J.) 255-268 (2003).

[0152] Here, regarding antibody affinity, in an embodiment, the antibody binds to one or more tumor - associated antigens or cell - surface receptors selected from (1) to (53):

[0153] (1) BMPR1B (bone morphogenetic protein receptor type IB, Genbank accession number NM_001203) ten Dijke, P. et al., "Science" 264(5155):101 - 104 (1994), "Oncogene" 14(11):1377 - 1382 (1997), International Publication No. WO 2004 / 063362 (Claim 2), International Publication No. WO 2003 / 042661 (Claim 12), US Patent Application Publication No. 2003 / 134790 A1 (pages 38 - 39), International Publication No. WO 2002 / 102235 (Claim 13, page 296), International Publication No. WO 2003 / 055443 (pages 91 - 92), International Publication No. WO 2002 / 99122 (Example 2, pages 528 - 530), International Publication No. WO 2003 / 029421 (Claim 6), International Publication No. WO 2003 / 024392 (Claim 2, Figure 112), International Publication No. WO 2002 / 98358 (Claim 1, page 183), WO2002 / 54940 (pages 100 - 101), International Publication No. WO 2002 / 59377 (pages 349 - 350), International Publication No. WO 2002 / 30268 (Claim 27, page 376), International Publication No. WO 2001 / 48204 (Example, Figure 4) NP_001194 bone morphogenetic protein receptor, type IB / pid = NP_001194.1 - Cross - reference: MIM:603248; NP_001194.1; AY065994

[0154] (2) E16 (LAT1, SLC7A5, Genbank accession number NM_003486) "Biochem. Biophys. Res. Commun." 255(2), pp. 283 - 288 (1999), "Nature" 395(6699): pp. 288 - 291 (1998), Gaugitsch, H.W. et al., (1992) "J. Biol. Chem." 267(16): pp. 11267 - 11273; International Publication No. 2004048938 (Example 2); International Publication No. 2004032842 (Example IV); International Publication No. 2003042661 (Claim 12); International Publication No. 2003016475 (Claim 1); International Publication No. 200278524 (Example 2); International Publication No. 200299074 (Claims 19; pp. 127 - 129); International Publication No. 200286443 (Claims 27; pp. 222, 393); International Publication No. 2003003906 (Claim 10; pp. 293); International Publication No. 200264798 (Claim 33; pp. 93 - 95); International Publication No. 200014228 (Claim 5; pp. 133 - 136); U.S. Patent Application Publication No. 2003224454 (Figure 3); International Publication No. 2003025138 (Claim 12; p. 150); NP_003477 Solute Carrier Family 7 (cationic amino acid transporter, y+ system), member 5 / pid=NP_003477.3 - Homo sapiens Cross - reference: MIM:600182; NP_003477.3; NM_015923; NM_003486_1

[0155] (3) STEAP1 (prostate six - transmembrane epithelial antigen, Genbank accession number NM_012449) "Cancer Res." 61(15), pp. 5857 - 5860 (2001), Hubert, R. S. et al. (1999) "Proc. Natl. Acad. Sci. U.S.A." 96(25): 14523 - 14528; International Publication No. 2004065577 (Claim 6); International Publication No. 2004027049 (Figure 1L); European Patent No. 1394274 (Example 11); International Publication No. 2004016225 (Claim 2); International Publication No. 2003042661 (Claim 12); U.S. Patent Application Publication No. 2003157089 (Example 5); U.S. Patent Application Publication No. 2003185830 (Example 5); U.S. Patent Application Publication No. 2003064397 (Figure 2); International Publication No. 200289747 (Examples 5; pp. 618 - 619); International Publication No. 2003022995 (Example 9; Figure 13A, Example 53; p. 173, Example 2; Figure 2A); NP_036581 Prostate 6 - transmembrane epithelial antigen Cross - reference: MIM:604415; NP_036581.1; NM_012449_1

[0156] (4)0772P (CA125, MUC16, Genbank Accession Number AF361486) "J. Biol. Chem." 276(29), pp. 27371 - 27375 (2001)); International Publication No. 2004045553 (Claim 14); International Publication No. 200292836 (Claim 6; Figure 12); International Publication No. 200283866 (Claim 15; pp. 116 - 121); U.S. Patent Application Publication No. 2003124140 (Example 16); U.S. Patent Application Publication No. 798959. Cross - reference: GI:34501467; AAK74120.3; AF361486_1

[0157] (5)MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession number NM_005823) Yamaguchi, N. et al., "Biol. Chem.", 269(2), pp. 805 - 808 (1994), "Proc. Natl. Acad. Sci. U.S.A.", 96(20): 11531 - 11536 (1999), "Proc. Natl. Acad. Sci. U.S.A.", 93(1): 136 - 140 (1996), "J. Biol. Chem.", 270(37): 21984 - 21990 (1995)); International Publication No. 2003 / 101283 (Claim 14); (International Publication No. 2002 / 102235 (Claim 13; pp. 287 - 288); International Publication No. 2002 / 101075 (Claim 4; pp. 308 - 309); International Publication No. 2002 / 71928 (pp. 320 - 321); International Publication No. 94 / 10312 (pp. 52 - 57); Cross - reference: MIM:601051; NP_005814.2; NM_005823_1

[0158] (6) Napi2b (Napi3b, NAPI - 3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium - dependent phosphate transporter 3b, Genbank accession number NM_006424) J. Biol. Chem. 277(22): 19665 - 19672 (2002), "Genomics", 62(2): 281 - 284 (1999), Feild, J.A. et al. (1999) "Biochem. Biophys. Res. Commun.", 258(3): 578 - 582); International Publication No. 2004 / 022778 (Claim 2); European Patent No. 1394274 (Example 11); International Publication No. 2002 / 102235 (Claim 13; p. 326); European Patent No. 875569 (Claim 1; pp. 17 - 19); International Publication No. 2001 / 57188 (Claim 20; p. 329); International Publication No. 2004 / 032842 (Example IV); International Publication No. 2001 / 75177 (Claim 24; pp. 139 - 140); Cross - reference: MIM:604217; NP_006415.1; NM_006424_1

[0159] (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, Semadomain, 7 thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM), and short cytoplasmic domain, (Semaphorin) 5B, Genbank accession number AB040878) Nagase T. et al. (2000) "DNA Res." 7(2): 143-150; International Publication No. WO 2004 / 000997 (Claim 1), International Publication No. WO 2003 / 003984 (Claim 1), International Publication No. WO 2002 / 06339 (Claim 1, page 50), International Publication No. WO 2001 / 088133 (Claim 1, pages 41-43, 48-58), International Publication No. WO 2003 / 054152 (Claim 20), International Publication No. WO 2003 / 101400 (Claim 11), Deposit: Q9P283; EMBL; AB040878; BAA95969.1.Genew; HGNC: 10737;

[0160] (8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628); Ross et al. (2002) "Cancer Res." 62: 2546-2553; US Patent Application Publication No. 2003 / 129192 (Claim 2); US Patent Application Publication No. 2004 / 044180 (Claim 12); US Patent Application Publication No. 2004 / 044179 (Claim 11); US Patent Application Publication No. 2003 / 096961 (Claim 11); US Patent Application Publication No. 2003 / 232056 (Example 5); International Publication No. WO 2003 / 105758 (Claim 12); US Patent Application Publication No. 2003 / 206918 (Example 5); European Patent EP1347046 (Claim 1); International Publication No. WO 2003 / 025148 (Claim 20); Cross-reference: GI:37182378; AAQ88991.1; AY358628_1

[0161] (9) ETBR (Endothelin B receptor, Genbank accession number AY275463); Nakamuta M et al., "Biochem. Biophys. Res. Commun.", 177, pp. 34 - 39, 1991; Ogawa Y. et al., "Biochem. Biophys. Res. Commun.", 178, pp. 248 - 255, 1991; Arai H. et al., "Jpn. Circ. J.", 56, pp. 1303 - 1307, 1992; Arai H. et al., "J. Biol. Chem.", 268, pp. 3463 - 3470, 1993; Sakamoto A., Yanagisawa M. et al., "Biochem. Biophys. Res. Commun.", 178, pp. 656 - 663, 1991; Elshourbagy N.A. et al., "J. Biol. Chem.", 268, pp. 3873 - 3879, 1993; Haendler B., et al., "J. Cardiovasc. Pharmacol.", 20, s1 - S4, 1992; Tsutsumi M. et al., "Gene", 228, pp. 43 - 49, 1999; Strausberg R.L. et al., "Proc. Natl. Acad. Sci. U.S.A.", 99, pp. 16899 - 16903, 2002; Bourgeois C. et al., "J. Clin. Endocrinol. Metab.", 82, pp. 3116 - 3123, 1997; Okamoto Y. et al., "Biol. Chem.", 272, pp. 21589 - 21596, 1997; Verheij J.B. et al., "Am. J. Med. Genet.", 108, pp. 223 - 225, 2002; Hofstra R.M.W. et al., "Eur. J. Hum. Genet.", 5, pp. 180 - 185, 1997; Puffenberger E.G. et al., "Cell", 79, pp. 1257 - 1266, 1994; Attie T. et al., "Hum. Mol. Genet.", 4, pp. 2407 - 2409, 1995; Auricchio A. et al., "Hum. Mol. Genet.", 5: pp. 351 - 354, 1996; Amiel J. et al., "Hum. Mol. Genet.", 5, pp. 355 - 357, 1996; Hofstra R.M.W. et al., "Nat. Genet.", 12, pp. 445 - 447, 1996; Svensson P.J. et al., "Hum. Genet.", 103, pp. 145 - 148, 1998; Fuchs S. et al., "Mol. Med.", 7, pp. 115 - 124, 2001; Pingault V.ら(2002) "Hum. Genet." 111, pp. 198 - 206; International Publication No. 2004045516 (Claim 1); International Publication No. 2004048938 (Example 2); International Publication No. 2004040000 (Claim 151); International Publication No. 2003087768 (Claim 1); International Publication No. 2003016475 (Claim 1); International Publication No. 2003016475 (Claim 1); International Publication No. 200261087 (Figure 1); International Publication No. 2003016494 (Figure 6); International Publication No. 2003025138 (Claims 12; p. 144); International Publication No. 200198351 (Claims 1; pp. 124 - 125); European Patent No. 522868 (Claim 8; Figure 2); International Publication No. 200177172 (Claims 1; pp. 297 - 299); US Patent Application Publication No. 2003109676; US Patent No. 6518404 (Figure 3); US Patent No. 5773223 (Claim 1a; Columns 31 - 34); International Publication No. 2004001004;.

[0162] (10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number M_017763); International Publication No. 2003104275 (Claim 1); International Publication No. 2004046342 (Example 2); International Publication No. 2003042661 (Claim 12); International Publication No. 2003083074 (Claim 14, p. 61); International Publication No. 2003018621 (Claim 1); International Publication No. 2003024392 (Claim 2, Figure 93); International Publication No. 200166689 (Example 6); Cross - reference: LocusID: 54894; NP_060233.2; NM_017763_1

[0163] (11) STEAP2 (HGNC_8639, IPCA - 1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer - related gene 1, prostate cancer - related protein 1, six - transmembrane epithelial antigen of the prostate 2, six - transmembrane prostate protein, Genbank accession number AF455138) "Lab. Invest." 82(11): 1573-1582 (2002); International Publication No. WO 2003 / 087306, US Patent Application Publication No. 2003 / 064397 (Claim 1, Figure 1); International Publication No. WO 2002 / 072596 (Claim 13, pages 54-55); International Publication No. WO 2001 / 072962 (Claim 1, Figure 4B); International Publication No. WO 2003 / 104270 (Claim 11); International Publication No. WO 2003 / 104270 (Claim 16); US Patent Application Publication No. 2004 / 005598 (Claim 22); International Publication No. WO 2003 / 042661 (Claim 12); US Patent Application Publication No. 2003 / 060612 (Claim 12, Figure 10); International Publication No. WO 2002 / 026822 (Claim 23, Figure 2); International Publication No. WO 2002 / 016429 (Claim 12, Figure 10); Cross References: GI: 22655488; AAN04080.1; AF455138_1

[0164] (12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, Transient Receptor Potential Cation Channel, Subfamily M, Member 4, Genbank Accession No. NM_017636) Xu, X.Z. et al. "Proc. Natl. Acad. Sci. U.S.A." 98(19): 10692-10697 (2001); "Cell" 109(3): 397-407 (2002); "J. Biol. Chem." 278(33): 30813-30820 (2003)); US Patent Application Publication No. 2003 / 143557 (Claim 4); International Publication No. WO 2000 / 040614 (Claim 14, pages 100-103); International Publication No. WO 2002 / 010382 (Claim 1, Figure 9A); International Publication No. WO 2003 / 042661 (Claim 12); International Publication No. WO 2002 / 030268 (Claim 27, page 391); US Patent Application Publication No. 2003 / 219806 (Claim 4); International Publication No. WO 2001 / 062794 (Claim 14, Figures 1A-D); Cross References: MIM: 606936; NP_060106.2; NM_017636_1

[0165] (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, Teratocarcinoma-derived growth factor, Genbank accession number NP_003203 or NM_003212) Ciccodicola, A. et al., "EMBO J." 8(7): 1987-1991 (1989), "Am. J. Hum. Genet." 49(3): 555-565 (1991)); US Patent Application Publication No. 2003224411 (Claim 1); International Publication No. 2003083041 (Example 1); International Publication No. 2003034984 (Claim 12); International Publication No. 200288170 (Claim 2; pp. 52-53); International Publication No. 2003024392 (Claim 2; Figure 58); International Publication No. 200216413 (Claim 1; pp. 94-95, 105); International Publication No. 200222808 (Claim 2; Figure 1); US Patent No. 5854399 (Example 2; Columns 17-18); US Patent No. 5792616 (Figure 2); Cross-reference: MIM: 187395; NP_003203.1; NM_003212_1

[0166] (14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d / Epstein-Barr virus receptor) or Hs.73792, Genbank accession number M26004) Fujisaku et al. (1989) "J. Biol. Chem." 264(4): 2118 - 2125; Weis J.J. et al. "J. Exp. Med." 167, 1047 - 1066, 1988; Moore M. et al. "Proc. Natl. Acad. Sci. U.S.A." 84, 9194 - 9198, 1987; Barel M. et al. "Mol. Immunol." 35, 1025 - 1031, 1998; Weis J.J. et al. "Proc. Natl. Acad. Sci. U.S.A." 83, 5639 - 5643, 1986; Sinha S.K. et al. (1993) J. Immunol. 150, 5311 - 5320; International Publication No. 2004 / 045520 (Example 4); U.S. Patent Application Publication No. 2004 / 005538 (Example 1); International Publication No. 2003 / 062401 (Claim 9); International Publication No. 2004 / 045520 (Example 4); International Publication No. 91 / 02536 (Figs. 9.1 - 9.9); International Publication No. 2004 / 020595 (Claim 1); Deposit: P20023; Q13866; Q14212; EMBL; M26004; AAA35786.1.

[0167] (15) CD79b (CD79B, CD79β, IGb (immunoglobulin - related β), B29, Genbank Accession No. NM_000626 or 11038674) 「Proc. Natl. Acad. Sci. U.S.A.」(2003) 100(7): 4126 - 4131,「Blood」(2002) 100(9): 3068 - 3076, Muller et al. (1992)「Eur. J. Immunol.」22(6): 1621 - 1625; WO 2004 / 016225 (Claim 2, Fig. 140); WO 2003 / 087768, US 2004 / 101874 (Claim 1, page 102); WO 2003 / 062401 (Claim 9); WO 2002 / 78524 (Example 2); US 2002 / 150573 (Claim 5, page 15); US Patent No. 5,644,033; WO 2003 / 048202 (Claim 1, pages 306 and 309); WO 99 / 558658, US Patent No. 6,534,482 (Claim 13, Figs. 17A / B); WO 2000 / 55351 (Claim 11, pages 1145 - 1146); Cross - Reference: MIM: 147245; NP_000617.1; NM_000626_1

[0168] (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain including phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession numbers NM_030764, AY358130) 「Genome Res.」13(10): 2265 - 2270 (2003),「Immunogenetics」54(2): 87 - 95 (2002),「Blood」99(8): 2662 - 2669 (2002),「Proc. Natl. Acad. Sci. U.S.A.」98(17): 9772 - 9777 (2001), Xu, M. J. et al. (2001)「Biochem. Biophys. Res. Commun.」280(3): 768 - 775; WO 2004 / 016225 (Claim 2); WO 2003 / 077836; WO 2001 / 38490 (Claim 5; Figs. 18D - 1 - 18D - 2); WO 2003 / 097803 (Claim 12); WO 2003 / 089624 (Claim 25); Cross-reference: MIM:606509; NP_110391.2; NM_030764_1

[0169] (17) HER2 (ErbB2, Genbank accession number M11730) Coussens L. et al., "Science" (1985), 230(4730): 1132 - 1139; Yamamoto T. et al., "Nature" 319, 230 - 234, 1986; Semba K. et al., "Proc. Natl. Acad. Sci. U.S.A." 82, 6497 - 6501, 1985; Swiercz J.M. et al., "J. Cell Biol." 165, 869 - 880, 2004; Kuhns J.J. et al., "J. Biol. Chem." 274, 36422 - 36427, 1999; Cho H.-S. et al., "Nature" 421, 756 - 760, 2003; Ehsani A. et al. (1993), "Genomics" 15, 426 - 429; International Publication No. WO 2004 / 048938 (Example 2); International Publication No. WO 2004 / 027049 (Figure 1I); International Publication No. WO 2004 / 009622; International Publication No. WO 2003 / 081210; International Publication No. WO 2003 / 089904 (Claim 9); International Publication No. WO 2003 / 016475 (Claim 1); U.S. Patent Application Publication No. 2003 / 118592; International Publication No. WO 2003 / 008537 (Claim 1); International Publication No. WO 2003 / 055439 (Claim 29; Figures 1A - B); International Publication No. WO 2003 / 025228 (Claim 37; Figure 5C); International Publication No. WO 2002 / 22636 (Example 13; pp. 95 - 107); International Publication No. WO 2002 / 12341 (Claim 68; Figure 7); International Publication No. WO 2002 / 13847 (pp. 71 - 74); International Publication No. WO 2002 / 14503 (pp. 114 - 117); International Publication No. WO 2001 / 53463 (Claim 2; pp. 41 - 46); International Publication No. WO 2001 / 41787 (p. 15); International Publication No. WO 2000 / 44899 (Claim 52; Figure 7); International Publication No. WO 2000 / 20579 (Claim 3; Figure 2); U.S. Patent No. 5,869,445 (Claim 3; Columns 31 - 38); International Publication No. WO 96 / 30514 (Claim 2; pp. 56 - 61); European Patent No. 1,439,393 (Claim 7); International Publication No. WO 2004 / 043361 (Claim 7); International Publication No. WO 2004 / 022709; International Publication No. WO 2001 / 00244 (Example 3; Figure 4); Deposit: P04626; EMBL; M11767; AAA35808.1.EMBL; M11761; AAA35808.1.

[0170] (18) NCA (CEACAM6, Genbank accession number M18728); Barnett T. et al., "Genomics" 3, 59-66 (1988); Tawaragi Y. et al., "Biochem. Biophys. Res. Commun." 150, 89-96 (1988); Strausberg R.L. et al., "Proc. Natl. Acad. Sci. U.S.A." 99: 16899-16903 (2002); International Publication No. 2004063709; European Patent No. 1439393 (Claim 7); International Publication No. 2004044178 (Example 4); International Publication No. 2004031238; International Publication No. 2003042661 (Claim 12); International Publication No. 200278524 (Example 2); International Publication No. 200286443 (Claim 27; page 427); International Publication No. 200260317 (Claim 2); Deposit: P40199; Q14920; EMBL; M29541; AAA59915.1.EMBL; M18728;

[0171] (19) MDP (DPEP1, Genbank accession number BC017023) "Proc. Natl. Acad. Sci. U.S.A." 99(26): 16899-16903 (2002)); International Publication No. 2003016475 (Claim 1); International Publication No. 200264798 (Claim 33; pages 85-87); Japanese Patent Application Publication No. 05003790 (Figs. 6-8); International Publication No. 9946284 (Fig. 9); Cross-reference: MIM:179780; AAH17023.1; BC017023_1

[0172] (20) IL20Rα (IL20Ra, ZCYTOR7, Genbank accession number AF184971); Clark H.F. et al., "Genome Res.", 13, pp. 2265 - 2270, 2003; Mungall A.J. et al., "Nature", 425, pp. 805 - 811, 2003; Blumberg H. et al., "Cell", 104, pp. 9 - 19, 2001; Dumoutier L. et al., "J. Immunol.", 167, pp. 3545 - 3549, 2001; Parrish - Novak J. et al., "J. Biol. Chem.", 277, pp. 47517 - 47523, 2002; Pletnev S. et al. (2003), "Biochemistry", 42:12617 - 12624; Sheikh F. et al. (2004), "J. Immunol.", 172, pp. 2006 - 2010; European Patent No. 1394274 (Example 11); US Patent Application Publication No. 2004005320 (Example 5); International Publication No. 2003029262 (pp. 74 - 75); International Publication No. 2003002717 (Claim 2; p. 63); International Publication No. 200222153 (pp. 45 - 47); US Patent Application Publication No. 2002042366 (pp. 20 - 21); International Publication No. 200146261 (pp. 57 - 59); International Publication No. 200146232 (pp. 63 - 65); International Publication No. 9837193 (Claim 1; pp. 55 - 59); Deposit: Q9UHF4; Q6UWA9; Q96SH8; EMBL; AF184971; AAF01320.1.

[0173] (21) Brevican (BCAN, BEHAB, Genbank Accession Number AF229053) Gary S.C. et al., "Gene" 256, pp. 139-147, 2000; Clark H.F. et al., "Genome Res." 13, pp. 2265-2270, 2003; Strausberg R.L. et al., "Proc. Natl. Acad. Sci. U.S.A." 99, pp. 16899-16903, 2002; U.S. Patent Application Publication No. 2003186372 (Claim 11); U.S. Patent Application Publication No. 2003186373 (Claim 11); U.S. Patent Application Publication No. 2003119131 (Claim 1; Fig. 52); U.S. Patent Application Publication No. 2003119122 (Claim 1; Fig. 52); U.S. Patent Application Publication No. 2003119126 (Claim 1); U.S. Patent Application Publication No. 2003119121 (Claim 1; Fig. 52); U.S. Patent Application Publication No. 2003119129 (Claim 1); U.S. Patent Application Publication No. 2003119130 (Claim 1); U.S. Patent Application Publication No. 2003119128 (Claim 1; Fig. 52); U.S. Patent Application Publication No. 2003119125 (Claim 1); International Publication No. 2003016475 (Claim 1); International Publication No. 200202634 (Claim 1);

[0174] (22) EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5, Genbank Accession No. NM_004442) Chan, J. and Watt, V.M., "Oncogene" 6(6), pp. 1057-1061 (1991), "Oncogene" 10(5): 897-905 (1995), "Annu. Rev. Neurosci." 21: 309-345 (1998), "Int. Rev. Cytol. 196: 177-244 (2000)); International Publication No. 2003042661 (Claim 12); International Publication No. 200053216 (Claim 1, page 41); International Publication No. 2004065576 (Claim 1); International Publication No. 2004020583 (Claim 9); International Publication No. 2003004529 (pages 128-132); International Publication No. 200053216 (Claim 1, page 42); Cross-reference: MIM: 600997; NP_004433.2; NM_004442_1

[0175] (23)ASLG659 (B7h, Genbank accession number AX092328) U.S. Patent Application Publication No. 20040101899 (Claim 2); International Publication No. 2003104399 (Claim 11); International Publication No. 2004000221 (Figure 3); U.S. Patent Application Publication No. 2003165504 (Claim 1); U.S. Patent Application Publication No. 2003124140 (Example 2); U.S. Patent Application Publication No. 2003065143 (Figure 60); International Publication No. 2002102235 (Claims 13; 299); U.S. Patent Application Publication No. 2003091580 (Example 2); International Publication No. 200210187 (Claims 6; Figure 10); International Publication No. 200194641 (Claims 12; Figure 7b); International Publication No. 200202624 (Claims 13; Figures 1A - 1B); U.S. Patent Application Publication No. 2002034749 (Claims 54; pages 45 - 46); International Publication No. 200206317 (Example 2; pages 320 - 321, Claims 34; pages 321 - 322); International Publication No. 200271928 (pages 468 - 469); International Publication No. 200202587 (Example 1; Figure 1); International Publication No. 200140269 (Example 3; pages 190 - 192); International Publication No. 200036107 (Example 2; pages 205 - 207); International Publication No. 2004053079 (Claim 12); International Publication No. 2003004989 (Claim 1); International Publication No. 200271928 (pages 233 - 234, 452 - 453); International Publication No. 0116318;

[0176] (24)PSCA (Prostate Stem Cell Antigen Precursor, Genbank accession number AJ297436) Reiter R.E. et al., "Proc. Natl. Acad. Sci. U.S.A.", 95, pp. 1735 - 1740, 1998; Gu Z. et al., "Oncogene", 19, pp. 1288 - 1296, 2000; "Biochem. Biophys. Res. Commun." (2000) 275(3): 783 - 788; International Publication No. 2004022709; European Patent No. 1394274 (Example 11); U.S. Patent Application Publication No. 2004018553 (Claim 17); International Publication No. 2003008537 (Claim 1); International Publication No. 200281646 (Claim 1; page 164); International Publication No. 2003003906 (Claim 10; page 288); International Publication No. 200140309 (Example 1; Figure 17); U.S. Patent Application Publication No. 2001055751 (Example 1; Figure 1b); International Publication No. 200032752 (Claim 18; Figure 1); International Publication No. 9851805 (Claim 17; page 97); International Publication No. 9851824 (Claim 10; page 94); International Publication No. 9840403 (Claim 2; Figure 1B); Deposit: O43653; EMBL; AF043498; AAC39607.1.

[0177] (25) GEDA (Genbank accession number AY260763); AAP14954 lipoma HMGIC fusion - partner - like protein / pid = AAP 14954.1 - Homo sapiens Species Homo sapiens (human) International Publication No. 2003054152 (Claim 20); International Publication No. 2003000842 (Claim 1); International Publication No. 2003023013 (Example 3, Claim 20); US2003194704 (Claim 45); Cross - reference: GI:30102449; AAP14954.1; AY260763_1

[0178] (26) BAFF - R (B - cell activating factor receptor, BLyS receptor 3, BR3, Genbank accession number AF116456); BAFF receptor / pid = NP_443177.1 - Homo sapiens Thompson, J. S. et al., "Science" 293(5537), pp. 2108 - 2111 (2001); International Publication No. WO 2004 / 058309; International Publication No. WO 2004 / 011611; International Publication No. WO 2003 / 045422 (Examples; pp. 32 - 33); International Publication No. WO 2003 / 014294 (Claim 35; Figure 6B); International Publication No. WO 2003 / 035846 (Claim 70; pp. 615 - 616); International Publication No. WO 2002 / 94852 (Columns 136 - 137); International Publication No. WO 2002 / 38766 (Claim 3; p. 133); International Publication No. WO 2002 / 24909 (Example 3; Figure 3); Cross - References: MIM:606269; NP_443177.1; NM_052945_1; AF132600

[0179] (27) CD22 (B - cell receptor CD22 - B isoform, BL - CAM, Lyb - 8, Lyb8, SIGLEC - 2, FLJ22814, Genbank accession number AK026467); Wilson et al. (1991) "J. Exp. Med." 173: pp. 137 - 146; International Publication No. WO 2003 / 072036 (Claim 1; Figure 1); Cross - References: MIM:107266; NP_001762.1; NM_001771_1

[0180] (28) CD79a (CD79A, CD79α, immunoglobulin - associated alpha, which interacts covalently with Ig beta (CD79B) and forms a complex on the surface with IgM molecules, and transmits signals involved in B - cell differentiation), pI: 4.84, MW: 25028 TM: 2 [P] Gene chromosome: 19q13.2, Genbank accession number NP_001774.10) WO 2003 / 088808, US 2003 / 0228319; WO 2003 / 062401 (claim 9); US 2002 / 0150573 (claims 4, 13-14); WO 99 / 58658 (claim 13, Fig. 16); WO 92 / 07574 (Fig. 1); US 5,644,033; Ha et al. (1992) J. Immunol. 148(5):1526-1531; Mueller et al. (1992) Eur. J. Biochem. 22:1621-1625; Hashimoto et al. (1994) Immunogenetics 40(4):287-295; Preud’homme et al. (1992) Clin. Exp. Immunol. 90(1):141-146; Yu et al. (1992) J. Immunol. 148(2)633-637; Sakaguchi et al. (1988) EMBO J. 7(11):3457-3464;

[0181] (29) CXCR5 (Burkitt lymphoma receptor 1, a G protein-coupled receptor activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense and plays a role in HIV-2 infection and perhaps the development of AIDS, lymphoma, myeloma, and leukemia); 372 aa, pI: 8.54 MW: 41959 TM: 7 [P] Gene Chromosome: 11q23.3, Genbank accession number NP_001707.1) WO 2004 / 040000; WO 2004 / 015426; US 2003 / 105292 (Example 2); US 6555339 (Example 2); WO 2002 / 61087 (Figure 1); WO 2001 / 57188 (Claims 20, page 269); WO 2001 / 72830 (pages 12 - 13); WO 2000 / 22129 (Example 1, pages 152 - 153, Example 2, pages 254 - 256); WO 99 / 28468 (Claim 1, page 38); US 2003 / 5440021 (Example 2, columns 49 - 52); WO 94 / 28931 (pages 56 - 58); WO 92 / 17497 (Claim 7, Figure 5); Dobner et al. (1992) Eur. J. Immunol. 22: 2795 - 2799; Barella et al. (1995) Biochem. J. 309: 773 - 779;

[0182] (30) HLA - DOB (beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes); 273 aa, pI: 6.56 MW: 30820 TM: 1 [P] Gene Chromosome: 6p21.3, Genbank accession number NP_002111.1) Tonnelle et al. (1985) "EMBO J." 4(11): 2839-2847; Jonsson et al. (1989) "Immunogenetics" 29(6): 411-413; Beck et al. (1992) "J. Mol. Biol." 228: 433-441; Strausberg et al. (2002) "Proc. Natl. Acad. Sci USA" 99: 16899-16903; Servenius et al. (1987) "J. Biol. Chem." 262: 8759-8766; Beck et al. (1996) "J. Mol. Biol." 255: 1-13; Naruse et al. (2002) "Tissue Antigens" 59: 512-519; WO 9958658 (claim 13, Fig. 15); US Patent No. 6153408 (cols. 35-38); US Patent No. 5976551 (cols. 168-170); US Patent No. 6011146 (cols. 145-146); Kasahara et al. (1989) "Immunogenetics" 30(1): 66-68; Larhammar et al. (1985) "J. Biol. Chem." 260(26): 14111-14119;

[0183] (31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, may be involved in synaptic transmission and neurogenesis, and deficiency may contribute to the pathophysiology of idiopathic detrusor instability); 422 aa), pI: 7.63, MW: 47206 TM: 1 [P] Gene Chromosome: 17p13.3, Genbank accession number NP_002552.2) Le et al. (1997) "FEBS Lett." 418(1-2): 195-199; WO 2004047749; WO 2003072035 (claim 10); Touchman et al. (2000) "Genome Res." 10: 165-173; WO 200222660 (claim 20); WO 2003093444 (claim 1), WO 2003087768 (claim 1); WO 2003029277 (82 pages);

[0184] (32) CD72 (B cell differentiation antigen CD72, Lyb-2) PROTEIN SEQUENCE Full maeaity...tafrfpd (1..359; 359aa), pI: 8.66, MW: 40225 TM: 1 [P] Gene Chromosome: 9p13.3, Genbank accession number NP_001773.1) International Publication No. 2004042346 (Claim 65); International Publication No. 2003026493 (pages 51 - 52, 57 - 58); International Publication No. 200075655 (pages 105 - 106); Von Hoegen et al. (1990) "J. Immunol." 144(12): 4870 - 4877; Strausberg et al. (2002) "Proc. Natl. Acad. Sci USA" 99: 16899 - 16903;

[0185] (33) LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein of the leucine - rich repeat (LRR) family, regulates B - cell activation and apoptosis, and loss of function is associated with increased disease activity in patients with systemic lupus erythematosus); 661 aa, pI: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12, Genbank accession number NP_005573.1) US Patent Application Publication No. 2002193567; International Publication No. 9707198 (Claims 11, pages 39 - 42); Miura et al. (1996) "Genomics" 38(3): 299 - 304; Miura et al. (1998) "Blood" 92: 2815 - 2822; International Publication No. 2003083047; International Publication No. 9744452 (Claims 8, pages 57 - 61); International Publication No. 200012130 (pages 24 - 26);

[0186] (34) FcRH1 (Fc receptor - like protein 1, a putative receptor for the immunoglobulin Fc domain containing C2 - type Ig - like and ITAM domains, may have a role in B - lymphocyte differentiation.); 429 aa, pI: 5.28, MW: 46925 TM: 1 [P] Gene Chromosome: 1q21 - 1q22, Genbank accession number NP_443170.1) International Publication No. 2003077836; International Publication No. 200138490 (Claim 6, FIGS. 18E-1 to 18-E-2); Davis et al. (2001) "Proc. Natl. Acad. Sci USA" 98(17):9772-9777; International Publication No. 2003089624 (Claim 8); European Patent No. 1347046 (Claim 1); International Publication No. 2003089624 (Claim 7);

[0187] (35) FCRH5 (IRTA2, Immunoglobulin Superfamily Receptor Translocation Associated 2, Putative Immune Receptor Having a Possible Role in B Cell Development and Lymphopoiesis; Gene Deregulation by Translocation Occurs in Some B Cell Malignancies); 977 aa, pI: 6.88 MW: 106468 TM: 1 [P] Gene Chromosome: 1q21, Genbank Accession Numbers Human: AF343662, AF343663, AF343664, AF343665, AF369794, AF397453, AK090423, AK090475, AL834187, AY358085; Mouse: AK089756, AY158090, AY506558; NP_112571.1 International Publication No. 2003024392 (Claim 2, FIG. 97); Nakayama et al. (2000) "Biochem. Biophys. Res. Commun." 277(1):124-127; International Publication No. 2003077836; International Publication No. 200138490 (Claim 3, FIGS. 18B-1 to 18B-2);

[0188] (36) TENB2 (TMEFF2, Tomoregulin, TPEF, HPP1, TR, Putative Transmembrane Proteoglycan, Related to Growth Factors of the EGF / Heregulin Family and Folistatin); 374 aa, NCBI Accession: AAD55776, AAF91397, AAG49451, NCBI Reference Sequence: NP_057276; NCBI Gene: 23671; OMIM: 605734; SwissProt Q9UIK5; Genbank Accession Number AF179274; AY358907, CAF85723, CQ782436 WO 2004 / 074320 (SEQ ID NO: 810); JP 2004 / 113151 A (SEQ ID NOs: 2, 4, 8); WO 2003 / 042661 (SEQ ID NO: 580); WO 2003 / 009814 (SEQ ID NO: 411); EP 1295944 B1 (pages 69-70); WO 2002 / 030268 (page 329); WO 2001 / 090304 (SEQ ID NO: 2706); US 2004 / 249130 A1; US 2004 / 022727 A1; WO 2004 / 063355; US 2004 / 197325 A1; US Pat. No. 6,623,50 B1; US Pat. No. 6,605,563; US 2003 / 124579 A1; Horie et al. (2000) Genomics 67:146-152; Uchida et al. (1999) Biochem. Biophys. Res. Commun. 266:593-602; Liang et al. (2000) Cancer Res. 60:4907-4912; Glynne-Jones et al. (2001) Int J Cancer. Oct 15; 94(2):178-184;

[0189] (37) PMEL17 (Silver Homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp100) BC001414; BT007202; M32295; M77348; NM_006928; McGlinchey, R. P. et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106(33), 13731-13736; Kummer, M. P. et al. (2009) J. Biol. Chem. 284(4), 2296-2306;

[0190] (38) TMEFF1 (Transmembrane protein 1 with EGF-like domain and two follistatin-like domains; Tomoregulin-1); H7365; C9orf2; C9ORF2; U19878; X83961; NM_080655; NM_003692; Harms, P.W. (2003) "Genes Dev." 17(21), 2624 - 2629; Gery, S. et al. (2003) "Oncogene" 22(18):2723 - 2727;

[0191] (39) GDNF-Ra1 (GDNF family receptor alpha 1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1L; GDNFR-alpha1; GFR-ALPHA-1); U95847; BC014962; NM_145793NM_005264; Kim, M.H. et al. (2009) "Mol. Cell. Biol." 29(8), 2264 - 2277; Treanor, J.J. et al. (1996) "Nature" 382(6586):80 - 83;

[0192] (40) Ly6E (Lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-1); NP_002337.1; NM_002346.2; de Nooij-van Dalen, A.G. et al. (2003) "Int. J. Cancer" 103(6), 768 - 774; Zammit, D.J. et al. (2002) "Mol. Cell. Biol." 22(3):946 - 952; International Publication No. 2013 / 17705;

[0193] (41) TMEM46 (shisa homolog 2 (Xenopus laevis); SHISA2); NP_001007539.1; NM_001007538.1; Furushima, K. et al. (2007) "Dev. Biol." 306(2), 480 - 492; Clark, H.F. et al. (2003) "Genome Res." 13(10):2265 - 2270;

[0194] (42) Ly6G6D (lymphocyte antigen 6 complex, locus G6D; Ly6-D, MEGT1); NP_067079.2; NM_021246.2; Mallya, M. et al. (2002) "Genomics" 80(1): 113-123; Ribas, G. et al. (1999) "J. Immunol." 163(1): 278-287;

[0195] (43) LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR67); NP_003658.1; NM_003667.2; Salanti, G. et al. (2009) "Am. J. Epidemiol." 170(5): 537-545; Yamamoto, Y. et al. (2003) "Hepatology" 37(3): 528-533;

[0196] (44) RET (ret proto-oncogene; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.168114; RET51; RET-ELE1); NP_066124.1; NM_020975.4; Tsukamoto, H. et al. (2009) "Cancer Sci." 100(10): 1895-1901; Narita, N. et al. (2009) "Oncogene" 28(34): 3058-3068;

[0197] (45) LY6K (lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226); NP_059997.3; NM_017527.3; Ishikawa, N. et al. (2007) "Cancer Res." 67(24): 11601-11611; de Nooij-van Dalen, A.G. et al. (2003) "Int. J. Cancer" 103(6): 768-774;

[0198] (46) GPR19 (G Protein-Coupled Receptor 19; Mm.4787); NP_006134.1; NM_006143.2; Montpetit, A. and Sinnett, D. (1999) "Hum. Genet." 105(1-2): 162-164; O’Dowd, B.F. et al. (1996) "FEBS Lett." 394(3): 325-329;

[0199] (47) GPR54 (KISS1 Receptor; KISS1R; GPR54; HOT7T175; AXOR12); NP_115940.2; NM_032551.4; Navenot, J.M. et al. (2009) "Mol. Pharmacol." 75(6): 1300-1306; Hata, K. et al. (2009) "Anticancer Res." 29(2): 617-623;

[0200] (48) ASPHD1 (Aspartic Acid Beta-Hydroxylase Domain Containing 1; LOC253982); NP_859069.2; NM_181718.3; Gerhard, D.S. et al. (2004) "Genome Res." 14(10B): 2121-2127;

[0201] (49) Tyrosinase (TYR; OCAIA; OCA1A; Tyrosinase; SHEP3); NP_000363.1; NM_000372.4; Bishop, D.T. et al. (2009) "Nat. Genet." 41(8): 920-925; Nan, H. et al. (2009) "Int. J. Cancer" 125(4): 909-917;

[0202] (50) TMEM118 (Ring Finger Protein, Transmembrane 2, RNFT2, FLJ14627); NP_001103373.1; NM_001109903.1; Clark, H.F. et al. (2003) "Genome Res." 13(10): 2265-2270, Scherer, S.E. et al. (2006) "Nature" 440(7082): 346-351

[0203] (51) GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15Ertd747e); NP_078807.1; NM_024531.3; Ericsson, T. A. et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100(11):6759-6764; Takeda, S. et al. (2002) FEBS Lett. 520(1-3):97-101.

[0204] (52) CD33, a member of the immunoglobulin-like lectin family that binds to sialic acid, is a 67 kDa glycosylated transmembrane protein. CD33 is expressed on most myeloid leukemia cells and monocytic leukemia cells, in addition to restricted myelomonocytic progenitor cells and erythroid progenitor cells. It is not found on early pluripotent stem cells, mature granulocytes, lymphocytes, or non-hematopoietic cells (Sabbath et al., (1985) J. Clin. Invest. 75:756-56; Andrews et al., (1986) Blood 68:1030-5). CD33 contains two tyrosine residues in its cytoplasmic tail, each of which is followed by hydrophobic residues similar to the immunoreceptor tyrosine-based inhibitory motif (ITIM) found in many inhibitory receptors.

[0205] (53)CLL-1 (CLEC12A, MICL, and DCAL2) encodes a member of the C-type lectin / C-type lectin-like domain (CTL / CTLD) superfamily. Members of this family share a common protein fold and have diverse functions such as roles in cell adhesion, intercellular signaling, glycoprotein turnover, and inflammation and immune responses. The protein encoded by this gene is a negative regulator of granulocyte and monocyte function. Several alternative splice transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL / CTLD superfamily members within the natural killer gene complex region on chromosome 12p13 (Drickamer K (1999) Curr. Opin. Struct. Biol. 9(5):585-90; van Rhenen A et al. (2007) Blood 110(7):2659-66; Chen CH et al. (2006) Blood 107(4):1459-67; Marshall AS et al. (2006) Eur. J. Immunol. 36(8):2159-69; Bakker AB et al. (2005) Cancer Res. 64(22):8443-50; Marshall AS et al. (2004) J. Biol. Chem. 279(15):14792-802). CLL-1 has been shown to be a type II transmembrane receptor containing a single C-type lectin-like domain (not predicted to bind either calcium or carbohydrates), a stalk region, a transmembrane domain, and a short cytoplasmic tail containing an ITIM motif.

[0206] In one aspect, the antibody of Ab-CIDE can be an antibody against a protein found on a number of cell or tissue types. Examples of such antibodies include gD and EpCAM. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that mediates Ca2+-independent homotypic cell-cell adhesion in epithelia (Litvinov, S. et al. (1994) "Journal of Cell Biology" 125(2):437-46). It is also known as DIAR5, EGP-2, EGP314, EGP40, ESA, HNPCC8, KS1 / 4, KSA, M4S1, MIC18, MK-1, TACSTD1, TROP1, EpCAM, and is also involved in cell signaling (Maetzel, D. et al. (2009) "Nature Cell Biology" 11(2):162-71), migration (Washinton State Ostea; et al. (2004), "Cancer Res.", 64(16):5818-24), proliferation and differentiation (Litvinov, S. et al. (1996) "Am J Pathol." 148(3):865-75). Furthermore, EpCAM has carcinogenic potential through its ability to upregulate c-myc, e-fabp, and cyclins A and E (Munz, M. et al. (2004) "Oncogene" 23(34):5748-58). Since EpCAM is exclusively expressed in epithelia and epithelial-derived neoplasms, EpCAM can be used as a diagnostic marker for various cancers. In other words, Ab-CIDE can be used to deliver CIDE to many cells or tissues, rather than a specific cell type or tissue type as in the case of using a targeted antibody.

[0207] As described herein, Ab-CIDE can include an antibody, for example, an antibody selected from the following:

[0208] Anti-Ly6E antibody In certain embodiments, Ab-CIDE can include an anti-Ly6E antibody. Lymphocyte antigen 6 complex, locus E (Ly6E), also known as retinoic acid inducible gene E (RIG-E) and stem cell antigen 2 (SCA-2). It is an unknown function with an unknown binding partner of a GPI-linked 131 amino acid long, approximately 8.4 kDa protein. It was first identified as a transcript expressed in immature thymocytes and thymic medullary epithelial cells of mice (Mao et al. (1996) "Proc. Natl. Acad. Sci. U.S.A." 93: 5910-5914). In some embodiments, the subject matter described herein provides an Ab-CIDE that includes an anti-Ly6E antibody as described in PCT Publication No. WO2013 / 177055.

[0209] In some embodiments, the subject matter described herein provides an Ab-CIDE that includes an anti-Ly6E antibody that includes at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 that includes the amino acid sequence of SEQ ID NO: 12, (b) HVR-H2 that includes the amino acid sequence of SEQ ID NO: 13, (c) HVR-H3 that includes the amino acid sequence of SEQ ID NO: 14, (d) HVR-L1 that includes the amino acid sequence of SEQ ID NO: 9, (e) HVR-L2 that includes the amino acid sequence of SEQ ID NO: 10, and (f) HVR-L3 that includes the amino acid sequence of SEQ ID NO: 11.

[0210] In one aspect, the subject matter described herein provides an Ab-CIDE that includes an antibody that includes at least 1, at least 2, or all 3 VH HVR sequences selected from: (a) HVR-H1 that includes the amino acid sequence of SEQ ID NO: 12, (b) HVR-H2 that includes the amino acid sequence of SEQ ID NO: 13, and (c) HVR-H3 that includes the amino acid sequence of SEQ ID NO: 14. In a further embodiment, the antibody includes (a) HVR-H1 that includes the amino acid sequence of SEQ ID NO: 12, (b) HVR-H2 that includes the amino acid sequence of SEQ ID NO: 13, and (c) HVR-H3 that includes the amino acid sequence of SEQ ID NO: 14.

[0211] In another aspect, the subject matter described herein provides an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0212] In another aspect, the Ab-CIDE comprises an antibody comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 14, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0213] In another aspect, the subject matter described herein provides an Ab-CIDE comprising an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0214] In any of the above embodiments, the anti-Ly6E antibody of Ab-CIDE is humanized. In one embodiment, the anti-Ly6E antibody comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework.

[0215] In another aspect, the anti-Ly6E antibody of Ab-CIDE 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: 8. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 8 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-Ly6E antibody comprising such sequence retains the ability to bind Ly6E. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 8. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 8. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-Ly6E antibody comprises the VH sequence of SEQ ID NO: 8 and includes post-translational modifications of such sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14.

[0216] In another aspect, an anti-Ly6E antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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: 7. In certain embodiments, a VKL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 7 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-Ly6E antibody comprising such sequence retains the ability to bind to Ly6E. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 7. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 7. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-Ly6E antibody comprises the VL sequence of SEQ ID NO: 7, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11.

[0217] In another aspect, an Ab-CIDE comprising an anti-Ly6E antibody is provided, which antibody comprises a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0218] In one embodiment, an Ab-CIDE is provided, which antibody comprises the VH and VL sequences of SEQ ID NO: 8 and SEQ ID NO: 7, respectively, including post-translational modifications of such sequences.

[0219] In a further aspect, provided herein is an Ab-CIDE comprising an antibody that binds to the same epitope as the anti-Ly6E antibody provided herein. For example, in certain embodiments, provided is an Ab-CIDE comprising an antibody that binds to the same epitope as an anti-Ly6E antibody comprising the VH sequence of SEQ ID NO: 8 and the VL sequence of SEQ ID NO: 7, respectively.

[0220] In a further aspect, the anti-Ly6E antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody comprising a human antibody. In one embodiment, the anti-Ly6E antibody of the Ab-CIDE is an antibody fragment, e.g., Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the antibody is a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein. In some embodiments, the Ab-CIDE comprises an anti-Ly6E antibody comprising a heavy chain and a light chain comprising the amino acid sequences of SEQ ID NOs: 16 and 15, respectively

[0221] Anti-HER2 antibody In certain embodiments, the Ab-CIDE comprises an anti-HER2 antibody. In one embodiment, the anti-HER2 antibody of the Ab-CIDE is a humanized anti-HER2 antibody, e.g., huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7, and huMAb4D5-8, as described in Table 3 of U.S. Patent No. 5,821,337. These antibodies comprise a human framework region having the complementarity determining regions of a mouse antibody (4D5) that binds HER2. The humanized antibody huMAb4D5-8 is also known as trastuzumab and is commercially available under the trade name HERCEPTIN®. In another embodiment, the anti-HER2 antibody of the Ab-CIDE is a humanized anti-HER2 antibody as described in U.S. Patent No. 7,862,817, e.g., humanized 2C4. An exemplary humanized 2C4 antibody is pertuzumab, which is commercially available under the trade name PERJETA®.

[0222] In another embodiment, the anti-HER2 antibody of Ab-CIDE comprises a humanized 7C2 anti-HER2 antibody. The humanized 7C2 antibody is an anti-HER2 antibody.

[0223] In some embodiments, described herein is an Ab-CIDE comprising an anti-HER2 antibody that comprises at least one, two, three, four, five, or six HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 27, or 28, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24 or 29, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, described herein is a PAC comprising an anti-HER2 antibody that comprises at least one, two, three, four, five, or six HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0224] In one aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 27, or 28, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24 or 29. In one aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 68, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 27, or 28, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24 or 29. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24.

[0225] In another aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0226] In another aspect, Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 27, or 28, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 24 or 29, and a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In another aspect, Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 24, and a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (b) (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0227] In another aspect, described herein is Ab-CIDE, which comprises an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 27, or 28, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24 or 29, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In another aspect, described herein is Ab-CIDE, which comprises an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0228] In any of the above embodiments, the anti-HER2 antibody of Ab-CIDE is humanized. In one embodiment, the anti-HER2 antibody of Ab-CIDE comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework.

[0229] In another aspect, the anti-HER2 antibody of Ab-CIDE 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: 18. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 18 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-HER2 antibody comprising such a sequence retains the ability to bind to HER2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 18. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 18. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-HER2 antibody comprises the VH sequence of SEQ ID NO: 18 and includes post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24.

[0230] In another aspect, an anti-HER2 antibody of Ab-CIDE is provided, and the antibody comprises a light chain variable domain (VL) 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: 17. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 17 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-HER2 antibody comprising the sequence retains the ability to bind to HER2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 17. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 17. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-HER2 antibody comprises the VL sequence of SEQ ID NO: 17, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 19, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21.

[0231] In another aspect, an Ab-CIDE comprising an anti-HER2 antibody is provided, and the antibody comprises a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0232] In one embodiment, an Ab-CIDE comprising an antibody is provided, and the antibody comprises a VH sequence and a VL sequence of SEQ ID NO: 18 and SEQ ID NO: 17, respectively, including post-translational modifications of those sequences.

[0233] In one embodiment, an Ab-CIDE comprising an antibody comprising the humanized 7C2.v2.2.LA (hu7C2) K149C kappa light chain sequence of SEQ ID NO: 30 is provided.

[0234] In one embodiment, an Ab-CIDE is provided that includes an antibody comprising the Hu7C2 A118C IgG1 heavy chain sequence of SEQ ID NO: 31.

[0235] In a further aspect, provided herein is a PAC that includes an antibody that binds to the same epitope as the anti-HER2 antibody provided herein. For example, in certain embodiments, an Ab-CIDE is provided that includes an antibody that binds to the same epitope as an anti-HER2 antibody comprising the VH sequence of SEQ ID NO: 18 and the VL sequence of SEQ ID NO: 17, respectively.

[0236] In a further aspect, the anti-HER2 antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody comprising a human antibody. In one embodiment, the anti-HER2 antibody of the Ab-CIDE is an antibody fragment, e.g., an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the Ab-CIDE includes a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or an antibody of another antibody class or isotype as defined herein.

[0237] Anti-B7-H4 antibody In certain embodiments, the Ab-CIDE can include an anti-B7-H4 antibody. B7-H4 is a type I transmembrane protein and a member of the B7 superfamily of proteins that provide co-signals in conjunction with T cell receptor antigenic signals. B7-H4 is a negative regulator of T cell function, and ligation of T cells inhibits their growth, cytokine secretion, and cytotoxicity. Elimination of B7-H4 in mice does not affect immune cell homeostasis and there are no signs of autoimmunity. Zhu et al., “Blood” 113(8):1759-1767 (2009); Suh et al., “Molecular and Cellular Biology” 26(17):6403-6411 (2006). The receptor for B7-H4 is unknown and has not been identified.

[0238] Human B7-H4 is a 282 amino acid protein (including the amino-terminal signal sequence), of which approximately 227 amino acids are predicted to be in the extracellular space after cleavage of the amino-terminal signal sequence. B7-H4 contains an Ig-like V domain, an Ig-like C domain, a transmembrane domain and a short cytoplasmic tail. B7-H4 is a member of the B7 family that has the potential to downregulate the immune system via its co-inhibitory signal in conjunction with antigen-dependent signaling by the T cell receptor. B7-H4 is nominally expressed in normal human tissues but is highly overexpressed in numerous human cancers, including cancers of the female reproductive system (breast, ovary and endometrium). The morbidity of B7-H4 has been reported to be high in invasive ductal and lobular carcinomas, including both primary (approximately 95%) and metastatic (approximately 97%) breast cancers. Increased B7-H4 staining was associated with negative PR and HER2 status, but expression was independent of tumor grade or stage. In addition to the high percentage of B7H4-stained cells in these types of breast cancer, the number of infiltrating lymphocytes was also simultaneously decreased. Recently, in a B7-H4 knockout model of lung metastatic breast cancer, the authors reported that B7-H4− / − mice had fewer lung tumor nodules and showed improved survival and memory responses to tumor challenge compared to wild-type mice. This was attributed to the immunosuppressive effect of tumor-associated neutrophils bound to the B7-H4-Ig fusion protein on CD4 and CD8 cells. This may also explain why transplanted SKOV3 cells overexpressing B7-H4 in SCID mice grew more aggressively than wild-type SKOV3 cells. Furthermore, knockdown of B7-H4 mRNA and protein in SKBR3 cells was shown to result in increased caspase activity and apoptosis. In some embodiments, the subject matter described herein provides Ab-CIDE comprising an anti-B7-H4 antibody described in PCT Publication No. WO2016 / 040724.

[0239] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (ii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129, and (iii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200; or (b) (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (ii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129, and (iii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200.

[0240] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128; or (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201.

[0241] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises the heavy chain framework FR3 sequence of SEQ ID NO: 213.

[0242] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129. In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises the light chain framework FR3 sequence of SEQ ID NO: 207.

[0243] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) A VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 198; (b) A VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 126; or (c) A VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 127; or (d) A VH sequence as in (a) and a VL sequence as in (b); or (e) A VH sequence as in (c) and a VL sequence as in (b).

[0244] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence of SEQ ID NO: 198 or 127. In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 126.

[0245] In some embodiments, an anti-B7-H4 antibody of Ab-CIDE, comprising: (a) a VH sequence of SEQ ID NO: 198 and a VL sequence of SEQ ID NO: 126, or (b) a VH sequence of SEQ ID NO: 127 and a VL sequence of SEQ ID NO: 126.

[0246] In some embodiments, an anti-B7-H4 antibody of Ab-CIDE is provided, the antibody comprising: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129; or (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0247] In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can be a monoclonal antibody. In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can be a human antibody, a humanized antibody, or a chimeric antibody. In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can be an antibody fragment that binds B7-H4. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, as well as other fragments described below.

[0248] In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can be an IgG1, IgG2a, or IgG2b antibody. In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can contain one or more engineered cysteine amino acid residues. In any of the embodiments described herein, one or more engineered cysteine amino acid residues can be located in the heavy chain. In any of the embodiments described herein, one or more engineered cysteine amino acid residues can be located in the light chain. In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can contain at least one mutation in the heavy chain constant region selected from A118C and S400C. In any of the embodiments described herein, the anti-B7-H4 antibody of Ab-CIDE can contain at least one mutation in the light chain constant region selected from K149C and V205C.

[0249] In some embodiments, an anti-B7-H4 of Ab-CIDE is provided, the antibody comprising: (a) a heavy chain sequence of SEQ ID NO: 132 and a light chain sequence of SEQ ID NO: 134; or (b) a heavy chain sequence of SEQ ID NO: 133 and a light chain sequence of SEQ ID NO: 134; or (c) a heavy chain sequence of SEQ ID NO: 130 and a light chain sequence of SEQ ID NO: 140; or (d) a heavy chain sequence of SEQ ID NO: 130 and a light chain sequence of SEQ ID NO: 141; or (e) a heavy chain sequence of SEQ ID NO: 131 and a light chain sequence of SEQ ID NO: 140; or (f) a heavy chain sequence of SEQ ID NO: 131 and a light chain sequence of SEQ ID NO: 141; or (g) a heavy chain sequence of SEQ ID NO: 144 and a light chain sequence of SEQ ID NO: 142; or (h) a heavy chain sequence of SEQ ID NO: 144 and a light chain sequence of SEQ ID NO: 143; or (i) a heavy chain sequence of SEQ ID NO: 137 and a light chain sequence of SEQ ID NO: 138; or (j) a heavy chain sequence of SEQ ID NO: 130 and a light chain sequence of SEQ ID NO: 145; or (d) a heavy chain sequence of SEQ ID NO: 130 and a light chain sequence of SEQ ID NO: 146; or (e) a heavy chain sequence of SEQ ID NO: 131 and a light chain sequence of SEQ ID NO: 145; or (f) a heavy chain sequence of SEQ ID NO: 131 and a light chain sequence of SEQ ID NO: 146; or (g) a heavy chain sequence of SEQ ID NO: 144 and a light chain sequence of SEQ ID NO: 147; or (h) a heavy chain sequence of SEQ ID NO: 144 and a light chain sequence of SEQ ID NO: 148.

[0250] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE is a bivalent epitope antibody comprising a first half-antibody and a second half-antibody, which is provided, the first half-antibody comprising a first VH / VL unit that binds to a first epitope of B7-H4, and the second half-antibody comprising a second VH / VL unit that binds to a second epitope of B7-H4. In some embodiments, the first epitope or the second epitope is an epitope within all or a portion of the B7-H4 Ig-V-containing domain. In some embodiments, the first epitope or the second epitope is not within the B7-H4 Ig-V domain or is not completely within the B7-H4 Ig-V-containing domain. In some embodiments, the first epitope is within all or a portion of the B7-H4 Ig-V-containing domain, and the second epitope is not within the B7-H4 Ig-V domain or is not completely within the B7-H4 Ig-V-containing domain; or the first epitope is not within the B7-H4 Ig-V domain or is not completely within the B7-H4 Ig-V-containing domain, and the second epitope is within all or a portion of the B7-H4 Ig-V-containing domain. In some embodiments, the first epitope and the second epitope are each independently selected from: a) an epitope within all or a portion of the B7-H4 Ig-V-containing domain; b) an epitope within all or a portion of the B7-H4 Ig-C-containing domain; and c) an epitope within all or a portion of the B7-H4 Ig-V and Ig-C-containing domains.

[0251] In some embodiments, the B7-H4 Ig-V-containing domain has the sequence of amino acids 29-157 of SEQ ID NO: 233. In some embodiments, the B7-H4 Ig-C-containing domain has the sequence of amino acids 158-250 of SEQ ID NO: 233.

[0252] In some embodiments, a) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - C - containing domain; or b) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains; or c) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - C - containing domain, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains; or d) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - C - containing domain, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain; or e) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain; or f) The first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - C - containing domain.

[0253] In some embodiments, the first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains; or, the first half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V and Ig - C - containing domains, and the second half - antibody binds to an epitope within all or part of the B7 - H4 Ig - V - containing domain.

[0254] In some embodiments, the first half - antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129; (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129; (c) The VH sequence of SEQ ID NO: 198 and the VL sequence of SEQ ID NO: 126; or (d) The VH sequence of SEQ ID NO: 127 and the VL sequence of SEQ ID NO: 126.

[0255] In some embodiments, the second half-antibody comprises the following: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129; (b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129; (c) The VH sequence of SEQ ID NO: 198 and the VL sequence of SEQ ID NO: 126; or (d) The VH sequence of SEQ ID NO: 127 and the VL sequence of SEQ ID NO: 126.

[0256] In some embodiments, the first half-antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223; or (b) the VH sequence of SEQ ID NO: 216 and the VL sequence of SEQ ID NO: 215.

[0257] In some embodiments, the second half-antibody comprises: (a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223; or (b) the VH sequence of SEQ ID NO: 216 and the VL sequence of SEQ ID NO: 215.

[0258] In some embodiments, the Ab-CIDE anti-B7-H4 antibody, which is a bispecific epitope antibody, is an IgG1 or IgG4 antibody. In some embodiments, the first half-antibody comprises a first heavy chain constant region containing a knob mutation, and the second heavy chain comprises a second heavy chain constant region containing a hole mutation; or the first half-antibody comprises a first heavy chain constant region containing a hole mutation, and the second heavy chain comprises a second heavy chain constant region containing a knob mutation. In some embodiments, the bispecific epitope antibody is an IgG1 antibody, and the knob mutation comprises a T366W mutation. In some embodiments, the bispecific epitope antibody is an IgG1 antibody, and the hole mutation comprises at least one, at least two, or three mutations selected from T366S, L368A, and Y407V. In some embodiments, the bispecific epitope antibody is an IgG4 antibody, and the knob mutation comprises a T366W mutation. In some embodiments, the bispecific epitope antibody is an IgG4 antibody, and the hole mutation comprises at least one, at least two, or three mutations selected from the mutations of T366S, L368A, and Y407V.

[0259] In some embodiments, there is provided an Ab-CIDE anti-B7-H4 antibody that is a bispecific epitope antibody: a) the first half-antibody comprises the heavy chain sequence of SEQ ID NO: 159 or 163 and the light chain sequence of SEQ ID NO: 145 or 146, b) the first half-antibody comprises the heavy chain sequence of SEQ ID NO: 160 or 164 and the light chain sequence of SEQ ID NO: 145 or 146; c) the first half-antibody comprises the heavy chain sequence of SEQ ID NO: 161 or 165 and the light chain sequence of SEQ ID NO: 147 or 148; d) the first half-antibody comprises the heavy chain sequence of SEQ ID NO: 162 or 166 and the light chain sequence of SEQ ID NO: 147 or 148; e) the second half-antibody comprises the heavy chain sequence of SEQ ID NO: 159 or 163 and the light chain sequence of SEQ ID NO: 145 or 146; f) the second half-antibody comprises the heavy chain sequence of SEQ ID NO: 160 or 164 and the light chain sequence of SEQ ID NO: 145 or 146; g) The second half-antibody comprises the heavy chain sequence of SEQ ID NO: 161 or 165 and the light chain sequence of SEQ ID NO: 147 or 148; or h) The second half-antibody comprises the heavy chain sequence of SEQ ID NO: 162 or 166 and the light chain sequence of SEQ ID NO: 147 or 148.

[0260] In some embodiments, provided is an anti-B7-H4 antibody of Ab-CIDE, which is a bispecific epitope antibody: a) The first half-antibody comprises the heavy chain sequence of SEQ ID NO: 159 or 163 and the light chain sequence of SEQ ID NO: 145 or 146, and the second half-antibody comprises the heavy chain sequence of SEQ ID NO: 162 or 166 and the light chain sequence of SEQ ID NO: 147 or 148; or b) The first half-antibody comprises the heavy chain sequence of SEQ ID NO: 161 or 165 and the light chain sequence of SEQ ID NO: 147 or 148, and the second half-antibody comprises the heavy chain sequence of SEQ ID NO: 160 or 164 and the light chain sequence of SEQ ID NO: 145 or 146.

[0261] In some embodiments, provided is an anti-B7-H4 antibody of Ab-CIDE, which is a bispecific epitope antibody and comprises a first half-antibody and a second half-antibody. The first half-antibody comprises a first VH / VL unit that binds to a first epitope of B7-H4, and the second half-antibody comprises a second VH / VL unit that binds to a second epitope of B7-H4. The first half-antibody comprises the heavy chain sequence of SEQ ID NO: 159 or 163 and the light chain sequence of SEQ ID NO: 145, and the second half-antibody comprises the heavy chain sequence of SEQ ID NO: 162 or 166 and the light chain sequence of SEQ ID NO: 147.

[0262] In any of the embodiments described herein, B7-H4 can be the human B7-H4 of SEQ ID NO: 233.

[0263] An exemplary native human B7-H4 precursor protein sequence having a signal sequence (amino acids 1-28) is provided in SEQ ID NO: 233, and the corresponding mature B7-H4 protein sequence is shown in SEQ ID NO: 234 (corresponding to amino acids 29-282 of SEQ ID NO: 233).

[0264] In certain embodiments, the anti-B7-H4 antibody has one or more of the following characteristics in any combination: (a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor), and (b) binds B7-H4 with an affinity of ≦100 nM, ≦50 nM, ≦10 nM, or ≦9 nM, or ≦8 nM, or ≦7 nM, or ≦6 nM, or ≦5 nM, or ≦4 nM, or ≦3 nM, or ≦2 nM, or ≦1 nM, optionally ≧0.0001 nM, or ≧0.001 nM, or ≧0.01 nM.

[0265] Non-limiting exemplary anti-B7-H4 antibodies of Ab-CIDE include hu1D11.v1.9 varC2 and hu1D11.v1.9 varD described herein. In some embodiments, B7-H4 is human B7-H4. In some embodiments, B7-H4 is selected from human, cynomolgus monkey, mouse, and rat B7-H4.

[0266] In some embodiments, the Ab-CIDE anti-B7-H4 antibody binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233). In some embodiments, the Ab-CIDE anti-B7-H4 antibody binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233). In some embodiments, the Ab-CIDE anti-B7-H4 antibody binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C containing domains (amino acids 29-250 of SEQ ID NO: 233). In some embodiments, the Ab-CIDE anti-B7-H4 antibody binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4). In some embodiments, the Ab-CIDE anti-B7-H4 antibody binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor). In some such embodiments, the Ab-CIDE anti-B7-H4 antibody binds B7-H4 with an affinity of ≤100 nM, ≤50 nM, ≤10 nM, or ≤9 nM, or ≤8 nM, or ≤7 nM, or ≤6 nM, or ≤5 nM, or ≤4 nM, or ≤3 nM, or ≤2 nM, or ≤1 nM, and optionally ≥0.0001 nM, or ≥0.001 nM, or ≥0.01 nM.

[0267] Antibody 1D11v1.9 variants and other embodiments In some embodiments, the Ab-CIDE anti-B7-H4 antibody comprises at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0268] In some embodiments, the Ab-CIDE anti-B7-H4 antibody comprises at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0269] In one aspect, the Ab-CIDE anti-B7-H4 antibody comprises at least 1, at least 2, or all 3 VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128. In one embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In another embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128.

[0270] In one aspect, the Ab-CIDE anti-B7-H4 antibody comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In one embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In another embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201.

[0271] In another aspect, provided is an Ab-CIDE anti-B7-H4 antibody comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129. In one embodiment, the Ab-CIDE anti-B7-H4 antibody comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0272] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 128, and a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (b)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0273] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 201, and a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (b)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0274] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0275] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0276] In any of the above embodiments, the anti-B7-H4 antibody of Ab-CIDE is humanized. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework. In certain embodiments, the human acceptor framework is a human VL kappa I consensus (VL KI ) framework and / or VH framework VH1. In certain embodiments, the human acceptor framework is a human VL kappa I consensus (VL KI ) framework and / or VH framework VH1 that comprises any one of the following mutations: Y49H, V58I, T69R, and / or F71Y mutations in the light chain framework region FR3; V67A, I69L, R71A, T73K, and / or T75S mutations in the heavy chain framework region FR3.

[0277] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises HVRs of any of the above embodiments and further comprises the heavy chain framework FR3 sequence of SEQ ID NO: 213. In some such embodiments, the heavy chain variable domain framework is a modified human VH1 framework having the FR3 sequence of SEQ ID NO: 213.

[0278] In another aspect, the Ab-CIDE anti-B7-H4 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: 198 or 127. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 198 or 127 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 198 or 127. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 198 or 127. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs).

[0279] Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence of SEQ ID NO: 198, including post-translational modifications of the sequence. In certain embodiments, VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence of SEQ ID NO: 127, including post-translational modifications of the sequence. In certain embodiments, VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128. In another aspect, an anti-B7-H4 antibody is provided, which antibody comprises a light chain variable domain (VL) 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: 126. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 126 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 126. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 126. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 126, including post-translational modifications of the sequence. In certain embodiments, VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129.

[0280] In another aspect, an anti-B7-H4 antibody of Ab-CIDE is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.

[0281] In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 198 and SEQ ID NO: 126, respectively, including post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 127 and SEQ ID NO: 126, respectively, including post-translational modifications of those sequences.

[0282] In certain embodiments, there is provided an anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments that binds to B7-H4 and has at least one of the following characteristics: (a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor). In some embodiments, the anti-B7-H4 antibody has one or more of the following characteristics, in any combination: (a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor).

[0283] In a further aspect, the anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE is an antibody fragment, such as an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE is a substantially full-length antibody, such as an IgG1 antibody as defined herein, or another antibody class or isotype.

[0284] Antibody 1D11 and other embodiments In some embodiments, the Ab-CIDE anti-B7-H4 antibody comprises at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10. In another embodiment, the Ab-CIDE anti-B7-H4 antibody comprises at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204.

[0285] In one aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167.

[0286] In one aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201.

[0287] In another aspect, provided is an anti-B7-H4 antibody of Ab-CIDE comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170.

[0288] In another aspect, provided are Ab-CIDE anti-B7-H4 antibodies comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204.

[0289] In another aspect, the Ab-CIDE anti-B7-H4 antibody comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 167, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170.

[0290] In another aspect, the Ab-CIDE anti-B7-H4 antibody comprises: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 201, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204.

[0291] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170.

[0292] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204.

[0293] In any of the above embodiments, the anti-B7-H4 antibody of Ab-CIDE is humanized. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, for example, a human immunoglobulin framework or a human consensus framework. In certain embodiments, the human acceptor framework is a human VL kappa I consensus (VL KI ) framework and / or VH framework VH1. In certain embodiments, the human acceptor framework is a human VL kappa I consensus (VL KI ) framework and / or VH framework VH1 that comprises any one of the following mutations: Y49H, V58I, T69R, and / or F71Y mutations in the light chain framework region FR3; V67A, I69L, R71A, T73K, and / or T75S mutations in the heavy chain framework region FR3.

[0294] In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises any of the HVRS of the above embodiments and further comprises a heavy chain framework FR3 sequence of SEQ ID NO: 211, 212, or 213. In some such embodiments, the heavy chain variable domain framework is a modified human VH1 framework having the FR3 sequence of SEQ ID NO: 211, 212, or 213.

[0295] In another aspect, the anti-B7-H4 antibody of Ab-CIDE 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: 4. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 4 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 4. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 4. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRS (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence of SEQ ID NO: 4 and includes post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 167.

[0296] In another aspect, the Ab-CIDE anti-B7-H4 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: 196, 197, 198, 99, 100, 101, 102, or 103. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 196, 197, 198, 99, 100, 101, 102, or 103 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 196, 197, 198, 99, 100, 101, 102, or 103. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 196, 197, 198, 99, 100, 101, 102, or 103. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the Ab-CIDE anti-B7-H4 antibody comprises the VH sequence of SEQ ID NO: 196, 197, 198, 99, 100, 101, 102, or 103, including post-translational modifications of such sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 199, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 200, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 201.

[0297] In another aspect, an anti-B7-H4 antibody of Ab-CIDE is provided, the antibody comprising a light chain variable domain (VL) 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: 3. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 3 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-B7-H4 antibody comprising the sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 3. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 3. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 3 and includes post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 169, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 170.

[0298] In another aspect, an anti-B7-H4 antibody is provided, which antibody comprises a light chain variable domain (VL) 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: 195, 253, 254, 255, 256, 257, or 258. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 195, 253, 254, 255, 256, 257, or 258 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 195, 253, 254, 255, 256, 257, or 258. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 195, 253, 254, 255, 256, 257, or 258. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs). Optionally, the Ab-CIDE anti-B7-H4 antibody comprises the VL sequence of SEQ ID NO: 195, 253, 254, 255, 256, 257, or 258, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 204.

[0299] In another aspect, an Ab-CIDE anti-B7-H4 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.

[0300] In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 4 and SEQ ID NO: 3, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 101 and SEQ ID NO: 253, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 101 and SEQ ID NO: 257, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 102 and SEQ ID NO: 258, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 103 and SEQ ID NO: 258, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 101 and SEQ ID NO: 256, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 101 and SEQ ID NO: 255, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 101 and SEQ ID NO: 254, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 100 and SEQ ID NO: 253, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 99 and SEQ ID NO: 253, respectively, including post-translational modifications of these sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 196 and SEQ ID NO: 253, respectively, including post-translational modifications of these sequences.In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 196 and SEQ ID NO: 195, respectively, including post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 197 and SEQ ID NO: 195, respectively, including post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 198 and SEQ ID NO: 195, respectively, including post-translational modifications of those sequences.

[0301] In a further aspect, provided herein are Ab-CIDE anti-B7-H4 antibodies that bind to the same epitope as the anti-B7-H4 antibody. For example, in certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 3. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 101 and the VL sequence of SEQ ID NO: 253. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 101 and the VL sequence of SEQ ID NO: 257. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 102 and the VL sequence of SEQ ID NO: 258. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 103 and the VL sequence of SEQ ID NO: 258. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 101 and the VL sequence of SEQ ID NO: 256. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 101 and the VL sequence of SEQ ID NO: 255. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 101 and the VL sequence of SEQ ID NO: 254. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 100 and the VL sequence of SEQ ID NO: 253. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 99 and the VL sequence of SEQ ID NO: 253. In certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 256 and the VL sequence of SEQ ID NO: 253.In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 256 and the VL sequence of SEQ ID NO: 255, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope. In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 257 and the VL sequence of SEQ ID NO: 195, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope. In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 198 and the VL sequence of SEQ ID NO: 195, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope.

[0302] In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody according to any of the above embodiments that binds to B7-H4 and has at least one of the following characteristics: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor). In some embodiments, the anti-B7-H4 antibody has one or more of the following characteristics in any combination: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor).

[0303] In a further aspect, the anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE is an antibody fragment, for example, an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE is a substantially full-length antibody, for example, an IgG1 antibody as defined herein, or another antibody class or isotype.

[0304] Antibody 22C10 and other embodiments In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194.

[0305] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223.

[0306] In one aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191.

[0307] In another aspect, the Ab-CIDE anti-B7-H4 antibody comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220. In one embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220. In another embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219. In a further embodiment, the Ab-CIDE anti-B7-H4 antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220.

[0308] In another aspect, provided is an Ab-CIDE anti-B7-H4 antibody comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194. In one embodiment, the Ab-CIDE anti-B7-H4 antibody comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194.

[0309] In another aspect, provided is an anti-B7-H4 antibody of Ab-CIDE comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223.

[0310] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194.

[0311] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223.

[0312] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 194.

[0313] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 218, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 219, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 220, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 223.

[0314] In any of the above embodiments, the anti-B7-H4 antibody of Ab-CIDE is a human antibody.

[0315] In another aspect, the Ab-CIDE anti-B7-H4 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: 188. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 188 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such a sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 188. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 188. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the Ab-CIDE anti-B7-H4 antibody comprises the VH sequence of SEQ ID NO: 188, including post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 189, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 190, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 191.

[0316] In another aspect, an anti-B7-H4 antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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: 187. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 187 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 187. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 187. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 187 and includes post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 192, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 193, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 194.

[0317] In another aspect, an anti-B7-H4 antibody is provided, the antibody comprising a light chain variable domain (VL) 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: 215, 217, 104, 105, or 106. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 215, 217, 104, 105, or 106 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such a sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 215, 217, 104, 105, or 106. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 215, 217, 104, 105, or 106. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the Ab-CIDE anti-B7-H4 antibody comprises a VL sequence of SEQ ID NO: 215, 217, 104, 105, or 106, including post-translational modifications of such a sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 221, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 222, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 223.

[0318] In another aspect, the anti-B7-H4 antibody of Ab-CIDE, wherein the antibody comprises a VH as in any of the embodiments provided above and a VL as in any of the embodiments provided above. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 111 and SEQ ID NO: 104 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 111 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 112 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 113 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 114 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 111 and SEQ ID NO: 105 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 111 and SEQ ID NO: 106 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 110 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 109 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence and VL sequence of SEQ ID NO: 108 and SEQ ID NO: 215 respectively, which includes post-translational modifications of those sequences.In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 107 and SEQ ID NO: 215, respectively, including post-translational modifications of those sequences. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 216 and SEQ ID NO: 215, respectively, including post-translational modifications of those sequences. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 216 and SEQ ID NO: 217, respectively, including post-translational modifications of those sequences.

[0319] In a further aspect, provided herein are Ab-CIDE anti-B7-H4 antibodies that bind to the same epitope as the anti-B7-H4 antibody. For example, in certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 188 and the VL sequence of SEQ ID NO: 187. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 111 and the VL sequence of SEQ ID NO: 104. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 111 and the VL sequence of SEQ ID NO: 215. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 112 and the VL sequence of SEQ ID NO: 215. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 113 and the VL sequence of SEQ ID NO: 215. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 114 and the VL sequence of SEQ ID NO: 215. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 111 and the VL sequence of SEQ ID NO: 105. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 111 and the VL sequence of SEQ ID NO: 106. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 110 and the VL sequence of SEQ ID NO: 215. In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 109 and the VL sequence of SEQ ID NO: 215.In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 108 and the VL sequence of SEQ ID NO: 215, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope. In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 107 and the VL sequence of SEQ ID NO: 215, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope. In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 216 and the VL sequence of SEQ ID NO: 215, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope. In certain embodiments, an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 216 and the VL sequence of SEQ ID NO: 217, and an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope.

[0320] In certain embodiments, provided is an anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments that binds to B7-H4 and has at least one of the following characteristics: (a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor). In some embodiments, the anti-B7-H4 antibody has one or more of the following characteristics, in any combination: (a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or a portion of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 233 (human B7-H4 precursor).

[0321] In a further aspect, the anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments is a monoclonal antibody that includes a human antibody. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE is an antibody fragment, e.g., Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE is a substantially full-length antibody, e.g., an IgG2a antibody as defined herein, or another antibody class or isotype.

[0322] Antibody 32D6 and other embodiments In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178.

[0323] In one aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least 1, at least 2, or all 3 VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175.

[0324] In another aspect, provided is an anti-B7-H4 antibody of Ab-CIDE comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178.

[0325] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178.

[0326] In another aspect, the anti-B7-H4 antibody of Ab-CIDE comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 178.

[0327] In any of the above embodiments, the anti-B7-H4 antibody of Ab-CIDE is a human antibody.

[0328] In another aspect, the anti-B7-H4 antibody of Ab-CIDE 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: 172. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 172 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such a sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 172. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 172. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VH sequence of SEQ ID NO: 172, including post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 173, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 174, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 175.

[0329] In another aspect, an anti-B7-H4 antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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: 171. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 171 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 171. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 171. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 171, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 176, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 177, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 178.

[0330] In another aspect, an anti-B7-H4 antibody of Ab-CIDE, which antibody comprises a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 172 and SEQ ID NO: 171, respectively, including post-translational modifications of such sequences. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 172 and SEQ ID NO: 171, respectively, including post-translational modifications of such sequences.

[0331] In a further aspect, provided herein are Ab-CIDE anti-B7-H4 antibodies that bind to the same epitope as the anti-B7-H4 antibody. For example, in certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 172 and the VL sequence of SEQ ID NO: 171.

[0332] In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody according to any of the above embodiments that binds to B7-H4 and has at least one of the following characteristics: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor). In some embodiments, the anti-B7-H4 antibody has one or more of the following characteristics in any combination: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor).

[0333] In a further aspect, the anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments is a monoclonal antibody including human antibodies. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE is an antibody fragment, for example, Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE is a substantially full-length antibody, for example, an IgG2a antibody as defined herein, or other antibody class or isotype.

[0334] Antibody 9B9 and other embodiments In some embodiments, the anti-B7-H4 antibody of Ab-CIDE comprises at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186.

[0335] In one aspect, the anti-B7-H4 antibody of Ab-CIDE comprises at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183 and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183, HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182. In a further embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183.

[0336] In another aspect, provided is an anti-B7-H4 antibody of Ab-CIDE comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186.

[0337] In another aspect, an anti-B7-H4 antibody of Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; and a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (b)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186.

[0338] In another aspect, an anti-B7-H4 antibody of Ab-CIDE comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (f) HVR-L3 comprising the amino acid sequence selected from SEQ ID NO: 186.

[0339] In any of the above embodiments, the anti-B7-H4 antibody of Ab-CIDE is a human antibody.

[0340] In another aspect, the Ab-CIDE anti-B7-H4 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: 180. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 180 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-B7-H4 antibody comprising such a sequence retains the ability to bind to B7-H4. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 180. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 180. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the Ab-CIDE anti-B7-H4 antibody comprises the VH sequence of SEQ ID NO: 180, including post-translational modifications of the sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183.

[0341] In another aspect, an anti-B7-H4 antibody is provided, which antibody comprises a light chain variable domain (VL) 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: 179. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 179 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-B7-H4 antibody comprising such sequence retains the ability to bind B7-H4. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 179. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 179. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-B7-H4 antibody of Ab-CIDE comprises the VL sequence of SEQ ID NO: 171, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186.

[0342] In another aspect, an anti-B7-H4 antibody of Ab-CIDE, which antibody comprises a VH as in any of the embodiments provided above and a VL as in any of the embodiments provided above. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE comprises the VH and VL sequences of SEQ ID NO: 180 and SEQ ID NO: 179, respectively, including post-translational modifications of such sequences.

[0343] In a further aspect, provided herein are Ab-CIDE anti-B7-H4 antibodies that bind to the same epitope as the anti-B7-H4 antibody. For example, in certain embodiments, an Ab-CIDE anti-B7-H4 antibody that binds to the same epitope as an anti-B7-H4 antibody comprising the VH sequence of SEQ ID NO: 180 and the VL sequence of SEQ ID NO: 179 is provided.

[0344] In certain embodiments, provided is an Ab-CIDE anti-B7-H4 antibody according to any of the above embodiments, having at least one of the following characteristics with respect to B7-H4: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor); In some embodiments, the anti-B7-H4 antibody has one or more of the following characteristics in any combination: (a) binds to an epitope within all or part of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 233); or binds to an epitope within all or part of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO: 233); or binds to an epitope within all or part of SEQ ID NO: 234 (mature human B7-H4); or binds to an epitope within all or part of SEQ ID NO: 233 (human B7-H4 precursor).

[0345] In a further aspect, the anti-B7-H4 antibody of Ab-CIDE according to any of the above embodiments is a monoclonal antibody, including a human antibody. In one embodiment, the anti-B7-H4 antibody of Ab-CIDE is an antibody fragment, for example, Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the anti-B7-H4 antibody of Ab-CIDE is a substantially full-length antibody, for example, an IgG2a antibody as defined herein, or another antibody class or isotype.

[0346] Anti-MUC16 antibody In certain embodiments, Ab-CIDE includes an anti-MUC16 antibody.

[0347] In some embodiments, described herein is a PAC comprising an anti-MUC16 antibody, which comprises at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34.

[0348] In one aspect, described herein is an Ab-CIDE comprising an antibody that comprises at least 1, at least 2, or all 3 VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37. In a further embodiment, the antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37.

[0349] In another aspect, described herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three of the VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34.

[0350] In another aspect, the Ab-CIDE comprises an antibody comprising (a) a VH domain comprising at least one, at least two, or all three of the VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 37, and (b) a VL domain comprising at least one, at least two, or all three of the VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34.

[0351] In another aspect, described herein is an Ab-CIDE comprising an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34.

[0352] In any of the above embodiments, the anti-MUC16 antibody of Ab-CIDE is humanized. In one embodiment, the anti-MUC16 antibody comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework.

[0353] In another aspect, the anti-MUC16 antibody of Ab-CIDE 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: 39. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 39 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-MUC16 antibody comprising such a sequence retains the ability to bind to MUC16. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted at SEQ ID NO: 39. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted at SEQ ID NO: 39. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-MUC16 antibody comprises the VH sequence of SEQ ID NO: 39 and includes post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37.

[0354] In another aspect, an anti-MUC16 antibody of Ab-CIDE is provided, the antibody comprising a light chain variable domain (VL) 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: 38. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 38 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-MUC16 antibody comprising the sequence retains the ability to bind to MUC16. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 38. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 38. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-MUC16 antibody comprises the VL sequence of SEQ ID NO: 38, including post-translational modifications of the sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 34.

[0355] In another aspect, an Ab-CIDE comprising an anti-MUC16 antibody is provided, the antibody comprising a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0356] In one embodiment, an Ab-CIDE is provided, the antibody comprising the VH and VL sequences of SEQ ID NO: 39 and SEQ ID NO: 38, respectively, including post-translational modifications of those sequences.

[0357] In a further aspect, provided herein is an Ab-CIDE that includes an antibody that binds to the same epitope as the anti-MUC16 antibodies provided herein. For example, in certain embodiments, provided is a PAC that includes an antibody that binds to the same epitope as an anti-MUC16 antibody that includes the VH sequence of SEQ ID NO: 39 and the VL sequence of SEQ ID NO: 38, respectively.

[0358] In a further aspect, the anti-MUC16 antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody that includes a human antibody. In one embodiment, the anti-MUC16 antibody of the Ab-CIDE is an antibody fragment, e.g., an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the antibody is a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

[0359] Anti-STEAP-1 antibody In certain embodiments, the Ab-CIDE includes an anti-STEAP-1 antibody.

[0360] In some embodiments, provided herein is a PAC that includes an anti-STEAP-1 antibody that includes at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 that includes the amino acid sequence of SEQ ID NO: 40, (b) HVR-H2 that includes the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 that includes the amino acid sequence of SEQ ID NO: 42, (d) HVR-L1 that includes the amino acid sequence of SEQ ID NO: 43, (e) HVR-L2 that includes the amino acid sequence of SEQ ID NO: 44, and (f) HVR-L3 that includes the amino acid sequence of SEQ ID NO: 45.

[0361] In one aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 40, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 42. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 40, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 42.

[0362] In another aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45.

[0363] In another aspect, the Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 40, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 42, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45.

[0364] In another aspect, described herein is Ab-CIDE, which comprises an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 40, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 42, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45.

[0365] In any of the above embodiments, the anti-STEAP-1 antibody of Ab-CIDE is humanized. In one embodiment, the anti-STEAP-1 antibody comprises HVRs as in any of the above embodiments and further comprises a human acceptor framework, e.g., a human immunoglobulin framework or a human consensus framework.

[0366] In another aspect, the anti-STEAP-1 antibody of Ab-CIDE 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: 46. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 46 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-STEAP-1 antibody comprising such a sequence retains the ability to bind to STEAP-1. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 46. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 46. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-STEAP-1 antibody comprises the VH sequence of SEQ ID NO: 46 and includes post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 40, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 41, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 42.

[0367] In another aspect, an anti-STEAP-1 antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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 certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 47 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-STEAP-1 antibody comprising such sequence retains the ability to bind to STEAP-1. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted within SEQ ID NO: 47, and in certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted within SEQ ID NO: 47. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-STEAP-1 antibody comprises the VL sequence of SEQ ID NO: 47, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 43, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 45.

[0368] In another aspect, an Ab-CIDE comprising an anti-STEAP-1 antibody is provided, which antibody comprises a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0369] In one embodiment, an Ab-CIDE is provided, which antibody comprises the VH and VL sequences of SEQ ID NO: 46 and SEQ ID NO: 47, respectively, including post-translational modifications of those sequences.

[0370] In a further aspect, provided herein is an Ab-CIDE comprising an antibody that binds to the same epitope as the anti-STEAP-1 antibody provided herein. For example, in certain embodiments, provided is an Ab-CIDE comprising an antibody that binds to the same epitope as an anti-STEAP-1 antibody comprising the VH sequence of SEQ ID NO: 46 and the VL sequence of SEQ ID NO: 47, respectively.

[0371] In a further aspect, the anti-STEAP-1 antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody, including a human antibody. In one embodiment, the anti-STEAP-1 antibody of the Ab-CIDE is an antibody fragment, such as an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the antibody is a substantially full-length antibody, such as an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

[0372] Anti-NaPi2b antibody In certain embodiments, the Ab-CIDE comprises an anti-NaPi2b antibody.

[0373] In some embodiments, described herein is an Ab-CIDE comprising an anti-NaPi2b antibody comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53.

[0374] In one aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50.

[0375] In another aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53.

[0376] In another aspect, the Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 50, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53.

[0377] In another aspect, the present specification describes Ab-CIDE, which includes an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53.

[0378] In any of the above-described embodiments, the anti-NaPi2b antibody of Ab-CIDE is humanized. In one embodiment, the anti-NaPi2b antibody comprises an HVR as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework.

[0379] In another aspect, the anti-NaPi2b antibody of Ab-CIDE 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: 54. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 54 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-NaPi2b antibody comprising such sequence retains the ability to bind to NaPi2b. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 54. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 54. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-NaPi2b antibody comprises the VH sequence of SEQ ID NO: 54 and includes post-translational modifications of that sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 48, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 49, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50.

[0380] In another aspect, an anti-NaPi2b antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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: 55. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 55 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but the anti-NaPi2b antibody comprising such sequence retains the ability to bind to anti-NaPi2b. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 55. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 55. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-NaPi2b antibody comprises the VL sequence of SEQ ID NO: 55 and includes post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 51, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 53.

[0381] In another aspect, an Ab-CIDE comprising an anti-NaPi2b antibody is provided, which antibody comprises a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0382] In one embodiment, an Ab-CIDE is provided, which antibody comprises the VH and VL sequences of SEQ ID NO: 54 and SEQ ID NO: 55, respectively, including post-translational modifications of those sequences.

[0383] In a further aspect, provided herein is an Ab-CIDE comprising an antibody that binds to the same epitope as the anti-NaPi2b antibody provided herein. For example, in certain embodiments, provided is an Ab-CIDE comprising an antibody that binds to the same epitope as an anti-NaPi2b antibody comprising the VH sequence of SEQ ID NO: 54 and the VL sequence of SEQ ID NO: 55, respectively.

[0384] In a further aspect, the anti-NaPi2b antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody comprising a human antibody. In one embodiment, the anti-NaPi2b antibody of the Ab-CIDE is an antibody fragment, e.g., an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the antibody is a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

[0385] Anti-CD79b antibody In certain embodiments, the Ab-CIDE comprises an anti-CD79b antibody.

[0386] In some embodiments, described herein is an Ab-CIDE comprising an anti-CD79b antibody comprising at least 1, 2, 3, 4, 5, or 6 HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0387] In one aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60. In a further embodiment, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60.

[0388] In another aspect, provided herein is an Ab-CIDE comprising an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63. In one embodiment, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0389] In another aspect, the Ab-CIDE comprises an antibody comprising a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (a)(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 60, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0390] In another aspect, described herein is Ab-CIDE, which includes an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0391] In any of the above-described embodiments, the anti-CD79b antibody of Ab-CIDE is humanized. In one embodiment, the anti-CD79b antibody comprises an HVR as in any of the above embodiments and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework.

[0392] In another aspect, the anti-CD79b antibody of Ab-CIDE 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: 56. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 56 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-CD79b antibody comprising such sequence retains the ability to bind to CD79b. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 56. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 56. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-CD79b antibody comprises the VH sequence of SEQ ID NO: 8, including post-translational modifications of such sequence. In certain embodiments, the VH comprises two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60.

[0393] In another aspect, an anti-CD79b antibody of Ab-CIDE is provided, which antibody comprises a light chain variable domain (VL) 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: 57. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 57 contains substitutions (e.g., conservative substitutions), insertions, or deletions as compared to the reference sequence, but an anti-Ly6E antibody comprising such sequence retains the ability to bind to CD79b. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 57. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 57. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside of the HVRs (i.e., within the FRs). Optionally, the anti-CD79b antibody comprises the VL sequence of SEQ ID NO: 57, including post-translational modifications of such sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63.

[0394] In another aspect, an Ab-CIDE comprising an anti-CD79b antibody is described herein and provided, which antibody comprises a VH as in any of the above embodiments and a VL as in any of the above embodiments.

[0395] In one embodiment, an Ab-CIDE is provided, which antibody comprises the VH and VL sequences of SEQ ID NO: 56 and SEQ ID NO: 57, respectively, including post-translational modifications of those sequences.

[0396] In a further aspect, provided herein is an Ab-CIDE comprising an antibody that binds to the same epitope as the anti-CD79b antibody provided herein. For example, in certain embodiments, provided is an Ab-CIDE comprising an antibody that binds to the same epitope as an anti-CD79b antibody comprising the VH sequence of SEQ ID NO: 56 and the VL sequence of SEQ ID NO: 57, respectively.

[0397] In a further aspect, the anti-CD79b antibody of the Ab-CIDE according to any of the above embodiments is a monoclonal antibody comprising a human antibody. In one embodiment, the anti-CD79b antibody of the Ab-CIDE is an antibody fragment, e.g., an Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another embodiment, the antibody is a substantially full-length antibody, e.g., an IgG1 antibody, an IgG2a antibody, or other antibody class or isotype as defined herein.

[0398] Anti-CD22 antibody In certain embodiments, the Ab-CIDE can comprise an anti-CD22 antibody comprising three light chain hypervariable regions (HVR-L1, HVR-L2, and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2, and HVR-H3). In one embodiment, the anti-CD22 antibody of the Ab-CIDE comprises three light chain hypervariable regions and three heavy chain hypervariable regions (SEQ ID NOs: 66-71), the sequences of which are shown below. In one embodiment, the anti-CD22 antibody of the Ab-CIDE comprises the variable light chain sequence of SEQ ID NO: 72 and the variable heavy chain sequence of SEQ ID NO: 73. In one embodiment, the anti-CD22 antibody of the Ab-CIDEs of the present invention comprises the light chain sequence of SEQ ID NO: 74 and the heavy chain sequence of SEQ ID NO: 75:

[0399] Anti-CD33 antibody In certain embodiments, the Ab-CIDE can comprise an anti-CD33 antibody comprising three light chain hypervariable regions and three heavy chain hypervariable regions, the sequences of which (SEQ ID NOs: 76-81) are shown below. In one embodiment, the anti-CD33 antibody of the Ab-CIDE comprises the variable light chain sequence of SEQ ID NO: 82 and the variable heavy chain sequence of SEQ ID NO: 83.

[0400] In one embodiment, the anti-CD33 antibody of Ab-CIDE comprises the light chain sequence of SEQ ID NO: 84 and the heavy chain sequence of SEQ ID NO: 85. In one embodiment, the anti-CD33 antibody of Ab-CIDE comprises three light chain hypervariable regions and three heavy chain hypervariable regions, and their sequences (SEQ ID NOs: 84-89) are shown below. In one embodiment, the anti-CD33 antibody of Ab-CIDE comprises the variable light chain sequence of SEQ ID NO: 90 and the variable heavy chain sequence of SEQ ID NO: 91. In one embodiment, the anti-CD33 antibody of Ab-CIDE comprises the variable light chain sequence of SEQ ID NO: 92 and the variable heavy chain sequence of SEQ ID NO: 93. In one embodiment, the anti-CD33 antibody of the present invention comprises the variable light chain sequence of SEQ ID NO: 94 and the variable heavy chain sequence of SEQ ID NO: 95. In one embodiment, the anti-CD33 antibody of the present invention comprises the variable light chain sequence of SEQ ID NO: 96 and the variable heavy chain sequence of SEQ ID NO: 97.

[0401] 1. Antibody affinity In certain embodiments, the antibodies provided herein have a dissociation constant (Kd) of ≦1 μM, ≦100 nM, ≦50 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM, and optionally, ≧10 -13 M (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M).

[0402] In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA) performed using the Fab version of the antibody of interest and its antigen, as described by the following assay. The solution binding affinity of Fab for the antigen is determined in the presence of a series of titrations of unlabeled antigen, with Fab at the minimum concentration of ( 125I) It is measured by equilibration with the labeled antigen and subsequent capture of the antigen bound to the anti-Fab antibody-coated plate (see, for example, Chen et al., "J. Mol. Biol.", 293:865-881 (1999)). To establish the assay conditions, a MICROTITER® multiwell plate (Thermo Scientific) is coated overnight with 5 μg / ml of the capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In non-adsorbent plates (Nunc number 269620), 100 pM or 26 pM of 125 I]-antigen is mixed with serial dilutions of the Fab of interest (consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al., "Cancer Res.", 57:4593-4599 (1997), for example). Next, the Fab of interest is incubated overnight, although this incubation can be continued for a longer period (e.g., about 65 hours) to ensure that equilibrium is achieved. Thereafter, the mixture is transferred to the capture plate for incubation at room temperature (e.g., 1 hour). Next, the solution is removed and the plate is washed 8 times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate is dry, 150 μL / well of scintillant (MICROSCINT-20 (商標) , Packard) is added and the plate is counted on a TOPCOUNT (商標) gamma counter (Packard) for 10 minutes. The concentration of each Fab that results in 20% or less of the maximum binding is selected for use in the competitive binding assay.

[0403] According to another embodiment, Kd is measured at 25°C using a surface plasmon resonance assay with an antigen CM5 chip immobilized at approximately 10 response units (RU) using a BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ). Briefly, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (about 0.2 μM) with 10 mM sodium acetate at pH 4.8 and then injected at a flow rate of 5 μl / min to achieve approximately 10 response units (RU) of the coupled protein. After injection of the antigen, 1 M ethanolamine is injected to ...

Claims

1. A conjugate having the chemical structure: Ab-(L1-D) ｐ wherein D is a chemical decomposition inducer (CIDE) having the structure E3LB-L2-PB; E3LB is an E3 ligase binding ligand covalently bound to L2, said E3 ligase being the von Hippel-Lindau (VHL) tumor suppressor protein, and E3LB contains a hydroxyproline residue; L2 is a linker covalently bound to E3LB and PB; PB is a protein binding ligand that binds to a protein and is subject to degradation by the proteasome; Ab is an antibody covalently bound to L1; L1 is a linker covalently bound to Ab and to E3LB via the oxygen of a hydroxyproline residue; L1 has a formula selected from the group consisting of ; E3LB is p has a value from about 1 to about 8, The structure (wherein R １ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R １４ａ is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl; R １５ is optionally substituted heteroaryl or optionally substituted aryl) and has; the conjugate.

2. The conjugate according to claim 1, wherein L1 is covalently bound to a cysteine thiol group of the antibody.

3. The conjugate according to claim 1 or 2, wherein L2 is selected from the group consisting of ;

4. L1-D is The conjugate according to any one of claims 1 to 3, selected from the group consisting of ;

5. The conjugate according to claim 2, wherein the antibody is a cysteine-engineered antibody.

6. The conjugate according to claim 5, wherein the cysteine-engineered antibody comprises a mutation selected from the group consisting of LC-K149C, HC-A140C, HC-L174C and HC-Y373C.

7. The conjugate according to any one of claims 1 to 6, wherein p is from about 1 to about 6.

8. The conjugate according to claim 7, wherein p is about 2 or about 6.

9. A pharmaceutical composition comprising the conjugate according to claim 1 and at least one pharmaceutically acceptable excipient.

10. A medicament comprising an effective amount of the conjugate according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 for treating a subject having a condition regulated by a protein bound to the conjugate according to claim 1.

11. The medicament according to claim 10, wherein the protein is degraded.

12. The medicament according to claim 10, which is administered together with at least one additional therapeutic agent.

13. A compound having the formula L1-D wherein wherein D is a chemical decomposition inducer (CIDE) having the structure E3LB-L2-PB, where E3LB is an E3 ligase-binding ligand covalently bound to L2, the E3 ligase being the von Hippel-Lindau (VHL) tumor suppressor protein, and E3LB contains hydroxyproline residues; L2 is a linker covalently bound to E3LB and PB; PB is a protein-binding ligand that binds to a protein and undergoes degradation by a proteasome; L1 is covalently bound to E3LB via the oxygen of a hydroxyproline residue having a formula selected from the group consisting of E3LB is Structure (wherein R １ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R １４ａ is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl or cyclopropyl; R １５ is optionally substituted heteroaryl or optionally substituted aryl), a compound. **Claim 14** The compound according to claim 13, selected from the group consisting of the following ​

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