GSPT1-degrading compounds, Anti-CD33 antibodies and antibody-drug conjugates and uses thereof

Abstract

The present application relates to particular anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of making and using the antibodies, as well as immunoconjugates comprising the anti-CD33 antibodies. The present application also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present application also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates.

Description

GSPT1-DEGRADING COMPOUNDS, ANTI-CD33 ANTIBODIES AND ANTIBODY-DRUG CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of US Provisional Application No.63 / 591,013, filed October 17, 2023, which is incorporated by reference herein in its entirety for any purpose. SEQUENCE LISTING

[0002] The present application contains a Sequence Listing, which has been submitted electronically in XML format. Said XML copy was created on October 3, 2024, is named “01277-0040-00PCT_ST26.xml”, and is 93,755 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD

[0003] The present application relates to anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of making and using the antibodies. The present application also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present application also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates. BACKGROUND

[0004] There exists a need for safe and effective agents and methods for treating, preventing and managing cancer, including for cancers that are refractory to standard treatments, while reducing or avoiding the toxicities and / or side effects associated with some existing therapies.

[0005] The present disclosure provides such agents, including GSPT1 degraders and anti- CD33 antibody-drug conjugates comprising GSPT1 degraders. SUMMARY

[0006] The present disclosure relates to anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of both making and using the antibodies. The present disclosure also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present disclosure also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates. For example, embodiments of the disclosure include the following:

[0007] A compound of any of the structural formulas depicted herein (e.g., Structural Formula I', II', III', IV', V', a structure from Table A), or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.

[0008] An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28; b) (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; c) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; d) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57;and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; or e) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68.

[0009] An isolated nucleic acid encoding an antibody or antigen-binding portion thereof described herein, or a vector comprising same, or a host cell comprising the isolated nucleic acid or vector.

[0010] A method for making an anti-CD33 antibody or antigen-binding portion thereof, comprising culturing a host cell comprising an isolated nucleic acid encoding the anti-CD33 antibody or antigen-binding portion thereof, or a vector comprising the isolated nucleic acid under conditions suitable for expression of the antibody or antigen-binding portion thereof.

[0011] An antibody-drug conjugate comprising an antibody or antigen-binding portion thereof described herein and a cytotoxic agent.

[0012] An antibody-drug conjugate of any of the structural formulas depicted herein (e.g., Structural Formula I", II", III", IV", V"), or a pharmaceutically acceptable salt thereof.

[0013] A pharmaceutical composition comprising (i) a compound, isolated antibody or antigen-binding portion thereof, or antibody drug conjugate and (ii) a pharmaceutically acceptable carrier.

[0014] A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an isolated antibody or antigen-binding portion thereof described herein, an antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing.

[0015] Use of an isolated antibody or antigen-binding portion thereof described herein, or antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing for the preparation of a medicament for treating cancer in a subject in need thereof.

[0016] An isolated antibody or antigen-binding portion thereof described herein, or an antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing for use in treating cancer in a subject in need thereof.

[0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims. All references cited herein are incorporated in their entirety by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGs.1A-1E show the results of tests of CD33-M and its progeny antibodies for selective affinity for CD33+ cells compared to vadastuximab (VADA) or isotype control. Levels of antibody binding were analyzed by determining the mean fluorescence intensity (MFI) by flow cytometry. FIG.1A is a graph showing results in HEK293 cells engineered to express the full-length coding sequence of cynomolgus CD33. FIG.1B is a graph showing results in HEK293 cells engineered to express a truncated form of human CD33 lacking the V-domain. FIG.1C is a graph showing results in Molm13 cells, a CD33+ AML cancer cell line. FIG.1D is a graph showing results in MV4-11 cells, a CD33+ AML cancer cell line. FIG.1E is a graph showing results in CD33-negative Pfeiffer cells.

[0019] FIGS.2A-2F show the results of tests of binding affinity to endogenous CD33 in human and cynomolgus monocytes for CD33-M, vadastuximab, and isotype control. Monocytes were isolated from 3 human peripheral blood mononuclear cell (PBMC) samples and 3 cynomolgus samples by flow cytometry gating with anti-CD14 and anti-CD159a antibodies, excluding doublets and dead cells. The geometric MFI (gMFI) of AF647 at each concentration was graphed on a log scale as non-linear regression curve. Results in monocytes isolated from human PBMCs from donor 1, donor 2, and donor 3 are shown in graphs in FIGS.2A-2C. Results in monocytes isolated from cynomolgus PMBCs from donor 1, donor 2, and donor 3 are shown in graphs in FIGS.2D-2F.

[0020] FIGS.3A-3E show the results of tests of binding affinity to endogenous cynomolgus CD33 in neutrophils for CD33-M and the progeny antibodies of CD33-M. PBMCs isolated from three cynomolgus blood donors were stained with AF647-conjugated CD33 antibodies and CD33 binding analyzed by flow cytometry. The neutrophil population was gated using a side scatter / CD45+ plot after excluding doublets and dead cells. Geometric MFI (gMFI) at each concentration was graphed on a log scale as non-linear regression curves. CD33 expression and antigen density in cynomolgus neutrophils were confirmed by flow cytometry.

[0021] FIGS.4A-4C show the results of tests of ability to mediate internalization for antibodyies CD33-M and VADA. CD33+ MOLM-13 cells (left pane), CD33+ MV4-11 cells (middle pane), or CD33-negative Pfeiffer cells (right pane) were incubated with various concentrations (32 pM-10 nM) of antibody CD33-M or VADA labeled with acid-sensitivefluorescent Fab fragments that become fluorescent in the endosome. Cells were stained with the Fab-labeled antibody on ice and, after washing off unbound antibody, incubated at 37°C for four hours. Cells were then analyzed by flow cytometry, recording the geometric MFI (gMFI) at each concentration of antibody.

[0022] FIGS.5A-5B show the results of an immunogenicity assessment of CD33 C2 antibodies. Using the EpiMatrix platform T-cell epitope content of each antibody were expressed as EpiMatrix scores and Tregitope-adjusted EpiMatrix Scores of VH and VL domains (FIG.5A) or as Tregitope-adjusted EpiMatrix Score, Tregitope content, and predicted Ab response (FIG.5B).

[0023] FIG.6 shows a Western blot analysis of tumor tissue processed for GSPT1 degradation and apoptosis (cleaved caspase 3). The tumor tissue was collected from MV4-11- Luc AML xenograft mice that had been administered a single 10 mg / kg dose of antibody CD33-B conjugated to payload linker LP2. Terminal collection of tumor tissue was performed at 0, 6, 24, 48, 72, 168, and 216 hours post-dosing; results are shown for each time point.

[0024] FIG.7 shows a graph of GSPT1 and cleaved caspase 3 levels in tumor tissue collected from MV4-11-Luc AML xenograft mice that had been administered a single 10 mg / kg dose of antibody CD33-B conjugated to payload linker LP2. Terminal collection of tumor tissue was performed at 0, 6, 24, 48, 72, 168, and 216 hours post-dosing; results are shown for each time point.

[0025] FIGS.8A-8B show results from in vitro human serum stability of various CD33- GSPT1-ADCs having different linkers in an in vitro cytotoxicity assay in Molm13 cells (FIG.8A) and MV-411 AML cells (FIG.8B). Cultures were assayed for viability after 3 days by CellTiter –Glo and IC50 values were plotted over time.

[0026] FIGS.9A-9G show results of in vitro potency assays of novel C2 antibodies (CD33- B, CD33-C, CD33-F, CD33-M) when formatted as an ADC using various linker-payload configurations in Molm-13, MV4-11, OCI-AML2, HL-60, U-937, and Pfeiffer cells. ADCs were administered at concentrations ranging from 0.03pM to 55nM. Unconjugated payload compound 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea, was included for comparison. In FIG.9A, ADC cytotoxicity is expressed as IC50 values (nM). In FIGS.9B-9G, ADC cytotoxicity is expressed as dose- response curves.

[0027] FIGS.10A-10B show tumor growth inhibition and survival results in an AML xenograft model. MV-411-Luc tumor cells were engrafted by tail vein injection and allowedto acclimatize for approximately 10 days. After day 10, ADCs were administered at 10 or 3mg / kg, 3-times once per week (QWX3). Alternatively, vehicle or a non-conjugated, equimolar mixture (i.e., 1:8) of antibody and payload were administered as negative controls. The bioluminescent signature of the tumor cells was tracked at the indicated time points for approximately 30 days as indicated in FIG.10A. FIG.10B shows the Kaplan Meier survival profiles of the animals tracked for 120 days post-engraftment. Each experimental group was comprised of 8 animals (n=8, FIG.10A and FIG.10B). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS I. Definitions

[0028] Unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0029] The following abbreviations may be used herein:

[0030] In this application, the use of “or” means “and / or” unless stated otherwise. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim in the alternative only. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

[0031] Exemplary techniques used in connection with recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection), enzymatic reactions, and purification techniques are described, e.g., in Sambrook et al. Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), among other places.

[0032] As used herein, the term “about” refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term “about” generally refers to a range of numerical values (e.g., + / -5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure.

[0033] The term “polypeptide” refers to a polymer of amino acid residues, and is not limited to a minimum length. A “protein” may comprise one or more polypeptides. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present invention, a “polypeptide” or “protein” refers to a polypeptide or protein, respectively, which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site- directed mutagenesis, or may be accidental, such as through mutations of hosts that produce the proteins or errors due to PCR amplification. A protein may comprise two or more polypeptides.

[0034] “CD33” or “sialic acid binding immunoglobulin-like lectin 3 (Siglec-3),” or “SIGLEC-3,” or “SIGLEC3,” as used herein, refers to human CD33 (huCD33; UniProt ID: P20138-1), unless expressly noted otherwise (i.e., murine CD33, cynomolgus CD33, or the like). Exemplary human CD33 amino acid sequences are shown in SEQ ID NO: 97 and SEQ ID NO: 99.

[0035] The term “antibody” herein refers to a molecule comprising at least complementarity- determining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen. The term is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies, diabodies, etc.), full length antibodies, single-chain antibodies, antibody conjugates, and antibody fragments, so long as they exhibit the desired CD33-specific binding activity.

[0036] An “isolated” antibody is one that has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0037] An “antigen” refers to the target of an antibody, i.e., the molecule to which the antibody specifically binds. The term “epitope” denotes the site on an antigen, either proteinaceous or non-proteinaceous, to which an antibody binds. Epitopes on a protein can be formed both from contiguous amino acid stretches (linear epitope) or comprise non- contiguous amino acids (conformational epitope), e.g., coming in spatial proximity due to the folding of the antigen, i.e., by the tertiary folding of a proteinaceous antigen. Linear epitopes are typically still bound by an antibody after exposure of the proteinaceous antigen to denaturing agents, whereas conformational epitopes are typically destroyed upon treatment with denaturing agents.

[0038] An “anti-CD33 antibody” or a “CD33-antibody” or an “antibody that specifically binds to CD33” or an “antibody that binds to CD33” and similar phrases refer to an antibody that specifically binds to CD33 as defined herein.

[0039] The term “heavy chain” refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0040] The term “light chain” refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0041] The term “complementarity determining regions” (“CDRs”) as used herein refers to each of the regions of an antibody variable region which are hypervariable in sequence and which determine antigen binding specificity. Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 or heavy chain CDR1, CDR-H2, CDR-H3), and three in the VL (CDR- L1, CDR-L2, CDR-L3). Unless otherwise indicated, the CDRs are determined according to the sequence table herein.

[0042] “Framework” or “FR” refers to the residues of the variable region residues that are not part of the complementary determining regions (CDRs). The FR of a variable region generally consists of four FRs: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR- L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.

[0043] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs). See, e.g., Kindt et al. Kuby Immunology, 6thed., W.H. Freeman and Co., page 91 (2007). A variable domain may comprise heavy chain (HC) CDR1-FR2-CDR2-FR3-CDR3 with or without all or a portion of FR1 and / or FR4; and light chain (LC) CDR1-FR2-CDR2-FR3-CDR3 with or without all or a portion of FR1 and / or FR4. That is, a variable domain may lack a portion of FR1 and / or FR4 so long as it retains antigen-binding activity. A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol.150 :880-887 (1993) ; Clarkson et al., Nature 352 :624-628 (1991).

[0044] The light chain and heavy chain “constant regions” of an antibody refer to additional sequence portions outside of the FRs and CDRs and variable regions. Certain antibody fragments may lack all or some of the constant regions. From N- to C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three constant heavy domains (CH1, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable domain (VL), also called a variable light domain or a light chain variable region, followed by a constant light (CL) domain.

[0045] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain at Gly446 and Lys447 (EU numbering). Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine and lysine, respectively. Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc region may or may not be present. Thus, a “full-length heavy chain constant region” or a “full length antibody” for example, which is a human IgG1antibody, includes an IgG1 with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0046] “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0047] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called ^, ^, ^, ^, and ^, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0048] An “antibody fragment” or “antigen-binding fragment” or “antigen-binding portion” refers to a fragment or portion of an antibody other than an intact antibody that binds the antigen (i.e., CD33) to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, and scFab); single domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005).

[0049] The terms “full length antibody”, “intact antibody”, and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or, in the case of an IgG antibody, having heavy chains that contain an Fc region as defined herein above.

[0050] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0051] A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the 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 optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0052] A “human antibody” as used herein refers to antibodies produced from human immunoglobulin sequences, such as antibodies produced in non-human animals that comprise human immunoglobulin genes (such as XenoMouse® and VelocImmune® mice), and antibodies selected using in vitro methods, such as phage display, wherein the antibody repertoire is based on a human immunoglobulin sequences.

[0053] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.

[0054] A “multispecific” antibody is one that binds specifically to more than one target antigen, while a “bispecific” antibody is one that binds specifically to two antigens. An “antibody conjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a therapeutic agent or a label.

[0055] Antibodies may be modified as part of the production process in certain host cells or through metabolism in vivo. An antibody or antibody region amino acid sequence herein is intended to encompass not only the specific amino acid sequence, but also that sequence as post-translationally modified, for instance, including side chain modifications and cleavages. Such a post-translational modification can occur, for instance, as a result of production of theantibody in a host cell and / or as a result of post-translational modification in vivo in an animal (e.g., a human).

[0056] In some embodiments, an antibody disclosed herein comprises a post-translational modification (e.g., one or more post-translational modifications). Post-translational modifications can include, e.g., ubiquitination, phosphorylation, acetylation, hydroxylation, methylation, glycyosylation, AMPylation, prenylation, deamidation, elimylation, citrullination, and carbamoylation. In some embodiments, the antibody is not post- translationally modified.

[0057] As noted above, antibodies can undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain, often a Gly-Lys. This cleavage can occur, for instance, as a result of the process of production of the antibody in a host cell. An antibody produced by expression of a specific nucleic acid molecule encoding a full-length heavy chain can include the full-length heavy chain, or it can include a cleaved variant of the full-length heavy chain, such as a heavy chain lacking a C-terminal Lys or a C-terminal Gly-Lys.

[0058] Other types of post-translational modifications can occur during production of antibodies, or otherwise in vivo, such as the modification of an amino acid side chain. For instance, an N-terminal Glu or Gln residue on an antibody chain can be post-translationally modified to an N-terminal pyroglutamate (also known as pyrrolidine carboxylate; abbreviated pE).

[0059] “Percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0060] The term “signal sequence” or “leader sequence” refers to a sequence of amino acid residues located at the N terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein. Leader sequences may be natural orsynthetic, and they may be heterologous or homologous to the protein to which they are attached. Nonlimiting exemplary leader sequences also include leader sequences from heterologous proteins. In some embodiments, an antibody lacks a leader sequence. In some embodiments, an antibody comprises at least one leader sequence, which may be selected from native antibody leader sequences and heterologous leader sequences.

[0061] The term “nucleic acid molecule” or “polynucleotide” includes any compound and / or substance that comprises a polymer of nucleotides. Each nucleotide is composed of a base, specifically a purine- or pyrimidine base (i.e. cytosine I, guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e. deoxyribose or ribose), and a phosphate group. Often, the nucleic acid molecule is described by the sequence of bases, whereby said bases represent the primary structure (linear structure) of a nucleic acid molecule. The sequence of bases is typically represented from 5’ to 3’. Herein, the term nucleic acid molecule encompasses deoxyribonucleic acid (DNA) including e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), in particular messenger RNA (mRNA), synthetic forms of DNA or RNA, and mixed polymers comprising two or more of these molecules. The nucleic acid molecule may be linear or circular. In addition, the term nucleic acid molecule includes both sense and antisense strands, as well as single stranded and double stranded forms. Moreover, the herein described nucleic acid molecule can contain naturally occurring or non- naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugars or phosphate backbone linkages or chemically modified residues. Nucleic acid molecules also encompass DNA and RNA molecules which are suitable as a vector for direct expression of an antibody of the invention in vitro and / or in vivo, e.g., in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA, circular RNA) vectors, can be unmodified or modified.

[0062] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain 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.

[0063] “Isolated nucleic acid encoding an anti-CD33 antibody” refers to one or more nucleic acid molecules encoding anti-CD33 antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0064] The term “vector”, as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.

[0065] The terms “host cell”, “host cell line”, and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells.

[0066] In this disclosure, “binds” or “binding” or “specific binding” and similar terms, when referring to a protein and its ligand or an antibody and its antigen target for example, or some other binding pair, means that the binding affinity between the members of the binding pair is sufficiently strong that the interaction cannot be due to random molecular associations (i.e. “nonspecific binding”). Such binding typically requires a dissociation constant (KD) of 1μM or less, and may often involve a KD of 100 nM or less.

[0067] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). Affinity can generally be represented by the dissociation constant (KD). Affinity of an antibody for an antigen can be measured by common methods known in the art, such as surface plasmon resonance (SPR), for instance.

[0068] The terms “reduce” or “inhibit” more generally refer to a decrease or cessation of any event (such as protein ligand binding) or to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. It is not necessary that the inhibition or reduction be complete. For example, in certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.

[0069] “Treatment” or “treating” as used herein, covers any administration or application of a therapeutic for disease in a human, and includes inhibiting the disease or progression of thedisease or one or more disease symptoms, inhibiting or slowing the disease or its progression or one or more of its symptoms, arresting its development, partially or fully relieving the disease or one or more of its symptoms, or preventing a recurrence of one or more symptoms of the disease.

[0070] The terms “subject” and “patient” are used interchangeably herein to refer to a human unless expressly indicated otherwise (i.e., a murine subject or the like).

[0071] The term “cancer” is used herein to refer to a group of cells that exhibit abnormally high levels of proliferation and growth. A cancer may be benign (also referred to as a benign tumor), pre-malignant, or malignant. Cancer cells may be solid cancer cells or leukemic cancer cells.

[0072] Examples of cancers applicable to methods of treatment herein include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular nonlimiting examples of such cancers include squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer (including squamous cell non-small cell lung cancer), adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, renal cell carcinoma, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and various types of head and neck cancer (including squamous cell carcinoma of the head and neck).

[0073] As used herein, the term “tumor,” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. “Neoplastic,” as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth.

[0074] As used herein, “hematologic malignancy” refers to cancer of the body's blood- forming and immune system—the bone marrow and lymphatic tissue. Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.

[0075] The term “leukemia” refers to malignant neoplasms of the blood-forming tissues. The leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or resistant to conventional therapy.

[0076] As used herein, “promyelocytic leukemia” or “acute promyelocytic leukemia” refers to a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. It is usually marked by an exchange of regions of chromosomes 15 and 17.

[0077] As used herein, “acute lymphocytic leukemia (ALL)”, also known as “acute lymphoblastic leukemia” refers to a malignant disease caused by the abnormal growth and development of early nongranular white blood cells, or lymphocytes.

[0078] As used herein, “T-cell leukemia” refers to a disease in which certain cells of the lymphoid system called T lymphocytes or T cells are malignant. T cells are white blood cells that normally can attack virus-infected cells, foreign cells, and cancer cells and produce substances that regulate the immune response.

[0079] The term “relapsed” refers to a situation where patients who have had a remission of leukemia after therapy have a return of leukemia cells in the marrow and a decrease in normal blood cells.

[0080] The term “refractory or resistant” refers to a circumstance where patients, even after intensive treatment, have residual leukemia cells in their marrow.

[0081] “Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.

[0082] The term “effective amount” or “therapeutically effective amount” refers to an amount of a drug effective for treatment of a disease or disorder in a subject, such as to partially or fully relieve one or more symptoms. In some embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0083] A “biological sample” as used herein refers to a sample taken from a subject or from an animal. Examples of biological samples include tissue samples and liquid biological samples, such as whole blood, serum, plasma, blood supernatant, or synovial fluid. A biological sample may be taken directly from a subject or may be first chemically or physically modified in some fashion prior to use, for example, in order to assist in analysis of the sample.

[0084] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non- toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. For example, if the therapeutic agent is to be administered orally, the carrier may be a gel capsule. If the therapeutic agent is to be administered subcutaneously, the carrier ideally is not irritable to the skin and does not cause injection site reaction.

[0085] “Aliphatic” refers to a straight or branched and / or cyclic hydrocarbon chain group consisting solely of carbon and hydrogen atoms, having from one to 25, one to 20, one to 15, one to ten, one to eight, one to six, one to five, or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., alkyl, alkenyl, cycloalkyl, and the like. In some embodiments, aliphatic contains no unsaturation. In some embodiments, aliphatic is a straight or branched chain. In some embodiments, aliphatic comprises a cycle. In some embodiments, aliphatic comprises a straight or branched chain and a cycle.

[0086] “Alkyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six, one to four, or one to three carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.

[0087] “Alkenyl” refers to a straight or branched chain unsaturated group consisting solely of carbon and hydrogen atoms, having from two to eight, two to six or two to four carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenyl, prop-1-enyl, but-2-enyl, and the like. The straight or branched chain unsaturated group is attached to the rest of the molecule by a single bond.

[0088] “Alkoxy” refers to the group having the formula —OR wherein R is alkyl. An “optionally substituted alkoxy” refers to the group having the formula —OR wherein R is an optionally substituted alkyl as defined herein.

[0089] “Alkoxyalkyl” refers to an alkoxy group as defined herein which is attached to the rest of the molecule by an alkyl group as defined herein.

[0090] “Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″ are each independently hydrogen, alkyl or haloalkyl. An “optionally substituted amino” refers to a radical having the formula —NR′R″ wherein one or both of R′ and R″ are optionally substituted alkyl as defined herein.

[0091] “Aryl” refers to a 5- to 18-membered, 6- to 18-membered, 6- to 10-membered, or 6- membered carbocylic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non- aromatic ring, examples of which are acenaphene, indene, and fluorene.

[0092] “Cycloalkyl” refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to 12, three to ten, or three to seven carbon atoms, which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl, bicyclo[2.2.2]octane and the like.

[0093] “Cycloalkoxy” refers to a cycloalkyl group as defined herein which is attached to the rest of the molecule by an oxygen atom.

[0094] “Ene” or “enyl,” when used as a suffix herein, means that the group being modified with the suffix is attached to the rest of the molecule through two or more points of attachment (typically, two), e.g., alkylene, alkenylene, and the like. The group may be attached to the rest of the molecule through any two suitable atoms in the group.

[0095] “Halo, “halogen” or “halide” refers to F, Cl, Br or I. In some embodiments, halo is fluoro or chloro. In a particular embodiment, halo is fluoro.

[0096] “Haloalkyl” refers to an alkyl group, in certain embodiments, C1-6alkyl group, in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl 1-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2- fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,3-difluoro-2- methylpropyl, 2,2-difluorocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and 2,2,2-trifluoro-1,1-dimethylethyl.

[0097] “Haloalkoxy” refers to the group having the formula —OR wherein R is haloalkyl, as defined herein.

[0098] “Heterocycle” or “Heterocyclyl” refers to a stable 3- to 15-membered, 3- to-12 membered, 4- to 12-membered, 4- to 7-membered, 5- to 12-membered, or 5- to 6-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one embodiment, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Exemplary heterocyclic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl, indolinyl and others.

[0099] “Heterocyclyloxy” refers to a heterocyclyl group as defined herein which is attached to the rest of the molecule by an oxygen atom.

[0100] “Heteroaryl” refers to a heterocyclyl group as defined above which is aromatic. The heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl groups, and may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl and others.

[0101] “Oxo” refers to =O.

[0102] “Sugar acid” refers to a monosaccharide with a carboxyl (-COO / -COOH) group at one or both ends of its chain, e.g., glyceric acid, xylonic acid, gluconic acid, ascorbic acid, neuraminic acid, ketodeoxyoctulosonic acid, glucuronic acid, galacturonic acid, iduronic acid, tartaric acid, mucic acid, and saccharic acid.

[0103] “EC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% potency or effect of a maximal response, such as cell growth or proliferation measured via any of the in vitro or cell-based assay described herein.

[0104] “IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as cell growth or proliferation, measured via any of the in vitro or cell-based assay described herein.

[0105] Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

[0106] As used herein and unless otherwise indicated, the term “hydrate” means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces.

[0107] As used herein and unless otherwise indicated, the term “solvate” means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

[0108] Unless stated otherwise specifically described in the specification, it is understood that the substitution can occur on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

[0109] Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens.

[0110] When the groups described herein, with the exception of alkyl group, are said to be “substituted,” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether;imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0111] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein.

[0112] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.

[0113] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0114] Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0115] Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res.308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact.117: 191 (1999).

[0116] Without being limited by any particular theory, isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of deleterious metabolites in specific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[0117] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al., Adv. Drug Res., vol.14, pp.1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp.79-88 (1999)).

[0118] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C—H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes formin the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0119] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has two neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life=12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and typically gives numerically larger isotope effects.

[0120] Similarly, substitution of isotopes for other elements, including, but not limited to,13C or14C for carbon,33S,34S, or36S for sulfur,15N for nitrogen, and17O or18O for oxygen, may provide kinetic isotope effects.

[0121] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) or carbon-carbon (C—C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long- term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. As a result, these drugs often require the administration of multiple or high daily doses.

[0122] Isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and / or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. In one embodiment, the deuterium enrichment is performed on the site of C—H bond cleavage during metabolism.

[0123] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.II. Exemplary Anti-CD33 Antibodies

[0124] Novel antibodies directed against CD33, such as human CD33, are provided. Anti- CD33 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibodies comprising the heavy chain and / or light chain CDRs discussed herein. In some embodiments, an isolated antibody that binds to CD33 is provided. In some embodiments, a monoclonal antibody that binds to CD33 is provided. In some embodiments, the antibody binds to human CD33. In some embodiments, the antibody binds to human CD33 comprising the amino acid sequence of SEQ ID NO: 97, and / or binds to human CD33 comprising the amino acid sequence of SEQ ID NO: 99.

[0125] In some embodiments, an anti-CD33 antibody comprises a heavy chain variable region and a light chain variable region. In some embodiments, an anti-CD33 antibody comprises at least one heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, an anti-CD33 antibody comprises two heavy chains, wherein each heavy chain comprises a heavy chain variable region and at least a portion of a heavy chain constant region, and two light chains, wherein each light chain comprises a light chain variable region and at least a portion of a light chain constant region. As used herein, a single-chain Fv (scFv), or any other antibody that comprises, for example, a single polypeptide chain comprising all six CDRs (three heavy chain CDRs and three light chain CDRs) is considered to have a heavy chain and a light chain. In some embodiments, the heavy chain is the region of the anti-CD33 antibody that comprises the three heavy chain CDRs. In some embodiments, the light chain is the region of the anti-CD33 antibody that comprises the three light chain CDRs.

[0126] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 27 or 28.

[0127] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chaincomplementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28.

[0128] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 4; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41.

[0129] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41.

[0130] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46.

[0131] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46.

[0132] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59.

[0133] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59.

[0134] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 61-66; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68.

[0135] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61- 66; (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68.

[0136] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0137] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising theamino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0138] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0139] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0140] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0141] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0142] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0143] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0144] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0145] In some embodiments, the anti-CD33 antibody comprises six CDRs an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0146] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0147] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27.

[0148] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acidsequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0149] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0150] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0151] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0152] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0153] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0154] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ IDNO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0155] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0156] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0157] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0158] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0159] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0160] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0161] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0162] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0163] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0164] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0165] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, anLCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40.

[0166] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0167] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0168] In some embodiments, an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0169] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0170] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0171] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence ofSEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0172] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0173] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0174] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46.

[0175] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46.

[0176] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0177] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0178] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0179] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0180] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0181] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0182] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the aminoacid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0183] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0184] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0185] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0186] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0187] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0188] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ IDNO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0189] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58.

[0190] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0191] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0192] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0193] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0194] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0195] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0196] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0197] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0198] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0199] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, anLCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0200] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0201] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0202] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0203] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0204] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0205] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising theamino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0206] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0207] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0208] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0209] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67.

[0210] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0211] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0212] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; and (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3.

[0213] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0214] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9.

[0215] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0216] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15.

[0217] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27 or 28.

[0218] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41.

[0219] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (iii) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46.

[0220] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59.

[0221] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68.

[0222] In some embodiments, any of the six CDRs provided herein can be combined as subparts with any of the other CDRs provided herein, for a total of six CDRs in a construct. Thus, in some embodiments, two CDRs from a first antibody (for example, HCDR1 and HCDR2) can be combined with four CDRs from a second antibody (HCDR3, LCDR1, LCDR2, and LCDR3). In some embodiments, two or fewer residues in one or more of the CDRs can be replaced to obtain a variant thereof. In some embodiments, two or fewer residues can be replaced in 1, 2, 3, 4, 5, or 6 of the CDRs.

[0223] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) an LCDR3 comprising the amino acidsequence of SEQ ID NO: 27 or 28; wherein the VH domain comprises a 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: 69, 70, 71, 72, or 73, and the VL domain comprises a 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82.

[0224] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; wherein the VH domain comprises a 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: 69, 70, 71, 72, or 73, and the VL domain comprises a 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82.

[0225] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; wherein the VH domain comprises a 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: 69, 70, 71, 72, or 73, and the VL domain comprises a 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82.

[0226] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; wherein the VH domain comprises a 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: 69, 70, 71, 72, or 73, and the VL domain comprises a 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82.

[0227] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68; wherein the VH domain comprises a 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: 69, 70, 71, 72, or 73, and the VL domain comprises a 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82.

[0228] In some embodiments, an anti-CD33 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: 69, 70, 71, 72, or 73. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind CD33. In some embodiments, atotal of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 69, 70, 71, 72, or 73. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VH sequence in SEQ ID NO: 69, 70, 71, 72, or 73, including post-translational modifications of that sequence.

[0229] In some embodiments, an anti-CD33 antibody is provided, wherein 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VL sequence in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82, including post-translational modifications of that sequence.

[0230] In some embodiments, an anti-CD33 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: 69, 70, 71, 72, or 73 and 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: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 69, 70, 71, 72, or 73. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, substitutions, insertions, or deletions occur in regions outside theCDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VH sequence in SEQ ID NO: 69, 70, 71, 72, or 73 and the VL sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82, including post-translational modifications of one or both sequences.

[0231] In some embodiments, an anti-CD33 antibody comprises a VH as in any of the embodiments provided herein, and a VL as in any of the embodiments provided herein. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 69 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 75, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 71 and SEQ ID NO: 76, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 75, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 77, respectively, including post- translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 78, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 78, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 79, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 80, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 69 and SEQ ID NO: 81, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 73 and SEQ ID NO: 82, respectively, including post- translational modifications of those sequences.

[0232] In some embodiments, an anti-CD33 antibody comprises a heavy chain (HC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, a HC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the HC sequence in SEQ ID NO: 83, 84, 85, 86, or 87, including post-translational modifications of that sequence.

[0233] In some embodiments, an anti-CD33 antibody is provided, wherein the antibody comprises a light chain (LC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, a LC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the LC sequence in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96, including post-translational modifications of that sequence.

[0234] In some embodiments, an anti-CD33 antibody comprises a heavy chain (HC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, 84, 85, 86, or 87 and a light chain (LC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, a HC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a LC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions),insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the HC sequence in SEQ ID NO: 83, 84, 85, 86, or 87 and the LC sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96, including post-translational modifications of one or both sequences.

[0235] In some embodiments, an anti-CD33 antibody comprises a HC as in any of the embodiments provided herein, and a LC as in any of the embodiments provided herein. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 83 and SEQ ID NO: 88, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 89, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 85 and SEQ ID NO: 90, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 89, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 91, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 88, respectively, including post- translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 88, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 92, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 92, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 93, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 94, respectively, including post-translational modifications of those sequences.In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 83 and SEQ ID NO: 95, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 87 and SEQ ID NO: 96, respectively, including post-translational modifications of those sequences.

[0236] In various embodiments, an anti-CD33 antibody provided herein may comprise pyroglutamic acid (pyroGlu or pE) in place of glutamic acid (Glu or E) at the N-terminus. In some embodiments, pyroGlu is formed by cyclization of an N-terminal Glu during expression and / or purification of the antibody. Thus, a Glu (E) at the N-terminus of an antibody chain sequence provided herein may be replaced with a pyroGlu, and antibodies comprising pyroGlu in place of Glu at the N-terminus the sequences provided herein are contemplated. Thus, in some embodiments, an anti-CD33 antibody is provided, wherein the antibody comprises a heavy chain variable domain comprising the sequence of any one of SEQ ID NO: 69, 70, 71, 72, or 73, wherein the N-terminal Glu (E) is replaced with a pyroGlu (pE). Similarly, an anti-CD33 antibody is provided, wherein the antibody comprises a heavy chain comprising the sequence of any one of SEQ ID NO: 83, 84, 85, 86, or 87, wherein the N- terminal Glu (E) is replaced with a pyroGlu (pE).

[0237] In various embodiments, the antibody is a monoclonal antibody.

[0238] In various embodiments, an anti-CD33 antibody specifically may comprise any of the following properties, singly or in combination.In some embodiments, the antibody binds to human CD33 with an affinity (KD) of less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, from 0.01 nM to 5 nM, from 0.01 nM to 1 nM, from 0.05 nM to 1 nM, from 0.1 nM to 1 nM, from 0.1 nM to 0.5 nM, from 0.05 nM to 0.5 nM, from 0.05 nM to 0.1 nM, or from 0.5 nM to 1 nM. In some embodiments, the antibody binds to cynomolgus monkey CD33 with a KD less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, from 0.01 nM to 5 nM, from 0.01 nM to 1 nM, from 0.05 nM to 1 nM, from 0.1 nM to 1 nM, from 0.1 nM to 0.5 nM, from 0.05 nM to 0.5 nM, from 0.05 nM to 0.1 nM, or from 0.5 nM to 1 nM. In some embodiments, the antibody binds to human CD33 with a KDof less than 1.5 nM. In some embodiments, the antibody binds to cynomolgus monkey CD33 with an affinity (KD) of less than 10 nM. In some embodiments, affinity is determined using biolayer interferometry.

[0239] In some embodiments, the antibody binds human CD33. In some embodiments, the human CD33 comprises the amino acid sequence of SEQ ID NO: 97. In some embodiments, the human CD33 comprises the amino acid sequence of SEQ ID NO: 99. In someembodiments, the antibody binds the monomeric form of human CD33. In some embodiments, the antibody binds the dimeric form of human CD33. In some embodiments, the antibody binds cynomolgus monkey CD33. In some embodiments, the cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody binds the monomeric form of cynomolgus monkey CD33. In some embodiments, the antibody binds the dimeric form of cynomolgus monkey CD33.

[0240] In some embodiments, the antibody does not significantly bind to human Siglec 6. In some embodiments, the antibody does not significantly bind to human Siglec 8.

[0241] In some embodiments, the antibody is capable of mediating internalization of the antibody in CD33+ cells. In some embodiments, the antibody internalizes after binding to CD33+ cells. In some embodiments, the antibody has a Tregitope-adjusted EpiMatrix Score equal to or less than 0, equal to or less than -25, or equal to or less than -45. III. Exemplary Antibody Variants, Fragments, and Constant Regions

[0242] In many embodiments, an antibody specifically binding to CD33 may further incorporate any of the features, singly or in combination, as described in the sections that follow. A. Antibody Fragments

[0243] In certain embodiments, an antibody provided herein is an antibody fragment. In some embodiments, the anti-CD33 antibody is an antibody fragment selected from an Fv, single- chain Fv (scFv), Fab, Fab’, or (Fab’)2. 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., Pluckthün, in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp.269-315 (1994); see also WO 93 / 16185; and U.S. Patent Nos.5,571,894 and 5,’87,458. For discussion of Fab and F(a’')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No.5,869,046.

[0244] Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med.9:129-134 (2003).

[0245] Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of anantibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No.6,248,516).

[0246] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein. B. Bispecific or Multispecific Antibodies

[0247] In certain embodiments, an antibody provided herein is a multispecific antibody, for example, a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is CD33 and the other is for any other antigen. In certain embodiments, bispecific antibodies may bind to two different epitopes of CD33. Bispecific antibodies may also be used to localize drugs such as cytotoxic agents or to localize detection labels to cells that express CD33. some embodiments, the multispecific antibody (e.g., bispecific antibody) comprises a first variable domain comprising the CDRs or variable regions as described herein. Bispecific antibodies can be prepared as full length antibodies or antibody fragments.

[0248] In some embodiments, an antibody provided herein is a bispecific antibody comprising a first antigen-binding domain that binds CD33 and a second antigen-binding domain that binds a second antigen. In various embodiments, the first antigen-binding domain is an antigen-binding domain that binds CD33 described herein. In some embodiments, the bispecific antibody is an immune cell engager. In some embodiments, the second antigen binding domain binds an antigen on the surface of T cells. In some embodiments, the second antigen binding domain binds an antigen on the surface of NK cells. In some embodiments, the second antigen binding domain of the bispecific antibody binds an antigen selected from CD3, CD16, CD16A, NKG2C, or NKG2D.

[0249] Techniques for making multispecific antibodies include, but are not limited to, 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-in-hole” engineering (see, e.g., U.S. Patent No.5,731,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009 / 089004A1); cross-linking two or more antibodies or fragments (see, e.g., US Patent No.4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 18(5):1547-1553 (1992)); using “diabod” technology for making 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 preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol.147: 60 (1991).

[0250] Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g. US 2006 / 0025576). C. Human Antibodies

[0251] In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be made by any suitable method. Nonlimiting exemplary methods include making human antibodies in transgenic mice that comprise human immunoglobulin loci. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA 90: 2551-55 (1993); Jakobovits et al., Nature 362: 255-8 (1993); Lonberg et al., Nature 368: 856-9 (1994); and U.S. Patent Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,545,807; 6,300,129; 6,255,458; 5,877,397; 5,874,299; and 5,545,806.

[0252] Nonlimiting exemplary methods also include selecting human antibodies from phage display libraries. See, e.g., Hoogenboom et al., J. Mol. Biol.227: 381-8 (1992); Marks et al., J. Mol. Biol.222: 581-97 (1991); and PCT Publication No. WO 99 / 10494. D. Chimeric and Humanized Antibodies

[0253] In certain embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0254] In certain embodiments, a chimeric antibody is a humanized antibody. In some embodiments, an antibody provided herein is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody fromwhich the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0255] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos.5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) 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 the “guided selection” approach to FR shuffling).

[0256] Human framework regions that may 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.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carte r et al. Pro c. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem.272:10678-10684 (1997) and Rosok et al., J. Biol. Chem.271:22611-22618 (1996)).

[0257] In some embodiments, the humanized antibodies may comprise a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. E. Glycosylation and Pegylation Variants

[0258] In certain embodiments, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos.5,714,350 and 6,350,861 by Co et al.

[0259] Glycosylation of the constant region on N297 can be prevented by mutating the N297 residue to another residue, e.g., N297A, and / or by mutating an adjacent amino acid, e.g., 298 to thereby reduce glycosylation on N297.

[0260] Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies described herein to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03 / 035835 by Presta describes a variant CHO cell line, Led 3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al. (2002) J. Biol. Chem.277:26733-26740). PCT Publication WO 99 / 54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases {e.g., beta(l,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech.17: 176-180).

[0261] Another modification of the antibodies described herein is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. In some embodiments, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (CI-CIO) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods forpegylating proteins are known in the art and can be applied to the antibodies described herein. See for example, EP 0154316 by Nishimura et al. and EP 0401384 by Ishikawa et al. F. Constant Regions

[0262] In some embodiments, the antibody is a full-length antibody. In some embodiments, an antibody described herein comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from κ and λ. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region. In some embodiments, an antibody described herein comprises a human IgG constant region, such as an IgG1, IgG2, IgG3, or IgG4. In some embodiments, the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, an antibody described herein comprises a human IgG4 heavy chain constant region. In some such embodiments, an antibody described herein comprises an S241P mutation in the human IgG4 constant region. In some embodiments, an antibody described herein comprises a human IgG4 constant region and a human κ light chain.

[0263] In some embodiments, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain at Gly446 and Lys447 (EU numbering). Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain and / or a cleaved variant of the full-length heavy chain. In some embodiments, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc region may or may not be present. Thus, a “full-length heavy chain constant region” or a “full length antibody” for example, which is a human IgG1 antibody, includes an IgG1 with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine.

[0264] The choice of heavy chain constant region can determine whether or not an antibody will have effector function in vivo. Such effector function, in some embodiments, includes antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), and can result in killing of the cell to which the antibody is bound. In some methods of treatment, including methods of treating some cancers, cell killing may be desirable, for example, when the antibody binds to a cell that supports the maintenance or growth of the tumor. Exemplary cells that may support the maintenance or growth of a tumorinclude, but are not limited to, tumor cells themselves, cells that aid in the recruitment of vasculature to the tumor, and cells that provide ligands, growth factors, or counter-receptors that support or promote tumor growth or tumor survival. In some embodiments, when effector function is desirable, an antibody comprising a human IgG1 heavy chain or a human IgG3 heavy chain is selected.

[0265] In certain embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0266] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibodies with certain improved properties. For example, in some embodiments an antibody may be afucosylated, for example, by mutating residues such as Asn297 that are normally glycosylated with fucose-containing glycosylations, or through other means. In some embodiments, antibodies herein may comprise an afucosylated human IgG1 constant region.

[0267] Antibodies are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibodies may have reduced fucosylation and / or improved ADCC function. Examples of such antibodies are described, e.g., in WO 2003 / 011878 (Jean-Mairet et al.); US Patent No.6,602,684 (Umana et al.); and US 2005 / 0123546 (Umana et al.). Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibodies may have improved CDC function. Such antibodies are described, e.g., in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0268] Antibodies are also provided with amino-terminal leader extensions. For example, one or more amino acid residues of the amino-terminal leader sequence are present at the amino- terminus of any one or more heavy or light chains of an antibody. An exemplary amino- terminal leader extension comprises or consists of three amino acid residues, VHS, present on one or both light chains of an antibody.

[0269] The in vivo or serum half-life of human FcRn high affinity binding polypeptides can be assayed, e.g., in transgenic mice, in humans, or in non-human primates to which the polypeptides with a variant Fc region are administered. See also, e.g., Petkova et al. International Immunology 18(12):1759-1769 (2006).

[0270] In some embodiments of the invention, an afucosylated antibody mediates ADCC in the presence of human effector cells more effectively than a parent antibody that comprises fucose, Generally, ADCC activity may be determined using the in vitro ADCC assay as herein disclosed, but other assays or methods for determining ADCC activity, e.g. in an animal model etc., are contemplated.

[0271] In certain embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320, 322, 330, and / or 331 (EU numbering) can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Patent Nos.5,624,821 and 5,648,260, both by Winter et al.

[0272] In some examples, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos.6,194,551 by Idusogie et al.

[0273] In some examples, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94 / 29351 by Bodmer et al. In some examples, the Fc region can be modified to decrease antibody dependent cellular cytotoxicity (ADCC) and / or to decrease the affinity for an Fcγ receptor by modifying one or more amino acids at the following positions: 234, 235, 236, 238, 239, 240, 241 , 243, 244, 245, 247, 248, 249, 252, 254, 255, 256, 258, 262, 263, 264, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 299, 301, 303, 305, 307, 309, 312, 313, 315, 320, 322, 324, 325, 326, 327, 329, 330, 331, 332, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 433, 434, 435, 436, 437, 438 or 439 (EU numbering). Exemplary substitutions include 236A, 239D, 239E, 268D, 267E, 268E, 268F, 324T, 332D, and 332E. Exemplary variants include 239D / 332E, 236A / 332E, 236A / 239D / 332E, 268F / 324T, 267E / 268F, 267E / 324T, and 267E / 268F7324T (EUnumbering). Other Fc modifications that can be made to Fcs are those for reducing or ablating binding to FcγR and / or complement proteins, thereby reducing or ablating Fc- mediated effector functions such as ADCC, ADCP, and CDC. Exemplary modifications include but are not limited substitutions, insertions, and deletions at positions 234, 235, 236, 237, 267, 269, 325, 328, 330, and / or 331 (e.g., 330 and 331), wherein numbering is according to the EU index. Exemplary substitutions include but are not limited to 234A, 235E, 236R, 237A, 267R, 269R, 325L, 328R, 330S, and 331S (e.g., 330S, and 331S), wherein numbering is according to the EU index. An Fc variant can comprise 236R / 328R. Other modifications for reducing FcγR and complement interactions include substitutions 297A, 234A, 235A, 237A, 318A, 228P, 236E, 268Q, 309L, 330S, 331 S, 220S, 226S, 229S, 238S, 233P, and 234V, as well as removal of the glycosylation at position 297 by mutational or enzymatic means or by production in organisms such as bacteria that do not glycosylate proteins. These and other modifications are reviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691. For example, the human IgG1.3 Fc constant region contains L234A, L235E, and G237A substitutions. The IgG1fa.P238K (or IgG1.P238K) contains a P238K substitution. The IgG1.1f comprises L234A, L235E, G237A, A330S, and P331S substitutions. (All numbering under the EU index.)

[0274] Fc variants that enhance affinity for an inhibitory receptor FcγRIIb can also be used. Such variants can provide an Fc fusion protein with immunomodulatory activities related to FcγRIIb cells, including for example, B cells and monocytes. In one embodiment, the Fc variants provide selectively enhanced affinity to FcγRIIb relative to one or more activating receptors. Modifications for altering binding to FcγRIIb include one or more modifications at a position selected from the group consisting of 234, 235, 236, 237, 239, 266, 267, 268, 325, 326, 327, 328, 330, 331, and 332, according to the EU index. Exemplary substitutions for enhancing FcγRllb affinity include but are not limited to 234A, 234D, 234E, 234F, 234W, 235D, 235E, 235F, 235R, 235Y, 236D, 236N, 237A, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, 330S, 331S, and 332E. Exemplary substitutions include 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y. Other Fc variants for enhancing binding to FcγRIIb include 235Y / 267E, 236D / 267E, 239D / 268D, 239D / 267E, 267E / 268D, 267E / 268E, and 267E / 328F. (All numbering under the EU index.)

[0275] Other modifications for enhancing FcγR and complement interactions include but are not limited to substitutions 298 A, 333A, 334A, 326A, 2471, 339D, 339Q, 280H, 290S, 298D, 298V, 243L, 292P, 300L, 396L, 3051, and 396L. These and other modifications arereviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691. Fc modifications that increase binding to an Fcγ receptor include amino acid modifications at any one or more of amino acid positions 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 279, 280, 283, 285, 298, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 312, 315, 324, 327, 329, 330, 335, 337, 338, 340, 360, 373, 376, 379, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439 of the Fc region, wherein the numbering of the residues in the Fc region is that of the EU index as in Patent Publication No. WO 00 / 42072.

[0276] Optionally, the Fc region can comprise a non-naturally occurring amino acid residue at additional and / or alternative positions known to one skilled in the art (see, e.g., U.S. Pat. Nos.5,624,821; 6,277,375; 6,737,056; 6,194,551; 7,317,091; 8,101,720; PCX Patent Publications WO 00 / 42072; WO 01 / 58957; WO 02 / 06919; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752; WO 04 / 074455; WO 04 / 099249; WO 04 / 063351; WO 05 / 070963; WO 05 / 040217, WO 05 / 092925 and WO 06 / 020114).

[0277] The affinities and binding properties of an Fc region for its ligand can be determined by a variety of in vitro assay methods (biochemical or immunological based assays) known in the art including but not limited to, equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA), or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods can utilize a label on one or more of the components being examined and / or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions.

[0278] In certain embodiments, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, this can be done by increasing the binding affinity of the Fc region for FcRn, For example, one or more of more of following residues can be mutated: 252, 254, 256, 433, 435, 436, as described in U.S. Pat. No.6,277,375. Specific exemplary substitutions include one or more of the following: T252L, T254S, and / or T256F. Alternatively, to increase the biological half life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2domain of an Fc region of an IgG, as described in U.S. Patent Nos.5,869,046 and 6,121,022 by Presta et al. Other exemplary variants that increase binding to FcRn and / orimprove pharmacokinetic properties include substitutions at positions 259, 308, 428, and 434, including for example 2591, 308F, 428L, 428M, 434S, 43411.434F, 434Y, and 434X1. Other variants that increase Fc binding to FcRn include: 250E, 250Q, 428 L, 428F, 250Q / 428L (Hinton et al.2004, J. Biol. Chem.279(8): 6213-6216, Hinton et al.2006 Journal of Immunology 176:346-356), 256A, 272A, 286A, 305A, 307A, 307Q, 311A, 312A, 376A, 378Q, 380A, 382A, 434A (Shields et al., Journal of Biological Chemistry, 2001, 276(9):6591-6604), 252F, 252T, 252Y, 252W, 254T, 256S, 256R, 256Q, 256E, 256D, 256T, 309P, 311 S, 433R, 433S, 4331, 433P, 433Q, 434H, 434F, 434Y, 252Y / 254T / 256E, 433K / 434F / 436H, 308T / 309P / 311S (Dall’Acqua et al. Journal of Immunology, 2002, 169:5171-5180, Dal’Acqua et al., 2006, Journal of Biological Chemistry 281:23514-23524). Other modifications for modulating FcRn binding are described in Yeung et al., 2010, J Immunol, 182:7663-7671.

[0279] In certain embodiments, hybrid IgG isotypes with particular biological characteristics can be used. For example, an IgG1 / IgG3 hybrid variant can be constructed by substituting IgG1 positions in the CH2and / or CH3region with the amino acids from IgG3 at positions where the two isotypes differ. Thus a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., 274Q, 276K, 300F, 339T, 356E, 358M, 384S, 392N, 397M, 4221, 435R, and 436F. In some embodiments described herein, an IgG1 / IgG2 hybrid variant can be constructed by substituting IgG2 positions in the CH2and / or CH3region with amino acids from IgG1 at positions where the two isotypes differ. Thus a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., one or more of the following amino acid substitutions: 233E, 234L, 235L, +236G (referring to an insertion of a glycine at position 236), and 327A.

[0280] Moreover, the binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R.L. et al. (2001) J. Biol. Chem.276:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 were shown to improve binding to FcγRIII. Additionally, the following combination mutants were shown to improve FcγRIII binding: T256A / S298A, S298A / E333A, S298A / K224A and S298A / E333A / K334A, which has been shown to exhibit enhanced FcγRIIIa binding and ADCC activity (Shields et al., 2001). Other IgG1 variants with strongly enhanced binding to FcγRIIIa have been identified, including variants with S239D / I332E and S239D / I332E / A330L mutations which showed the greatest increase in affinity for FcγRIIIa, a decrease in FcγRIIb binding, and strong cytotoxic activity in cynomolgus monkeys (Lazar et al., 2006). Introduction of the triple mutations into antibodiessuch as alemtuzumab (CD52-specific), trastuzumab (HER2 / neu-specific), rituximab (CD20- specific), and cetuximab (EGFR- specific) translated into greatly enhanced ADCC activity in vitro, and the S239D / I332E variant showed an enhanced capacity to deplete B cells in monkeys (Lazar et al., 2006). In addition, IgG1 mutants containing L235V, F243L, R292P, Y300L and P396L mutations which exhibited enhanced binding to FcγRIIIa and concomitantly enhanced ADCC activity in transgenic mice expressing human FcγRIIIa in models of B cell malignancies and breast cancer have been identified (Stavenhagen et al., 2007; Nordstrom et al., 2011). Other Fc mutants that can be used include: S298A / E333A / L334A, S239D / I332E, S239D / I332E / A330L, L235V / F243L / R292P / Y300L / P396L, and M428L / N434S.

[0281] In certain embodiments, an Fc is chosen that has reduced binding to FcγRs. An exemplary Fc, e.g., IgG1 Fc, with reduced FcγR binding comprises the following three amino acid substitutions: L234A, L235E and G237A.

[0282] In certain embodiments, an Fc is chosen that has reduced complement fixation. An exemplary Fc, e.g., IgG1 Fc, with reduced complement fixation has the following two amino acid substitutions: A330S and P331S.

[0283] In certain embodiments, an Fc is chosen that has essentially no effector function, i.e., it has reduced binding to FcγRs and reduced complement fixation. An exemplary Fc, e.g., IgG1 Fc, that is effectorless comprises the following five mutations: L234A, L235E, G237A, A330S and P331S.

[0284] When using an IgG4 constant domain, it can include the substitution S228P, which mimics the hinge sequence in IgG1 and thereby stabilizes IgG4 molecules. Fc modifications described in WO 2017 / 087678 or WO2016081746 may also be used.

[0285] In certain embodiments, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos.5,714,350 and 6,350,861 by Co et al.

[0286] Glycosylation of the constant region on N297 can be prevented by mutating the N297 residue to another residue, e.g., N297A, and / or by mutating an adjacent amino acid, e.g., 298 to thereby reduce glycosylation on N297.

[0287] Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies described herein to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03 / 035835 by Presta describes a variant CHO cell line, Led 3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al. (2002) J. Biol. Chem.277:26733-26740). PCT Publication WO 99 / 54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases {e.g., beta(l,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech.17: 176-180).

[0288] Another modification of the antibodies described herein is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. In some embodiments, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (CI-CIO) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods forpegylating proteins are known in the art and can be applied to the antibodies described herein. See for example, EP 0154316 by Nishimura et al. and EP 0401384 by Ishikawa et al. IV. Nucleic Acid Molecules Encoding Anti-CD33 Antibodies

[0289] Nucleic acid molecules comprising polynucleotides that encode one or more chains of anti-CD33 antibodies described herein are provided. In some embodiments, a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of an anti- CD33 antibody. In some embodiments, provided is an isolated nucleic acid encoding any one of the anti-CD33 antibodies provided herein. In some embodiments, a nucleic acid molecule comprises both a polynucleotide that encodes a heavy chain and a polynucleotide that encodes a light chain, of an anti-CD33 antibody. In some embodiments, a first nucleic acid molecule comprises a first polynucleotide that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide that encodes a light chain.

[0290] In some such embodiments, the heavy chain and the light chain are expressed from one nucleic acid molecule, or from two separate nucleic acid molecules, as two separate polypeptides. In some embodiments, such as when an antibody is an scFv, a single polynucleotide encodes a single polypeptide comprising both a heavy chain and a light chain linked together.

[0291] In some embodiments, a polynucleotide encoding a heavy chain or light chain of an anti-CD33 antibody comprises a nucleotide sequence that encodes a leader sequence, which, when translated, is located at the N terminus of the heavy chain or light chain. The leader sequence may be the native heavy or light chain leader sequence, or may be another heterologous leader sequence.

[0292] Nucleic acid molecules may be constructed using recombinant DNA techniques conventional in the art. In some embodiments, a nucleic acid molecule is an expression vector that is suitable for expression in a selected host cell. V. Anti-CD33 Antibody Expression and Production A. Vectors

[0293] Vectors comprising polynucleotides that encode anti-CD33 heavy chains and / or anti- CD33 light chains are provided. In some embodiments, provided herein is a vector comprising a nucleic acid encoding any one of the anti-CD33 antibodies described herein. Vectors comprising polynucleotides that encode anti-CD33 heavy chains and / or anti-CD33 light chains are also provided. Such vectors include, but are not limited to, DNA vectors, RNA vectors (e.g, mRNA and circular RNA, self-amplifying RNA vectors, etc.), phage vectors, viral vectors (e.g., pox virus vectors, vaccinia virus vectors, adenovirus vectors,modified vaccinia virus Ankara (MVA) vectors, etc.), retroviral vectors, etc. In some embodiments, a vector comprises a first polynucleotide sequence encoding a heavy chain and a second polynucleotide sequence encoding a light chain. In some embodiments, the heavy chain and light chain are expressed from the vector as two separate polypeptides. In some embodiments, the heavy chain and light chain are expressed as part of a single polypeptide, such as, for example, when the antibody is an scFv.

[0294] In some embodiments, a first vector comprises a polynucleotide that encodes a heavy chain and a second vector comprises a polynucleotide that encodes a light chain. In some embodiments, the first vector and second vector are transfected into host cells in similar amounts (such as similar molar amounts or similar mass amounts). In some embodiments, a mole- or mass-ratio of between 5:1 and 1:5 of the first vector and the second vector is transfected into host cells. In some embodiments, a mass ratio of between 1:1 and 1:5 for the vector encoding the heavy chain and the vector encoding the light chain is used. In some embodiments, a mass ratio of 1:2 for the vector encoding the heavy chain and the vector encoding the light chain is used.

[0295] In some embodiments, a vector is selected that is optimized for expression of polypeptides in CHO or CHO-derived cells, or in NSO cells. Exemplary such vectors are described, e.g., in Running Deer et al., Biotechnol. Prog.20:880-889 (2004).

[0296] In some embodiments, a vector is chosen for in vivo expression anti-CD33 heavy chains and / or anti-CD33 light chains in animals, including humans. In some such embodiments, expression of the polypeptide is under the control of a promoter that functions in a tissue-specific manner. For example, liver-specific promoters are described, e.g., in PCT Publication No. WO 2006 / 076288. B. Host Cells

[0297] In various embodiments, anti-CD33 heavy chains and / or anti-CD33 light chains may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be carried out, for example, according to procedures known in the art. In some embodiments, provided herein are host cells comprising an isolated nucleic acid encoding any one of the anti-CD33 antibodies described herein. In some embodiments, provided herein are host cells comprising a vector comprising a nucleic acid encoding any one of the anti-CD33 antibodies described herein. In some embodiments, provided herein is a host cell that produces any one of the anti-CD33 antibodies described herein. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293cells, including 293-6E cells; CHO cells, including CHO-S and DG44 cells; PER.C6® cells (Crucell); and NSO cells. In some embodiments, anti-CD33 heavy chains and / or anti-CD33 light chains may be expressed in yeast. See, e.g., U.S. Publication No. US 2006 / 0270045 A1. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the anti-CD33 heavy chains and / or anti-CD33 light chains. For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells.

[0298] Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Nonlimiting exemplary methods are described, e.g., in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3rded. Cold Spring Harbor Laboratory Press (2001). Nucleic acids may be transiently or stably transfected in the desired host cells, according to any suitable method.

[0299] In some embodiments, one or more polypeptides may be produced in vivo in an animal that has been engineered or transfected with one or more nucleic acid molecules encoding the polypeptides, according to any suitable method.

[0300] In some embodiments, provided herein is a method for making an anti-CD33 antibody described herein, comprising culturing a host cell described herein under conditions suitable for expression of the antibody. In some embodiments, the method further comprises recovering the antibody produced by the host cell. C. Purification of Anti-CD33 Antibodies

[0301] Anti-CD33 antibodies may be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography or size exclusion chromatography. D. Cell-free Production of Anti-CD33 Antibodies

[0302] In some embodiments, an anti-CD33 antibody is produced in a cell-free system. Nonlimiting exemplary cell-free systems are described, e.g., in Sitaraman et al., Methods Mol. Biol.498: 229-44 (2009); Spirin, Trends Biotechnol.22: 538-45 (2004); Endo et al., Biotechnol. Adv.21: 695-713 (2003).VI. Exemplary Linker-Drug Compounds and Antibody-Drug Conjugates A. Exemplary Linker-Drug Compounds

[0303] In one aspect, provided herein is a compound of Formula (I'):, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR11; R1is independently selected from hydrogen, halogen, -C1-C6alkyl or a 3 to 6 membered cycloalkyl; R2aand R2bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; or R2aand R2b, taken together, form oxo; R3is independently selected from hydrogen, halogen, -OR11, -N(R11R11), -NHR11, - C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, - N(R11R11), -NHR11or –OR11; R4aand R4bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -NHR11or –OR11; R5is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroarylring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R6is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; wherein two R5and R6substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R11substituents; R7is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R8aand R8bare each independently selected from hydrogen, halogen or a -C1-C6alkyl, optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R9is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(R11), -C(=O)N(R11R11), -S(O)2R11, -S(=O)R11, -SR11, -S(=O)2NH2, - S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R11is independently selected from hydrogen, halogen, -C1-C6alkyl, -C2-C6alkenyl, - C1-C6haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring;wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R11are each independently unsubstituted or substituted with 1, 2, or 3 R12substituents; R12in each instance is independently selected from hydrogen, -C1-C6alkyl, halogen, - OH, -O-(C1-C6alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R12are each independently unsubstituted or substituted with R13; R13is independently hydrogen, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C1- C6alkoxyalkyl, oxo, hydroxyl or -C1-C6alkoxy; Z is independently selected from -O-, -N(R11)-, C1-C6alkylene, C1-C6haloalkylene, - O-(C1-C6alkylene)-, -(C1-C6alkylene)-O-(C1-C6alkylene)-, -N(R11)-(C1-C6alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2- C6alkenylene, -O-(C1-C6haloalkylene)-O-(C1-C6alkylene)-, -C(=O)-(C1- C6alkylene)-, -C(=O)O-, -C(=O)-O-(C1-C6alkylene)-, -C(=O)N(R11)-, - C(=O)N(R11)(C1-C6alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R11)-, - S(=O)2N(H)(C1-C6alkylene)-, or -S(=O)2N(C1-C6alkyl)(C1-C6alkylene)-, or a bond; L' is a linker; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R9substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R13substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R3, R4, R5, R6, R7, R9, R10, R11, R12and R13may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

[0304] In another aspect, provided herein is a compound of Formula (II’):, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, or C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, C1-C6alkyl, or 3 to 6 membered cycloalkyl, or R2aand R2b, taken together, form oxo; each R3is independently hydrogen or halogen; X1and X2are each independently C(R7) or N; each R7is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; X3, X4, and X5are each independently C(R9) or N; each R9is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkoxy, C1-C6haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH2)n- or -O(CH2)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker.

[0305] In some embodiments, A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. In a particular embodiment, A and B are each phenylene. In other embodiments, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. In a particular embodiment, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene.

[0306] In some embodiments, b is 0. In a particular embodiment, b is 0 and X is O. In other embodiments, b is 1. In a particular embodiment, b is 1 and X is O. In another particular embodiment, b is 1 and X is N(H) or N(CH3). In another particular embodiment, b is 1 and X is N(CH3).

[0307] In some embodiments, c is 1. In a particular embodiment, c is 1 and R9is fluoro, chloro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In another embodiment, c is 0.

[0308] In some embodiments, d is 1. In a particular embodiment, d is 1 and R7is fluoro, chloro, or methyl. In another embodiment, d is 0.

[0309] In some embodiments, e is 1. In a particular embodiment, e is 1 and R3is fluoro. In another embodiment, e is 0.

[0310] In some embodiments, R1hydrogen, halogen, or C1-C6alkyl. In some embodiments, R1is hydrogen or methyl. In a particular embodiment, R1is hydrogen.

[0311] In some embodiments, R2ais hydrogen. In some embodiments, R2bis hydrogen. In a particular embodiment, R2aand R2bare each hydrogen.

[0312] In some embodiments, R3is hydrogen or fluoro. In a particular embodiment, R3is hydrogen.

[0313] In some embodiments, X1and X2are C(R7); or X1is C(R7) and X2is N; or X1and X2are N. In a particular embodiment, X1and X2are C(R7). In another particular embodiment, X1is C(R7) and X2is N. In another particular embodiment, X1is N and X2is C(R7). In another particular embodiment, X1and X2are N.

[0314] In some embodiments, each R7is independently hydrogen, fluoro, chloro, or methyl. In a particular embodiment, each R7is hydrogen. In another particular embodiment, each R7is independently fluoro, chloro, or methyl.

[0315] In some embodiments, X3, X4, and X5are C(R9); or X3and X5are N and X4is C(R9); or X3and X4are N and X5is C(R9); or X3is N and X4and X5are C(R9); or X3and X5are C(R9) and X4is N. In a particular embodiment, X3, X4, and X5are C(R9). In another particular embodiment, X3and X5are N and X4is C(R9). In yet another particular embodiment, X3and X4are N and X5is C(R9). In some embodiments, one of X3, X4, and X5is N and the remaining are C(R9). In a particular embodiment, X3is N and X4and X5are C(R9).

[0316] In some embodiments, each R9is independently hydrogen, fluoro, chloro, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In a particular embodiment, each R9is hydrogen. In some embodiments, each R9is independently fluoro, chloro, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1- C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy.

[0317] In some embodiments, Z is *-N(H)(CH2)n- or *-O(CH2)n-, and * indicates the point of attachment of Z to L. In a particular embodiment, Z is *-N(H)(CH2)n-. In a more particular embodiment, Z is *-N(H)CH2-.

[0318] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0 or 1. In a particular embodiment, n is 0. In another particular embodiment, n is 1.

[0319] In some embodiments,, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L3is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR23-, -O-, -NR23-, -(PEG)mC(O)NR23-, -C(O)NR23(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R23is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R23is C1-C6alkylene, the alkylene is point of attachment of L3to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0320] In some embodiments, AA is glycine. In some embodiments, AA is glutamic acid.

[0321] In some embodiments, L3is 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2. In some embodiments, L3is a 1-25 membered aliphatic comprising -(PEG)m-, -(PEG)mC(O)NR23-, or -C(O)NR23(PEG)m-, and further optionally comprising -C(O)NR23-, -O-, or -NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH,-COOH, or -NH2. In some embodiments, L3is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2.

[0322] In a particular embodiment,wherein: X6is C(R24) or N; X7is C(R25) or N; R24is hydrogen or hydroxy; R25is hydrogen, hydroxy, or -O(CH2CH2O)7CH3; and R26is -C(O)(CH2CH2O)8-12CH3., wherein: R20is hydrogenArg is arginine; Lys is lysine; Glu is glutamine; L1is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L1to -C(O)-(Glu)r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10.

[0324] In some embodiments, L1is a 1-25 membered aliphatic optionally comprising -C(O)NR21-, -(PEG)mC(O)NR21-, or -C(O)NR21(PEG)m-. In a more particular embodiment, L1is C1-C6alkyl.

[0325] In some embodiments, r is 0. In some embodiments, r is 1.

[0326] In some embodiments, p is an integer from 5 to 10. In a particular embodiment, p is 8.

[0327] In a particular embodiment,is:wherein: L2is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L2to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3;L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; and R22is an -O-linked sugar acid.

[0329] In some embodiments, the sugar acid is glucuronic acid.

[0330] In some embodiments, L2is a 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR21-.

[0331] In some embodiments, each R21is independently hydrogen, C1-C6alkyl, or - (CH2CH2O)mCH3.

[0332] In a particular embodiment,, .

[0334] In some embodiments,, wherein: Ala is alanine; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0335] In some embodiments, the aliphatic of L1, L2, and / or L3is a linear or branched aliphatic chain. In some embodiments, the aliphatic of L1, L2, and / or L3comprises a 3 to 8 membered cycloalkyl. In some embodiments, the aliphatic of L1, L2, and / or L3comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl.

[0336] In some embodiments, the aliphatic of L1, L2, and / or L3is 1-15 membered. In some embodiments, the aliphatic of L1, L2, and / or L3is 1-10 membered. In some embodiments, the aliphatic of L1, L2, and / or L3is 1-5 membered.

[0337] In some embodiments, m is an integer from 2 to 24. In some embodiments, m is an integer from 4 to 24. In some embodiments, m is an integer from 8 to 24. In someembodiments, m is an integer from 12 to 24. In some embodiments, m is an integer from 4 to 12. In some embodiments, m is an integer from 8 to 12.

[0338] In some embodiments, Cy is piperidinylene, piperazinylene, 2,5- diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH3.

[0339] In some embodiments, L4is absent. In some embodiments, L4is absent, and Z is *-N(H)(CH2)n-. In a particular embodiment, L4is absent, and Z is *-N(H)(CH2)-. In other embodiments, L4is **-CH2-N(R40)-, **-C(O)CH2CH2N(R40)-, or **- CH2-N(R40)C(O)CH2N(R40)-. In some embodiments, L4is **-CH2-N(R40)-, **- C(O)CH2CH2N(R40)-, or **-CH2-N(R40)C(O)CH2N(R40)-, and Z is *-O(CH2)n-. In a particular embodiment, L4is **-CH2-N(R40)-, **-C(O)CH2CH2N(R40)-, or **-CH2- N(R40)C(O)CH2N(R40)-, and Z is *-O(CH2)-.

[0340] In some embodiments, R40is hydrogen or methyl. In a particular embodiment, R40is hydrogen.

[0341] In yet another aspect, provided herein is a compound of Formula (III’):or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein for a compound of Formula (I’) or (II’), or any embodiment of the foregoing.

[0342] In another aspect, provided herein is a compound of Formula (IV’):,or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein for a compound of Formula (I’) or (II’), or any embodiment of the foregoing.

[0343] Examples of GSPT1-degrading compound include the compounds in Table A, or a pharmaceutically acceptable salt thereof. Table A. Exemplary Linker-Payloads (LPs)

[0344] In some embodiments, provided herein is a compound selected from:,,,B. Exemplary Antibody-Drug Conjugates

[0345] The anti-CD33 antibodies described herein may be included in an antibody-drug conjugate. An antibody-drug conjugate typically comprises three components: Antibody, Payload, and Linker. In some embodiments, the Antibody targets the ADC to a particular cell type and may also elicit a therapeutic response, the Payload elicits a desired therapeutic response, and the Linker attaches the Payload to the Antibody. Often, the Payload is coupled via the Linker to an Antibody that specifically targets a certain tumor antigen (e.g., a protein that is expressed at higher levels on tumor cells compared to normal cells). In some embodiments, an antibody binds its antigen on the surface of a cell, such as a cancer cell, and the ADC is internalized by the cell. In some such embodiments, after the ADC is internalized, the Payload elicits the desired therapeutic response, for example, in the case of a Payload which is an anticancer agent, the Payload inhibits the expansion of, or kills, the cancer cell.

[0346] In some embodiments, the Payload is an anticancer drug, such as any of the anticancer drugs described herein in connection with combination therapy. In certain embodiments, the Payload is a GSPT1-degrading compound.

[0347] Thus, in some embodiments, an antibody-drug conjugate comprising an anti-CD33 antibody provided herein, a GSPT1-degrading compound described herein (e.g., any of Examples 1-79), and a linker that attaches the GSPT1-degrading compound to the anti-CD33 antibody, is provided. In some embodiments, provided herein is an antibody-drug conjugate comprising an anti-CD33 antibody provided herein and a GSPT1-degrader-linker compound described herein (e.g., any of Examples LP1-78).

[0348] In one aspect, provided herein is an antibody-drug conjugate of Formula (I"):, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring;B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR11; R1is independently selected from hydrogen, halogen, -C1-C6alkyl or a 3 to 6 membered cycloalkyl; R2aand R2bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; or R2aand R2b, taken together, form oxo; R3is independently selected from hydrogen, halogen, -OR11, -N(R11R11), -NHR11, - C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, - N(R11R11), -NHR11or –OR11; R4aand R4bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -NHR11or –OR11; R5is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R6is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; wherein two R5and R6substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R11substituents; R7is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11,-NHR11or –OR11; R8aand R8bare each independently selected from hydrogen, halogen or a -C1-C6alkyl, optionally substituted with –R11,-NHR11or –OR11; R9is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11,-NHR11or –OR11; R11is independently selected from hydrogen, halogen, -C1-C6alkyl, -C2-C6alkenyl, - C1-C6haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R11are each independently unsubstituted or substituted with 1, 2, or 3 R12substituents; R12in each instance is independently selected from hydrogen, -C1-C6alkyl, halogen, - OH, -O-(C1-C6alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R12are each independently unsubstituted or substituted with R13; R13is independently hydrogen, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C1- C6alkoxyalkyl, oxo, hydroxyl or -C1-C6alkoxy;Z is independently selected from -O-, -N(R11)-, C1-C6alkylene, C1-C6haloalkylene, - O-(C1-C6alkylene)-, -(C1-C6alkylene)-O-(C1-C6alkylene)-, -N(R11)-(C1-C6alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2-C6alkenylene, -O-(C1-C6haloalkylene)-O-(C1-C6alkylene)-, -C(=O)-(C1- C6alkylene)-, -C(=O)O-, -C(=O)-O-(C1-C6alkylene)-, -C(=O)N(R11)-, - C(=O)N(R11)(C1-C6alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R11)-, - S(=O)2N(H)(C1-C6alkylene)-, or -S(=O)2N(C1-C6alkyl)(C1-C6alkylene)-, or a bond; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R9substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R13substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R3, R4, R5, R6, R7, R9, R10, R11, R12and R13may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

[0349] In another aspect, provided herein is an antibody-drug conjugate of Formula (II"):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, or C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, C1-C6alkyl, or 3 to 6 membered cycloalkyl, or R2aand R2b, taken together with the carbon atom to which they are attached, form oxo; each R3is independently hydrogen or halogen; X1and X2are each independently C(R7) or N; each R7is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl;X3, X4, and X5are each independently C(R9) or N; each R9is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkoxy, C1-C6haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH2)n- or -O(CH2)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; and b is 0 or 1.

[0350] In some embodiments, A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. In a particular embodiment, A and B are each phenylene. In other embodiments, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. In a particular embodiment, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene.

[0351] In some embodiments, b is 0. In a particular embodiment, b is 0 and X is O. In other embodiments, b is 1. In a particular embodiment, b is 1 and X is O. In another particular embodiment, b is 1 and X is N(H) or N(CH3). In another particular embodiment, b is 1 and X is N(CH3).

[0352] In some embodiments, c is 1. In a particular embodiment, c is 1 and R9is fluoro, chloro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In another embodiment, c is 0.

[0353] In some embodiments, d is 1. In a particular embodiment, d is 1 and R7is fluoro, chloro, or methyl. In another embodiment, d is 0.

[0354] In some embodiments, e is 1. In a particular embodiment, e is 1 and R3is fluoro. In another embodiment, e is 0.

[0355] In some embodiments, R1hydrogen, halogen, or C1-C6alkyl. In some embodiments, R1is hydrogen or methyl. In a particular embodiment, R1is hydrogen.

[0356] In some embodiments, R2ais hydrogen. In some embodiments, R2bis hydrogen. In a particular embodiment, R2aand R2bare each hydrogen.

[0357] In some embodiments, R3is hydrogen or fluoro. In a particular embodiment, R3is hydrogen.

[0358] In some embodiments, X1and X2are C(R7); or X1is C(R7) and X2is N; or X1and X2are N. In a particular embodiment, X1and X2are C(R7). In another particular embodiment, X1is C(R7) and X2is N. In another particular embodiment, X1is N and X2is C(R7). In another particular embodiment, X1and X2are N.

[0359] In some embodiments, each R7is independently hydrogen, fluoro, chloro, or methyl. In a particular embodiment, each R7is hydrogen. In another particular embodiment, each R7is independently fluoro, chloro, or methyl.

[0360] In some embodiments, X3, X4, and X5are C(R9); or X3and X5are N and X4is C(R9); or X3and X4are N and X5is C(R9); or X3is N and X4and X5are C(R9); or X3and X5are C(R9) and X4is N. In a particular embodiment, X3, X4, and X5are C(R9). In another particular embodiment, X3and X5are N and X4is C(R9). In yet another particular embodiment, X3and X4are N and X5is C(R9). In some embodiments, one of X3, X4, and X5is N and the remaining are C(R9). In a particular embodiment, X3is N and X4and X5are C(R9).

[0361] In some embodiments, each R9is independently hydrogen, fluoro, chloro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In a particular embodiment, each R9is hydrogen. In some embodiments, each R9is independently fluoro, chloro, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1- C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy.

[0362] In some embodiments, Z is *-N(H)(CH2)n- or *-O(CH2)n-, and * indicates the point of attachment of Z to L. In a particular embodiment, Z is *-N(H)(CH2)n-. In a more particular embodiment, Z is *-N(H)CH2-.

[0363] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0 or 1. In a particular embodiment, n is 0. In another particular embodiment, n is 1.

[0364] In some embodiments, L comprises, whereinindicates point of attachment to Ab.

[0365] For example, in some embodiments, L is , wherein: Phe is phenylalanine;Gly is glycine; AA is glycine or glutamic acid; L3is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR23-, -O-, -NR23-, -(PEG)mC(O)NR23-, -C(O)NR23(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R23is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R23is C1-C6alkylene, the alkylene is point of attachment of L3to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0366] In some embodiments, AA is glycine. In some embodiments, AA is glutamic acid.

[0367] In some embodiments, L3is 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2. In some embodiments, L3is a 1-25 membered aliphatic comprising -(PEG)m-, -(PEG)mC(O)NR23-, or -C(O)NR23(PEG)m-, and further optionally comprising -C(O)NR23-, -O-, or -NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2. In some embodiments, L3is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2.

[0368] In a particular embodiment,, wherein: X6is C(R24) or N; X7is C(R25) or N; R24is hydrogen or hydroxy; R25is hydrogen, hydroxy, or -O(CH2CH2O)7CH3; and R26is -C(O)(CH2CH2O)8-12CH3.

[0369] In some embodiments,wherein: R20is hydrogenArg is arginine;Lys is lysine; Glu is glutamine; L1is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L1to -C(O)-(Glu)r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10.

[0370] In some embodiments, L1is a 1-25 membered aliphatic optionally comprising -C(O)NR21-, -(PEG)mC(O)NR21-, or -C(O)NR21(PEG)m-. In a more particular embodiment, L1is C1-C6alkyl.

[0371] In some embodiments, r is 0. In some embodiments, r is 1.

[0372] In some embodiments, p is an integer from 5 to 10. In a particular embodiment, p is 8.attachment to Ab.

[0374] In some embodiments,, wherein: L2is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or -CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L2to phenylene; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; and R22is an -O-linked sugar acid.

[0375] In some embodiments, the sugar acid is glucuronic acid.

[0376] In some embodiments, L2is a 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR21-.

[0377] In some embodiments, each R21is independently hydrogen, C1-C6alkyl, or - (CH2CH2O)mCH3.

[0378] In a particular embodiment, L is:attachment to Ab.

[0379] In some embodiments,,wherein indicates point of attachment to Ab.

[0380] In some embodiments,, wherein: indicates point of attachment to Ab; Ala is alanine; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0381] In some embodiments, the aliphatic of L1, L2, and / or L3is a linear or branched aliphatic chain. In some embodiments, the aliphatic of L1, L2, and / or L3comprises a 3 to 8 membered cycloalkyl. In some embodiments, the aliphatic of L1, L2, and / or L3comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl.

[0382] In some embodiments, the aliphatic of L1, L2, and / or L3is 1-15 membered. In some embodiments, the aliphatic of L1, L2, and / or L3is 1-10 membered. In some embodiments, the aliphatic of L1, L2, and / or L3is 1-5 membered.

[0383] In some embodiments, m is an integer from 2 to 24. In some embodiments, m is an integer from 4 to 24. In some embodiments, m is an integer from 8 to 24. In some embodiments, m is an integer from 12 to 24. In some embodiments, m is an integer from 4 to 12. In some embodiments, m is an integer from 8 to 12.

[0384] In some embodiments, Cy is piperidinylene, piperazinylene, 2,5- diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH3.

[0385] In some embodiments, L4is absent. In some embodiments, L4is absent, and Z is *- N(H)(CH2)n-. In a particular embodiment, L4is absent, and Z is *-N(H)(CH2)-. In other embodiments, L4is **-CH2-N(R40)-, **-C(O)CH2CH2N(R40)-, or **-CH2- N(R40)C(O)CH2N(R40)-. In some embodiments, L4is **-CH2-N(R40)-, **- C(O)CH2CH2N(R40)-, or **-CH2-N(R40)C(O)CH2N(R40)-, and Z is *-O(CH2)n-. In a particular embodiment, L4is **-CH2-N(R40)-, **-C(O)CH2CH2N(R40)-, or **-CH2- N(R40)C(O)CH2N(R40)-, and Z is *-O(CH2)-.

[0386] In some embodiments, R40is hydrogen or methyl. In a particular embodiment, R40is hydrogen.

[0387] In some embodiments, the antibody or antigen-binding portion thereof binds CD33. In some embodiments, the antibody or antigen-binding portion thereof is an antibody or antigen- binding portion thereof described herein.

[0388] In some embodiments, a is 1-20, or 1-15, or 1-12, or 1-10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10. In some embodiments, a is 1-4. In some embodiments, a is 1-3. In some embodiments, a is 1-2.

[0389] In yet another aspect, provided herein is an antibody-drug conjugate of Formula III”:, or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein with respect to Formula I" or II", or any embodiment of the foregoing.

[0390] In another aspect, provided herein is an antibody-drug conjugate of Formula IV":or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein with respect to Formula I" or II", or any embodiment of the foregoing.

[0391] Another aspect provides a compound of Formula V":, or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., R1, R2a, R2b, R3, R7, R9, L3, Ab, a) are as described herein with respect to Formula I" or II", or any embodiment of the foregoing.

[0392] Nonlimiting examples of antibody-drug conjugates are described herein. For example, provided in an aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in yet another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein.

[0393] In some embodiments, a is 1-20. In some embodiments, a is 1-15, or 1-12, or 1-10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10. In some embodiments, a is 6-10.

[0394] In some embodiments, Ab is an antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding portion thereof binds CD33. In some embodiments, the antibody or antigen-binding portion thereof binds CD33 and is any of theantibodies or antigen-binding portions thereof described herein. In a particular embodiment, Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0395] In another particular embodiment: a is 6-10; andAb is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0396] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acidsequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 69 may be replaced with a pyroglutamic acid (pE).

[0397] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 83 may be replaced with a pyroglutamic acid (pE).

[0398] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

[0399] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE).

[0400] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 71 may be replaced with a pyroglutamic acid (pE).

[0401] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 85 may be replaced with a pyroglutamic acid (pE).

[0402] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE).

[0403] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain(LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE).

[0404] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE).

[0405] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE).

[0406] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

[0407] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE).

[0408] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE).

[0409] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88.

[0410] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VHcomprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78.

[0411] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92.

[0412] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78.

[0413] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92.

[0414] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79.

[0415] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93.

[0416] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80.

[0417] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94.

[0418] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81.

[0419] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95.

[0420] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82.

[0421] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96. VII. Therapeutic Compositions and Methods A. Methods of Treating Diseases

[0422] In one embodiment, provided herein is a method of treating and / or preventing cancer, which comprises administering to a patient a compound, antibody, or antibody-drug conjugate provided herein.

[0423] In another embodiment, provided herein is method of managing cancer, which comprises administering to a patient a compound, antibody, or antibody-drug conjugate provided herein.

[0424] Also provided herein are methods of treating patients who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. Also encompassed are methods of treating patients regardless of patient's age, although some diseases or disorders are more common in certain age groups. Further encompassed are methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his / her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer.

[0425] As used herein, the term “cancer” includes, but is not limited to, solid tumors and blood borne tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma.

[0426] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma.

[0427] In certain embodiments, the cancer is a blood borne tumor. In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia.

[0428] In one embodiment, methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound, antibody, or antibody-drug conjugate provided herein.

[0429] In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), which includes, but is not limited to, undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is undifferentiated AML (M0). In oneembodiment, the acute myeloid leukemia is myeloblastic leukemia (M1). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, the methods of treating, preventing or managing acute myeloid leukemia in a subject comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage acute myeloid leukemia alone or in combination. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia.

[0430] In some embodiments, the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. The acute lymphocytic leukemia can be categorized according to the French-American-British (FAB) Morphological Classification Scheme as L1—Mature-appearing lymphoblasts (T-cells or pre-B-cells), L2—Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3— Lymphoblasts (B-cells; Burkitt’s cells). In one embodiment, the acute lymphocytic leukemia originates in the blast cells of the bone marrow (B-cells). In one embodiment, the acute lymphocytic leukemia originates in the thymus (T-cells). In one embodiment, the acute lymphocytic leukemia originates in the lymph nodes. In one embodiment, the acute lymphocytic leukemia is L1 type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B- cells; Burkitt’s cells). In certain embodiments, the acute lymphocytic leukemia is T-cell leukemia. In one embodiment, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. Thus, the methods of treating, preventing or managing acutelymphocytic leukemia in a subject comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage acute lymphocytic leukemia alone or in combination with a second active agent. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia.

[0431] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a subject. The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage chronic myelogenous leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage chronic myelogenous leukemia.

[0432] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject. The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage chronic lymphocytic leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage chronic lymphocytic leukemia.

[0433] In some embodiments, the methods provided herein encompass treating, preventing or managing myelodysplastic syndrome (MDS) in a subject. MDS is characterized by immature blood cells in the bone marrow that do not mature and may progress to AML. In some embodiments, the subject has very low, low, intermediate, high, or very high risk MDS according to the International Prognostic Scoring System (IPSS-R). The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage MDS. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage MDS.

[0434] In certain embodiments, provided herein are methods of treating, preventing, and / or managing disease in patients with impaired renal function. In certain embodiments, provided herein are method of treating, preventing, and / or managing cancer in patients with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments for patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors.

[0435] In certain embodiments, provided herein are methods of treating, preventing, and / or managing lymphoma, including non-Hodgkin's lymphoma. In some embodiments, provided herein are methods for the treatment or management of non-Hodgkin's lymphoma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0436] In certain embodiments, provided herein are methods of treating, preventing, and / or managing multiple myeloma, including relapsed / refractory multiple myeloma in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of a compound, antibody, or antibody-drug conjugate provided herein to a patient having relapsed / refractory multiple myeloma with impaired renal function.

[0437] In certain embodiments, the patient to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of a compound, antibody, or antibody-drug conjugate provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of a compound, antibody, or antibody-drug conjugate provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy.

[0438] The methods provided herein encompass treating a patient regardless of patient's age, although some diseases or disorders are more common in certain age groups. B. Routes of Administration and Carriers

[0439] Provided herein are compositions (e.g., pharmaceutical compositions) comprising a compound, antibody, or antibody-drug conjugate provided herein and one or more pharmaceutically acceptable carriers.

[0440] In various embodiments, a compound, antibody, or antibody-drug conjugate provided herein may be administered in vivo by various routes, including, but not limited to, oral, intra- arterial, parenteral (including intravenous and subcutaneous), intranasal, intramuscular, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation. The subjectcompositions may be formulated into preparations, such as liquid formulations or formulations suitable for injections, inhalations, and the like. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid or carrier, for example, sterile water. The appropriate formulation and route of administration may be selected according to the intended application.

[0441] In various embodiments, compositions comprising a compound, antibody, or antibody-drug conjugate provided herein are provided in formulations with a wide variety of pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Various pharmaceutically acceptable carriers, which include vehicles, adjuvants, and diluents, are available. Moreover, various pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are also available. VIII. NUMBERED EMBODIMENTS

[0442] Embodiment 1. A compound of Formula (I'):, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR11; R1is independently selected from hydrogen, halogen, -C1-C6alkyl or a 3 to 6 membered cycloalkyl;R2aand R2bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; or R2aand R2b, taken together, form oxo; R3is independently selected from hydrogen, halogen, -OR11, -N(R11R11), -NHR11, - C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, - N(R11R11), -NHR11or –OR11; R4aand R4bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -NHR11or –OR11; R5is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R6is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; wherein two R5and R6substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R11substituents; R7is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(R11), -C(=O)N(R11R11), -S(O)2R11, -S(=O)R11, -SR11, -S(=O)2NH2, - S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11;R8aand R8bare each independently selected from hydrogen, halogen or a -C1-C6alkyl, optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R9is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R11is independently selected from hydrogen, halogen, -C1-C6alkyl, -C2-C6alkenyl, - C1-C6haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R11are each independently unsubstituted or substituted with 1, 2, or 3 R12substituents; R12in each instance is independently selected from hydrogen, -C1-C6alkyl, halogen, - OH, -O-(C1-C6alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R12are each independently unsubstituted or substituted with R13; R13is independently hydrogen, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C1- C6alkoxyalkyl, oxo, hydroxyl or -C1-C6alkoxy; Z is independently selected from -O-, -N(R11)-, C1-C6alkylene, C1-C6haloalkylene, - O-(C1-C6alkylene)-, -(C1-C6alkylene)-O-(C1-C6alkylene)-, -N(R11)-(C1-C6alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2- C6alkenylene, -O-(C1-C6haloalkylene)-O-(C1-C6alkylene)-, -C(=O)-(C1- C6alkylene)-, -C(=O)O-, -C(=O)-O-(C1-C6alkylene)-, -C(=O)N(R11)-, - C(=O)N(R11)(C1-C6alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R11)-, - S(=O)2N(H)(C1-C6alkylene)-, or -S(=O)2N(C1-C6alkyl)(C1-C6alkylene)-, or a bond; L' is a linker;b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R9substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R13substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R3, R4, R5, R6, R7, R9, R10, R11, R12and R13may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

[0443] Embodiment 2. The compound of embodiment 1, wherein A and B are independently selected from phenylene, pyridylene, pyrimidinylene, or pyridazinylene.

[0444] Embodiment 3. The compound of embodiment 2, wherein A and B are each phenylene.

[0445] Embodiment 4. The compound of embodiment 1, wherein A is phenylene and B is cyclohexylene, or A is cyclohexylene and B is phenylene.

[0446] Embodiment 5. The compound of any one of embodiments 1-4, wherein b is 0.

[0447] Embodiment 6. The compound of embodiment 5, wherein X is O.

[0448] Embodiment 7. The compound of any one of embodiments 1-4, wherein b is 1.

[0449] Embodiment 8. The compound of embodiment 7, wherein X is O.

[0450] Embodiment 9. The compound of embodiment 7, wherein X is N(H) or N(CH3).

[0451] Embodiment 10. The compound of any one of embodiments 1-9, wherein c is 1.

[0452] Embodiment 11. The compound of any one of embodiments 1-10, wherein d is 1.

[0453] Embodiment 12. The compound of any one of embodiments 1-11, wherein e is 1.

[0454] Embodiment 13. The compound of embodiment 1, of Formula (II'):, or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen, halogen, or C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, C1-C6alkyl, or 3 to 6 membered cycloalkyl, or R2aand R2b, taken together, form oxo; each R3is independently hydrogen or halogen; X1and X2are each independently C(R7) or N; each R7is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; X3, X4, and X5are each independently C(R9) or N; each R9is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6haloalkoxy, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH2)n- or -O(CH2)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker.

[0455] Embodiment 14. The compound of any one of embodiments 1-13, wherein R1is hydrogen or methyl.

[0456] Embodiment 15. The compound of embodiment 14, wherein R1is hydrogen.

[0457] Embodiment 16. The compound of any one of embodiments 1-15, wherein R2aand R2bare each hydrogen.

[0458] Embodiment 17. The compound of any one of embodiments 1-16, wherein R3is hydrogen or fluoro.

[0459] Embodiment 18. The compound of embodiment 17, wherein R3is hydrogen.

[0460] Embodiment 19. The compound of any one of embodiments 1-18, wherein X1and X2are C(R7); or X1is C(R7) and X2is N; or X1and X2are N.

[0461] Embodiment 20. The compound of embodiment 19, wherein X1and X2are C(R7).

[0462] Embodiment 21. The compound of any one of embodiments 1-20, wherein each R7is independently hydrogen, fluoro, chloro, or methyl.

[0463] Embodiment 22. The compound of embodiment 21, wherein each R7is hydrogen.

[0464] Embodiment 23. The compound of any one of embodiments 1-22, wherein X3, X4, and X5are C(R9); or X3and X5are N and X4is C(R9); or X3and X4are N and X5is C(R9); or X3is N and X4and X5are C(R9); or X3and X5are C(R9) and X4is N.

[0465] Embodiment 24. The compound of embodiment 23, wherein X3, X4, and X5are C(R9).

[0466] Embodiment 25. The compound of any one of embodiments 1-24, wherein each R9is independently hydrogen, fluoro, chloro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1- C3 haloalkoxy, 3 or 4 membered cycloalkyl, or oxetanyloxy.

[0467] Embodiment 26. The compound of embodiment 25, wherein each R9is hydrogen.

[0468] Embodiment 27. The compound of any one of embodiments 1-26, wherein Z is *- N(H)(CH2)n- or *-O(CH2)n-, and * indicates the point of attachment of Z to L'.

[0469] Embodiment 28. The compound of embodiment 27, wherein Z is *-N(H)(CH2)n-.

[0470] Embodiment 29. The compound of any one of embodiments 1-28, wherein n is 0, 1, 2, or 3.

[0471] Embodiment 30. The compound of embodiment 29, wherein n is 0 or 1.

[0472] Embodiment 31. The compound of any one of embodiments 1-30, wherein Z is *- N(H)CH2-.

[0473] Embodiment 32. The compound of any one of embodiments 1-31, having Formula (III'):, or a pharmaceutically acceptable salt thereof, wherein:

[0474] Embodiment 33. The compound of any one of embodiments 1-32, having Formula IV':or a pharmaceutically acceptable salt thereof.

[0475] Embodiment 34. The compound of any one of embodiments 1-33, wherein, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L3is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR23-, -O-, -NR23-, -(PEG)mC(O)NR23-, -C(O)NR23(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R23is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R23is C1-C6alkylene, the alkylene is point of attachment of L3to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; and L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0476] Embodiment 35. The compound of embodiment 34, wherein L3is 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or - NH2.

[0477] Embodiment 36. The compound of embodiment 34, wherein L3is a 1-25 membered aliphatic comprising -(PEG)m-, -(PEG)mC(O)NR23-, or -C(O)NR23(PEG)m-, and further optionally comprising -C(O)NR23-, -O-, or -NR23-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or - NH2.

[0478] Embodiment 37. The compound of embodiment 34, wherein L3is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphaticis unsubstituted or substituted with one or more substituents independently selected from - OH, -COOH, or -NH2.

[0479] Embodiment 38. The compound of embodiment 34 or 37, wherein Cy is piperidinylene, piperazinylene, 2,5-diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH3.

[0480] Embodiment 39. The compound of any one of embodiments 34-38, wherein the aliphatic of L3is a linear or branched aliphatic chain.

[0481] Embodiment 40. The compound of any one of embodiments 34-38, wherein the aliphatic of L3comprises a 3 to 8 membered cycloalkyl.

[0482] Embodiment 41. The compound of any one of embodiments 34-38 and 40, wherein the aliphatic of L3comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl.

[0483] Embodiment 42. The compound of embodiment 34, whereinis:wherein: X6is C(R24) or N; X7is C(R25) or N; R24is hydrogen or hydroxy; R25is hydrogen, hydroxy, or -O(CH2CH2O)7CH3; and R26is -C(O)(CH2CH2O)8-12CH3.

[0484] Embodiment 43. The compound of any one of embodiments 1-33, whereinArg is arginine; Val is valine; Glu is glutamic acid; L1is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L1to -C(O)-(Glu)r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10.

[0485] Embodiment 44. The compound of embodiment 43, wherein L1is a 1-25 membered aliphatic optionally comprising -C(O)NR21-, -(PEG)mC(O)NR21-, or -C(O)NR21(PEG)m-.

[0486] Embodiment 45. The compound of embodiment 43 or 44, wherein the aliphatic of L1is a linear or branched aliphatic chain.

[0487] Embodiment 46. The compound of embodiment 43, wherein

[0488] Embodiment 47. The compound of any one of embodiments 1-33, wherein, wherein: L2is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L2to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; and R22is an -O-linked sugar acid.

[0489] Embodiment 48. The compound of embodiment 47, wherein the sugar acid is glucuronic acid.

[0490] Embodiment 49. The compound of embodiment 47 or 48, wherein L2is a 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR21-.

[0491] Embodiment 50. The compound of any one of embodiments 43-49, wherein each R21is independently hydrogen, C1-C6alkyl, or -(CH2CH2O)mCH3.

[0492] Embodiment 51. The compound of embodiment 47, whereinis:.

[0493] Embodiment 52. The compound of any one of embodiments 1-33, wherein.

[0494] Embodiment 53. The compound of any one of embodiments 1-33, wherein, wherein: Ala is alanine; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

[0495] Embodiment 54. The compound of any one of embodiments 34-41, 43-45, and 47-50, wherein the aliphatic of L1, L2, or L3is 1-15 membered.

[0496] Embodiment 55. The compound of embodiment 54, wherein the aliphatic of L1, L2, or L3is 1-10 membered.

[0497] Embodiment 56. The compound of embodiment 55, wherein the aliphatic of L1, L2, or L3is 1-5 membered.

[0498] Embodiment 57. The compound of any one of embodiments 34-50 and 53-56, wherein L4is absent.

[0499] Embodiment 58. The compound of embodiment 57, wherein Z is *-N(H)(CH2)n-.

[0500] Embodiment 59. The compound of any one of embodiments 34-56, wherein L4is **-

[0501] Embodiment 60. The compound of embodiment 59, wherein Z is *-O(CH2)n-.

[0502] Embodiment 61. The compound of any one of embodiments 34-50, 53-56, 59, and 60, wherein R40is hydrogen.

[0503] Embodiment 62. The compound of any one of embodiments 13-42 and 54-56, having Formula IV':, or a pharmaceutically acceptable salt thereof.

[0504] Embodiment 63. A compound having a structure from Table A, or a pharmaceutically acceptable salt thereof.

[0505] Embodiment 64. A compound selected from:,,, and pharmaceutically acceptable salts thereof.

[0506] Embodiment 65. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises:a) (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28; b) (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; c) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; d) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; or e) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68.

[0507] Embodiment 66. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0508] Embodiment 67. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising theamino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41.

[0509] Embodiment 68. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; or c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acidsequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45.

[0510] Embodiment 69. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequenceof SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59.

[0511] Embodiment 70. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequenceof SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprisingthe amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; or h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0512] Embodiment 71. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the aminoacid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0513] Embodiment 72. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0514] Embodiment 73. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0515] Embodiment 74. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; b) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; c) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 71 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; d) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; e) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 77; f) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; g) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; h) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; i) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; j) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 79;k) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 80; l) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 81; or m) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 73 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0516] Embodiment 75. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

[0517] Embodiment 76. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77;f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

[0518] Embodiment 77. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

[0519] Embodiment 78. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-77, wherein the antibody or antigen-binding portion thereof is a monoclonal antibody.

[0520] Embodiment 79. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-78, wherein the antibody or antigen-binding portion thereof is a human antibody, chimeric antibody, or a humanized antibody.

[0521] Embodiment 80. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-79, wherein the antibody is a full-length antibody.

[0522] Embodiment 81. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-80, wherein the antibody or antigen-binding portion thereof is an IgG antibody.

[0523] Embodiment 82. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-81, wherein the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region.

[0524] Embodiment 83. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-82, wherein the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0525] Embodiment 84. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 83-87, and a light chain (LC) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-96, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE).

[0526] Embodiment 85. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises a heavy chain (HC) comprising an amino acid sequence selected from SEQ ID NOs: 83-87, and a light chain (LC) comprising an amino acid sequence selected from SEQ ID NOs: 88-96, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE).

[0527] Embodiment 86. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises: a) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising anamino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89; c) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88;h) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 92; j) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE).

[0528] Embodiment 87. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) sequence comprising an amino acid having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE).

[0529] Embodiment 88. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises: a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; c) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; h) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92;j) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE).

[0530] Embodiment 89. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE).

[0531] Embodiment 90. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-79, wherein the antibody or antigen-binding portion thereof is an antibody fragment selected from an Fv, single-chain Fv (scFv), Fab, Fab’, or (Fab’)2.

[0532] Embodiment 91. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-90, wherein the antibody or antigen-binding portion thereof binds human CD33.

[0533] Embodiment 92. The isolated antibody or antigen-binding portion thereof of embodiment 91, wherein human CD33 comprises the amino acid sequence of SEQ ID NO: 97 or SEQ ID NO: 99.

[0534] Embodiment 93. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-92, wherein the antibody or antigen-binding portion thereof binds the monomeric form of human CD33 and / or the dimeric form of human CD33.

[0535] Embodiment 94. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-93, wherein the antibody or antigen-binding portion thereof binds cynomolgus monkey CD33.

[0536] Embodiment 95. The antibody or antigen-binding portion thereof of embodiment 94, wherein cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO: 98.

[0537] Embodiment 96. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-95, wherein the antibody or antigen-binding portion thereof binds themonomeric form of cynomolgus monkey CD33 and / or the dimeric form of cynomolgus monkey CD33.

[0538] Embodiment 97. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-96, wherein the antibody or antigen-binding portion thereof binds to human CD33 with an affinity (KD) of less than 1.5 nM.

[0539] Embodiment 98. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-97, wherein the antibody or antigen-binding portion thereof binds to cynomolgus monkey CD33 with an affinity (KD) of less than 10 nM.

[0540] Embodiment 99. The isolated antibody or antigen-binding portion thereof of embodiment 97 or 98, wherein affinity is determined using biolayer interferometry.

[0541] Embodiment 100. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-99, wherein the antibody or antigen-binding portion thereof does not bind to human Siglec 6 or human Siglec 8.

[0542] Embodiment 101. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-100, wherein the antibody or antigen-binding portion thereof internalizes after binding to CD33+ cells.

[0543] Embodiment 102. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-101, wherein the antibody or antigen-binding portion thereof has a Tregitope-adjusted EpiMatrix Score equal to or less than 0, equal to or less than -25, or equal to or less than -45.

[0544] Embodiment 103. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-101, wherein the antibod...

Claims

What is Claimed is:

1. A compound of Formula (I'):, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR11; R1is independently selected from hydrogen, halogen, -C1-C6alkyl or a 3 to 6 membered cycloalkyl; R2aand R2bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; or R2aand R2b, taken together, form oxo; R3is independently selected from hydrogen, halogen, -OR11, -N(R11R11), -NHR11, - C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, - N(R11R11), -NHR11or –OR11; R4aand R4bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -NHR11or –OR11; R5is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroarylring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R6is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; wherein two R5and R6substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R11substituents; R7is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R8aand R8bare each independently selected from hydrogen, halogen or a -C1-C6alkyl, optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R9is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2, -C(=O)NH(R11), -C(=O)N(R11R11), -S(O)2R11, -S(=O)R11, -SR11, -S(=O)2NH2, - S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R11is independently selected from hydrogen, halogen, -C1-C6alkyl, -C2-C6alkenyl, - C1-C6haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring;wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R11are each independently unsubstituted or substituted with 1, 2, or 3 R12substituents; R12in each instance is independently selected from hydrogen, -C1-C6alkyl, halogen, - OH, -O-(C1-C6alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R12are each independently unsubstituted or substituted with R13; R13is independently hydrogen, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C1- C6alkoxyalkyl, oxo, hydroxyl or -C1-C6alkoxy; Z is independently selected from -O-, -N(R11)-, C1-C6alkylene, C1-C6haloalkylene, - O-(C1-C6alkylene)-, -(C1-C6alkylene)-O-(C1-C6alkylene)-, -N(R11)-(C1-C6alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2- C6alkenylene, -O-(C1-C6haloalkylene)-O-(C1-C6alkylene)-, -C(=O)-(C1- C6alkylene)-, -C(=O)O-, -C(=O)-O-(C1-C6alkylene)-, -C(=O)N(R11)-, - C(=O)N(R11)(C1-C6alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R11)-, - S(=O)2N(H)(C1-C6alkylene)-, or -S(=O)2N(C1-C6alkyl)(C1-C6alkylene)-, or a bond; L' is a linker; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R9substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R13substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R3, R4, R5, R6, R7, R9, R10, R11, R12and R13may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

2. The compound of claim 1, wherein A and B are independently selected from phenylene, pyridylene, pyrimidinylene, or pyridazinylene.

3. The compound of claim 2, wherein A and B are each phenylene.

4. The compound of claim 1, wherein A is phenylene and B is cyclohexylene, or A is cyclohexylene and B is phenylene.

5. The compound of any one of claims 1-4, wherein b is 0.

6. The compound of claim 5, wherein X is O.

7. The compound of any one of claims 1-4, wherein b is 1.

8. The compound of claim 7, wherein X is O.

9. The compound of claim 7, wherein X is N(H) or N(CH3).

10. The compound of any one of claims 1-9, wherein c is 1.

11. The compound of any one of claims 1-10, wherein d is 1.

12. The compound of any one of claims 1-11, wherein e is 1.

13. The compound of claim 1, of Formula (II'):, or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, or C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, C1-C6alkyl, or 3 to 6 membered cycloalkyl, or R2aand R2b, taken together, form oxo; each R3is independently hydrogen or halogen; X1and X2are each independently C(R7) or N; each R7is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; X3, X4, and X5are each independently C(R9) or N; each R9is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, C1-C6haloalkoxy, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH2)n- or -O(CH2)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker.

14. The compound of any one of claims 1-13, having Formula (III'):, or a pharmaceutically acceptable salt thereof, wherein:

15. The compound of any one of claims 1-14, having Formula IV':or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-15, wherein is, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L3is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR23-, -O-, -NR23-, -(PEG)mC(O)NR23-, -C(O)NR23(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O;each R23is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R23is C1-C6alkylene, the alkylene is point of attachment of L3to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; and L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

17. The compound of claim 16, whereinis:wherein: X6is C(R24) or N; X7is C(R25) or N; R24is hydrogen or hydroxy; R25is hydrogen, hydroxy, or -O(CH2CH2O)7CH3; and R26is -C(O)(CH2CH2O)8-12CH3.

18. The compound of any one of claims 1-15, whereinis:.

19. The compound of any one of claims 1-15, wherein.

20. The compound of any one of claims 1-15, wherein, wherein: Ala is alanine; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl.

21. The compound of any one of claims 13-17, having Formula IV':, or a pharmaceutically acceptable salt thereof.

22. A compound having a structure from Table A, or a pharmaceutically acceptable salt thereof. ,,,, and pharmaceutically acceptable salts thereof.

24. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 16, a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 19, and a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence ofSEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

25. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO:

68.

26. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH)comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

27. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 74- 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

28. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; b) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; c) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 71 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; d) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; e) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 77; f) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; g) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; h) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; i) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; j) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 79; k) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 80; l) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 81; or m) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 73 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 82;optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

29. The isolated antibody or antigen-binding portion thereof of acclaim 24 or 25, wherein the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

30. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80;l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE).

31. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE).

32. The isolated antibody or antigen-binding portion thereof of any one of claims 24-31, wherein the antibody or antigen-binding portion thereof is a monoclonal antibody.

33. The isolated antibody or antigen-binding portion thereof of any one of claims 24-32, wherein the antibody or antigen-binding portion thereof is a human antibody, chimeric antibody, or a humanized antibody.

34. The isolated antibody or antigen-binding portion thereof of any one of claims 24-33, wherein the antibody is a full-length antibody.

35. The isolated antibody or antigen-binding portion thereof of any one of claims 24-34, wherein the antibody or antigen-binding portion thereof is an IgG antibody.

36. The isolated antibody or antigen-binding portion thereof of any one of claims 24-35, wherein the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region.

37. The isolated antibody or antigen-binding portion thereof of any one of claims 24-36, wherein the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

38. The isolated antibody or antigen-binding portion thereof of any one of claims 24-37, wherein the antibody comprises: a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89;c) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; h) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; j) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE).

39. The isolated antibody or antigen-binding portion thereof of any one of claims 24-37, wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE).

40. The isolated antibody or antigen-binding portion thereof of any one of claims 24-33, wherein the antibody or antigen-binding portion thereof is an antibody fragment selected from an Fv, single-chain Fv (scFv), Fab, Fab’, or (Fab’)2.

41. The isolated antibody or antigen-binding portion thereof of any one of claims 24-40, wherein the antibody or antigen-binding portion thereof binds human CD33.

42. The isolated antibody or antigen-binding portion thereof of claim 41, wherein human CD33 comprises the amino acid sequence of SEQ ID NO: 97 or SEQ ID NO:

99.

43. The isolated antibody or antigen-binding portion thereof of any one of claims 24-42, wherein the antibody or antigen-binding portion thereof binds the monomeric form of human CD33 and / or the dimeric form of human CD33.

44. The isolated antibody or antigen-binding portion thereof of any one of claims 24-43, wherein the antibody or antigen-binding portion thereof binds cynomolgus monkey CD33.

45. The antibody or antigen-binding portion thereof of claim 44, wherein cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO:

98.

46. The isolated antibody or antigen-binding portion thereof of any one of claims 24-45, wherein the antibody or antigen-binding portion thereof binds the monomeric form of cynomolgus monkey CD33 and / or the dimeric form of cynomolgus monkey CD33.

47. The isolated antibody or antigen-binding portion thereof of any one of claims 24-46, wherein the antibody or antigen-binding portion thereof does not bind to human Siglec 6 or human Siglec 8.

48. A pharmaceutical composition comprising the isolated antibody or antigen-binding portion thereof of any one of claims 24-47 and a pharmaceutically acceptable carrier.

49. An isolated nucleic acid encoding the antibody or antigen-binding portion thereof of any one of claims 24-47.

50. An antibody-drug conjugate comprising the antibody or antigen-binding portion thereof of any one of claims 24-47 and a cytotoxic agent.

51. An antibody-drug conjugate of Formula (I"):, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring;B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR11; R1is independently selected from hydrogen, halogen, -C1-C6alkyl or a 3 to 6 membered cycloalkyl; R2aand R2bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; or R2aand R2b, taken together, form oxo; R3is independently selected from hydrogen, halogen, -OR11, -N(R11R11), -NHR11, - C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, - N(R11R11), -NHR11or –OR11; R4aand R4bare each independently selected from hydrogen, halogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -NHR11or –OR11; R5is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; R6is selected from hydrogen, -C1-C6alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R11, -N(R11R11), -NHR11or –OR11; wherein two R5and R6substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R11substituents; R7is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11,-NHR11or –OR11; R8aand R8bare each independently selected from hydrogen, halogen or a -C1-C6alkyl, optionally substituted with –R11,-NHR11or –OR11; R9is independently selected from hydrogen, halogen, -OR11, -C1-C6alkyl, -(C1- C6haloalkyl), -(C1-C6alkyl)-O-(C1-C6alkyl), -NHR11, -N(R11R11), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C6alkenyl, -O-(C1-C6haloalkyl)-O-(C1- C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)-O-(C1-C6alkyl), -C(=O)NH2,S(=O)2NH(C1-C6alkyl), or -S(=O)2N(C1-C6alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R11,-NHR11or –OR11; R11is independently selected from hydrogen, halogen, -C1-C6alkyl, -C2-C6alkenyl, - C1-C6haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R11are each independently unsubstituted or substituted with 1, 2, or 3 R12substituents; R12in each instance is independently selected from hydrogen, -C1-C6alkyl, halogen, - OH, -O-(C1-C6alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R12are each independently unsubstituted or substituted with R13; R13is independently hydrogen, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C1- C6alkoxyalkyl, oxo, hydroxyl or -C1-C6alkoxy;Z is independently selected from -O-, -N(R11)-, C1-C6alkylene, C1-C6haloalkylene, - O-(C1-C6alkylene)-, -(C1-C6alkylene)-O-(C1-C6alkylene)-, -N(R11)-(C1-C6alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2-C6alkenylene, -O-(C1-C6haloalkylene)-O-(C1-C6alkylene)-, -C(=O)-(C1- C6alkylene)-, -C(=O)O-, -C(=O)-O-(C1-C6alkylene)-, -C(=O)N(R11)-, - C(=O)N(R11)(C1-C6alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R11)-, - S(=O)2N(H)(C1-C6alkylene)-, or -S(=O)2N(C1-C6alkyl)(C1-C6alkylene)-, or a bond; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R9substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R13substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R3, R4, R5, R6, R7, R9, R10, R11, R12and R13may include 1, 2 or 3 heteroatoms independently selected from O, N or S.

52. The antibody-drug conjugate of claim 115, wherein A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene.

53. The antibody-drug conjugate of claim 116, wherein A and B are each phenylene.

54. The antibody-drug conjugate of claim 115, wherein A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene.

55. The antibody-drug conjugate of any one of claims 115-118, wherein b is 0.

56. The compound or antibody-drug conjugate of claim 119, wherein X is O.

57. The antibody-drug conjugate of any one of claims 115-118, wherein b is 1.

58. The compound or antibody-drug conjugate of claim 121, wherein X is O.

59. The compound or antibody-drug conjugate of claim 121, wherein X is N(H) or N(CH3).

60. The antibody-drug conjugate of any one of claims 115-123, wherein c is 1.

61. The antibody-drug conjugate of any one of claims 115-124, wherein d is 1.

62. The antibody-drug conjugate of any one of claims 115-125, wherein e is 1.

63. The antibody-drug conjugate of claim 115, of Formula (II"):or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen, halogen, or C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, C1-C6alkyl, or 3 to 6 membered cycloalkyl, or R2aand R2b, taken together with the carbon atom to which they are attached, form oxo; each R3is independently hydrogen or halogen; X1and X2are each independently C(R7) or N; each R7is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; X3, X4, and X5are each independently C(R9) or N; each R9is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH2)n- or -O(CH2)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; and b is 0 or 1.

64. The antibody-drug conjugate of any one of claims 51-63, wherein R3is hydrogen or fluoro.

65. The antibody-drug conjugate of any one of claims 51-64, wherein each R7is independently hydrogen, fluoro, chloro, or methyl.

66. The antibody-drug conjugate of any one of claims 51-65, wherein each R9is independently hydrogen, fluoro, chloro, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy.

67. The antibody-drug conjugate of any one of claims 51 and 63-66, of Formula (III"):or a pharmaceutically acceptable salt thereof.

68. The antibody-drug conjugate of any one of claims 51 and 63-67, having Formula IV":or a pharmaceutically acceptable salt thereof.

69. The antibody-drug conjugate of any one of claims 51-68, wherein L comprises, w eren indicates point of attachment to Ab.

70. The antibody-drug conjugate of claim 69, wherein L is, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L3is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR23-, -O-, -NR23-, -(PEG)mC(O)NR23-, -C(O)NR23(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R23is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R23is C1-C6alkylene, the alkylene is point of attachment of L3to -C(O)-AA-;m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl., ,,wherein: X6is C(R24) or N; X7is C(R25) or N; R24is hydrogen or hydroxy;R25is hydrogen, hydroxy, or -O(CH2CH2O)7CH3; and R26is -C(O)(CH2CH2O)8-12CH3.

72. The antibody-drug conjugate of claim 69, wherein L is RArg is arginine; Val is valine; Glu is glutamic acid; L1is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L1to -C(O)-(Glu)r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; and each R40is independently hydrogen or C1-C6alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10.

73. The antibody-drug conjugate of claim 72, wherein:point of attachment to Ab.

74. The antibody-drug conjugate of claim 69, wherein, wherein: L2is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR21-, -O-, -NR21-, -(PEG)mC(O)NR21-, -C(O)NR21(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH2CH2O; each R21is independently hydrogen, C1-C6alkyl, C1-C6alkylene, -(CH2CH2O)mCH3, or - CH2CH2C(O)N(H)(CH2CH2O)mCH3, provided that when R21is C1-C6alkylene, the alkylene is point of attachment of L2to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH3; L4is absentN(R40)C(O)CH2N(R40)-, wherein ** indicates point of attachment to Z; each R40is independently hydrogen or C1-C6alkyl; and R22is an -O-linked sugar acid.

75. The antibody-drug conjugate of claim 74, wherein L is:or, indicates point of attachment to Ab.

76. The antibody-drug conjugate of any one of claims 63-71, having Formula V":, or a pharmaceutically acceptable salt thereof.

77. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein:a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

78. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

79. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

80. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

81. An antibody drug conjugate of the following formula:or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

82. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof., or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof., or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

85. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

86. An antibody drug conjugate of the following formula:, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

87. The antibody-drug conjugate of any one of claims 51-86, wherein a is 1-15, or 1-12, or 1- 10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10.

88. The antibody-drug conjugate of any one of claims 51-87, wherein the antibody or antigen-binding portion thereof binds CD33.

89. The antibody-drug conjugate of claim 88, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 24- 47.

90. The antibody-drug conjugate of claim 89, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 25, 29, 31, and 39.

91. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 50-90 and a pharmaceutically acceptable carrier.

92. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated antibody or antigen-binding portion thereof of any one of claims 24-47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90.

93. The method of claim 92, wherein the cancer is leukemia.

94. The method of claim 93, wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, or acute myeloid leukemia.

95. The method of any one of claims 92-94, wherein the subject is a human.

96. Use of the isolated antibody or antigen-binding portion thereof of any one of claims 24- 47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90 for the preparation of a medicament for treating cancer in a subject in need thereof.

97. The isolated antibody or antigen-binding portion thereof of any one of claims 24-47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90 for use in treating cancer in a subject in need thereof.

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