WO2021171264A1

WO2021171264A1 - Dosing of a bispecific antibody that binds cd123 and cd3

Info

Publication number: WO2021171264A1
Application number: PCT/IB2021/051648
Authority: WO
Inventors: Raphael Clynes; Ying Ding; Paul Foster; Ramanjit GARCHA; Chelsea JOHNSON; Michael Wayne SAVILLE
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2020-02-28
Filing date: 2021-02-26
Publication date: 2021-09-02
Anticipated expiration: 2022-08-28
Also published as: TW202146452A

Abstract

The methods described here are directed to treating human subjects with bispecific anti- CD 123 x anti-CD3 antibodies.

Description

DOSING OF A BISPECIFIC ANTIBODY THAT BINDS CD123 AND CD3

PRIORITY CLAIM

[0001] This application claims benefit to U.S. Provisional Application Serial No. 63/121,976, filed December 6, 2020, U.S. Provisional Application Serial No. 63/121,971, filed December 6, 2020, U.S. Provisional Application Serial No. 63/109,731, filed November 4, 2020, and U.S. Provisional Application Serial No. 62/983,087, filed February 28, 2020, the contents of which are incorporated by reference in their entireties.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on Feburuary 18, 2021, is named PAT058772_SL.txt and is 45,209 bytes in size.

INCORPORATION BY REFERENCE

[0003] All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. In the event that there is an inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of the present specification controls.

BACKGROUND OF THE INVENTION

[0004] Antibody-based therapies have been used successfully to treat a variety of diseases, including cancer and autoimmune/inflammatory disorders. Improvements to this class of antibodies are still needed, particularly with respect to enhancing their clinical efficacy. One avenue being explored is the engineering of additional and novel antigen binding sites into an antibody such that a single immunoglobulin molecule co-engages two different antigens.

[0005] CD3 activation of T-cells occurs only when its associated T-cell receptor (TCR) engages antigen-loaded MHC on antigen presenting cells in a highly avid cell-to-cell synapse (Kuhns et al., 2006, Immunity 24: 133-139). Indeed, nonspecific bivalent cross-linking of CD3 using an anti-CD3 antibody elicits a cytokine storm and toxicity (Perruche et al., 2009, J Immunol 183 [2] : 953-61 ; Chatenoud & Bluestone, 2007, Nature Reviews Immunology 7:622-632; expressly incorporated by reference). Thus, for practical clinical use, the preferred mode of CD3 co-engagement for redirected killing of target cells is monovalent binding that results in activation only upon engagement with the co-engaged target.

[0006] CD 123, also known as interleukin-3 receptor alpha (IL-3Ra), is expressed on dendritic cells, monocytes, eosinophils and basophils. CD 123 is also constitutively expressed by committed hematopoietic stem/progenitor cells, by most of the myeloid lineage (CD13+, CD14+, CD33+, CD15i_ow), and by some CD19+ cells. It is absent from CD3+ cells.

[0007] There is a need for improved bispecific anti-CD-123 x anti-CD3 antibodies and the use of such antibodies for use in therapy.

BRIEF SUMMARY OF THE INVENTION

[0008] In one aspect, the invention provides a method for treating a CD 123 -expressing cancer in a human subject in need of treatment thereof, comprising administering to the human subject a bispecific anti-CD 123 x anti-CD3 antibody in at least a first phase and a second phase and a third phase and a fourth phase, wherein during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered three times a week for one week in a first, second, and third dose amounts, to the human subject, where the first dose amount is about 750 ng/kg, the second dose amount is between about 120% and 160% of the first dose amount, and the third dose amount is between about 120% and 160% of the second dose amount, wherein during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, to the human subject, in a dose amount between about 120% and 160% of the first phase third dose amount, wherein during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, to the human subject, in a dose amount between about 120% and 160% of the second phase dose amount, wherein during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week, to the human subject, in a dose amount between about 120% and 160% of the third phase dose amount, thereby treating the CD 123-expressing cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 depicts a useful bispecific antibody, the format of which is referred to as a “bottle opener”. XmAb 14045 is in this bottle opener format. It should be noted that the scFv and Fab domains can be switched (e.g., anti-CD3 as a Fab and anti-CD 123 as a scFv).

[0010] FIG. 2 depicts the sequences of the three polypeptide chains that make up XmAbl4045, abispecific anti-CD123 x anti-CD3 antibody. The CDRs are underlined and the junction between domains is denoted by a slash (“/”). The charged scFv linker is double underlined; the linker may be substituted with other linkers, for example, linkers that are depicted in FIG. 7 ofU.S. Pat. Appl. Pub. No. 2014/0288275 or other non-charged linkers such as SEQ ID NO:441 ofU.S. Pat. Appl. Pub. No. 2014/0288275.

[0011] FIG. 3 depicts the different anti-CD123 Fab constructs that were engineered to increase affinity to human CD 123 and to increase the stability of the 7G3 H1L1 construct (see, e.g., U.S. Pat. Appl. Pub. No. 2016/0229924, Figure 136, SEQ ID NOs: 455 and 456). The changes to the amino acid sequences are shown.

[0012] FIG. 4 depicts the affinity and stability properties of optimized humanized variants of the parental 7G3 murine antibody (see, e.g., U.S. Pat. Appl. Pub. No. 2016/0229924, Figure 136, SEQ ID NOs: 453 and 454).

[0013] FIG. 5A-5B depict additional anti-CD 123 Fab sequences with the CDRs underlined.

[0014] FIG. 6 depicts additional anti-CD 123 x anti-CD3 sequences. The CDRs are underlined and the junction between domains is denoted by a slash (‘7”). The charged scFv linker is double underlined; the linker may be substituted with other linkers, for example, linkers that are depicted in FIG. 7 ofU.S. Pat. Appl. Pub. No. 2014/0288275 or other non- charged linkers such as SEQ ID NO:441 ofU.S. Pat. Appl. Pub. No. 2014/0288275.

[0015] FIGs. 7A-7D depicts additional bispecific formats, as are generally described in FIG.

1 and the accompanying legend and supporting text ofU.S. Pat. Appl. Pub. No. 2016/0229924. [0016] FIG. 8 depicts RTCC with intact or T cell depleted PBMC against KG-la target cells. Effector cells (400k), intact or magnetically-depleted PBMC were incubated with carboxy fluorescein succinimidyl ester-labeled KG- la target cells (10k) for 24 hours and stained with annexin V for cell death.

[0017] FIG. 9 depicts CD123hiCD33hi depletion over a dose range of XmAb 14045 in AML human subject PBMC. Five AML human subject PBMC samples were incubated with a dose range of XmAb 14045 (0.12 to 90 ng/mL) for 6 days, and live cells were gated to count CD123hiCD33hi target cells. The lowest concentration (0.04 ng/mL) point is the no drug control for plotting on logarithmic scale. Each point is normalized to account for cell count variability.

[0018] FIG. 10 depicts Ki67 levels in T cells from AML human subject PBMC with XmAbl4045. Five AML human subject PBMC samples were incubated with a dose range of XmAbl4045 (0.12 to 90 ng/mL) for 6 days, and live cells were gated for CD4+ and CD8+ T cells to count Ki67+ cells. The lowest concentration (0.04 ng/mL) point is the no drug control, for plotting on a logarithmic scale.

[0019] FIG. 11 depicts number of AML blasts in human subject PBMCs treated with XmAb 14045. PBMC from a single AML human subject was incubated with 9 or 90 ng/mL XmAbl4045 for 24 or 48 hours and blast counts were plotted. Normal donor PBMCs were also used as a control.

[0020] FIG. 12 depicts leukemic blast cells in AML human subject PBMC. PBMCs from six AML human subjects were incubated with antibodies for 48 hours and blasts were counted and plotted. One donor (AML #1) did not have XENP13245 treatment and each line is a single donor.

[0021] FIG. 13 depicts KG-la tumor cell apoptosis with AML PBMC. Carboxyfluorescein succinimidyl ester-labeled CD123+ KG-la cells were added to the PBMC to examine target cell cytotoxicity stimulated by the AML effector T cells. Staining with the apoptosis marker annexin-V was used to detect KG-la cell death after 48 hours of incubation.

[0022] FIG. 14 depicts effect of XmAb 14045 on tumor burden over time in a mouse xenograft model of AML.

[0023] FIG. 15 depicts reduction of tumor burden after 3 once a week doses of XmAbl4045. [0024] FIG. 16 depicts effect of XmAb 14045 on T cell number in a mouse xenograft model of AML. Peripheral blood CD45+CD8+ events by flow cytometry. Samples taken on Day 11 and 20 after XmAb 14045 administration.

[0025] FIG. 17 depicts CRS severity by infusion (Cohorts 9A-2B) from a subset of tested human subjects.

[0026] FIG. 18 depicts peak serum IL-6 by infusion from a subset of tested human subjects.

[0027] FIG. 19 depicts percentage change in bone marrow blasts from pretreatment baseline from a subset of tested human subjects.

[0028] FIG. 20 depicts the time to treatment discontinuation from a subset of tested human subjects.

[0029] FIG. 21 depicts CR and CRi responder data from a subset of tested human subjects.

[0030] FIG. 22 depicts blast CD 123 expression, for responders versus non-responders, from a subset of tested human subjects.

[0031] FIG. 23 is a presentation entitled Complete Responses in Relapsed/ Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule ofVibecotamab (XmAb® 14045), a CD 123 x CD3 T Cell-Engaging Bispecific Antibody; Results of a Phase 1 Study. Regarding the slide entitled “XmAb® 14045 (SQZ622): CD 123 x CD3 Bispecific Antibody”, XmAb 14045 is a bispecific full-length immunoglobulin molecule targeting CD3 on T cells and CD 123 on AML blasts. CD 123 or the alpha-subunit of IL-3 receptor is expressed on early hematopoietic precursor cells as well as on the surface of a number of hematological cancers, including AML blasts. XmAb 14045 has a longer half-life related to its full-length immunoglobulin structure allowing its administration by short infusions. It recruits and activates T cells resulting in killing of CD 123 expressing blasts. Ablation of the Fc-gamma receptor binding eliminates the potential for nonspecific activation of T cells. Regarding the first slide entitled “XmAb 14045 Phase 1 Design” this Phase 1 study was designed to determine first and subsequent infusion maximum tolerated doses and safety of XmAbl4045 and a number of other secondary and exploratory objectives. Patients with relapsed and refractory AML or ALL with adequate performance status and adequate organ function were eligible to participate. Regarding the second slide entitled “XmAb 14045 Phase 1 Design” as of October 2020, 114 patients have been enrolled. The safety analysis population are those that have received as least 1 dose. The efficacy analysis included all patients who completed at least one cycle or 28 days of therapy. 5 dosing schedules have been evaluated including initially once weekly dosing schedules. More recent schedules include a first cycle dose escalation strategy with weekly dose step-ups. Each dose is administered by IV infusion over 2 hours. Regarding the slide entitled “Demographics (Safety Population)”, 112 patients with AML are evaluable for safety. 2 patients with ALL and CML in blast phase were not included in this analysis. Median # of prior therapies were 3 and 30% of patients had received prior allogeneic stem cell transplant. The majority of patients had adverse ELN risk features. Regarding the slide entitled “Safety Data: Related TEAEs Occurring in >10% of Subjects AML Safety Population (N=l 12)”, as expected the most significant TEAE was CRS, occurring in about 61% of patients with the majority between Grade 1 & Grade 2 events. There was no evidence of drug-related myelosuppression. Neurological events were also very infrequent and mostly Grade 1 & 2 headaches. Regarding the slide entitled “Safety Data: Priming Dose, Dosing Visit and IL-6 Levels” as expected, significant elevation of IL-6 was seen after the initial doses which subsided with subsequent dosing but rose to high levels again with weekly dosing, particularly after significantly weekly dose step-ups. Regarding the slide entitled “Safety Data: Weekly Dosing and IL-6 Levels”, this elevation of IL-6 correlated with incidence and severity of CRS. On the left of the slide, across all cohorts, 4.5% of stable weekly dosing had high IL-6 levels correlating with few Grade 2 or higher CRS. On the right of the slide, 15% of weekly step-up events had IL-6 greater than 1000 pg/mL and this was associated with a higher incidence of Grade 2 or higher CRS. Regarding the slide entitled “Safety Data:

Dosing Visit and CRS” similarly higher frequency and severity was noted with a priming dose of 0.75 pg/kg as compared to 0.43 pg/kg. Regarding the slide entitled “Safety Data: CRS Strategy for Luture Cohorts and Trials”, the above data has provided significant information for designing dose strategies to reduce the incidence and severity of CRS while maintaining efficacy. This is by selecting a lower priming dose, more frequent dosing in the first week to allow a higher cumulative exposure and avoiding the potential antigen sink and by avoiding weekly dose step-up. Regarding the slide entitled “Efficacy Data” the objective response rate among the 54 patients who received a dose of at least 0.75 pg/kg or higher is 14.8%. However, among the 27 patients with blast % less than 25%, the response rate is 25.9%. Overall, an additional 38 patients have stable disease with a reduction in marrow blasts in 52% of patients. Regarding the slide entitled “Efficacy Data: Time to Treatment Discontinuation”, responses including CR and CRi have been durable, lasting several months in some patients. Regarding the slide entitled “XmAbl4045/SQZ622 Data by Cohort” this table provides response information by cohorts treated. Overall responses were reported in most cohorts irrespective of cumulative dose administered in week 1 of cycle 1. Cohort IE with lower priming dose and stable dosing without weekly step-up is ongoing. Regarding the slide entitled “Responders Associated with Low Absolute Blast Counts”, it is noted that in general, responses have been associated with lower peripheral blood as well as bone marrow blast percentages. Regarding the slide entitled “Responders Associated with Low PD-1 Expression on CD8 and CD4 T Cells”, it is noted that responses have been associated with lower PD-1 expression on CD8⁺ and CD4⁺ T cells. Regarding the slide entitled “AML Blast Count % in Marrow vs % PD1⁺ of CD8⁺ Cells in Blood” it is noted that low blast percentages in bone marrow and low PD-1 expression on circulating CD8⁺ T cells appear to be predictors for response. This suggests possible strategies to select patients most likely to respond.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0032] In order that the application may be more completely understood, several definitions are set forth below. The definitions also include all grammatical equivalents.

[0033] The term “about” in relation to a reference numerical value can include the numerical value itself and a range of values plus or minus 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 9 to 11. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. In some cases, the numerical disclosed throughout can be “about” that numerical value even without specifically mentioning the term “about.”

[0034] Embodiments herein with the term ‘comprise’, ‘comprises’ or ‘comprising’ can have this term replaced with ‘consists of or ‘consisting of or ‘consists essentially of or ‘consisting essentially of.

[0035] The terms “CD3” or “cluster of differentiation 3” means a T-cell co-receptor that helps in activation of both cytotoxic T-cell ( e.g ., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells) and is composed of four distinct chains: one CD3y chain (e.g., Genbank Accession Numbers NM_000073 and MP_000064 (human)), one CD35 chain (e.g., Genbank Accession Numbers NM_000732, NM_001040651, NP_00732 and NP_001035741 (human)), and two CD3s chains (e.g., Genbank Accession Numbers NM_000733 and NP_00724 (human)). The chains of CD3 are highly related cell-surface proteins of the immunoglobulin superfamily containing a single extracellular immunoglobulin domain. CD3 molecule associates with the T-cell receptor (TCR) and z-chain to form the T-cell receptor (TCR) complex, which functions in generating activation signals in T lymphocytes.

[0036] The terms “CD123”, “Cluster of Differentiation 123”, “CD123 antigen”,

“interleukin-3 receptor alpha”, “IL3RA”, or “interleukin3 receptor subunit alpha” means an interleukin 3 specific subunit of a type I heterodimeric cytokine receptor (e.g., Genbank Accession Numbers NM_001267713, NM_002183, NP_001254642 and NP_002174 (human)). CD 123 interacts with a signal transducing beta subunit to form interleukin-3 receptor, which helps in the transmission of interleukin 3. CD 123 is found on pluripotent progenitor cells and induces tyrosine phosphorylation within the cell and promotes proliferation and differentiation within the hematopoietic cell lines. CD 123 is expressed across acute myeloid leukemia (AML) subtypes, including leukemic stem cells.

[0037] By “bispecific” or “bispecific antibody” herein is meant any non-native or alternate antibody formats, including those described herein, that engage two different antigens (e.g., CD3 x CD123 bispecific antibodies).

[0038] By "modification" herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. By "amino acid modification" herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence. For clarity, unless otherwise noted, the amino acid modification is always to an amino acid coded for by DNA, e.g. the 20 amino acids that have codons in DNA and RNA.

[0039] By "amino acid substitution" or "substitution" herein is meant the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced with tyrosine. For clarity, a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid (for example exchanging CGG (encoding arginine) to CGA (still encoding arginine) to increase host organism expression levels) is not an “amino acid substitution”; that is, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.

[0040] By "amino acid insertion" or "insertion" as used herein is meant the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, - 233E or 233E designates an insertion of glutamic acid after position 233 and before position 234. Additionally, -233ADE or A233ADE designates an insertion of AlaAspGlu after position 233 and before position 234.

[0041] By "amino acid deletion" or "deletion" as used herein is meant the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233# designates a deletion a deletion of glutamic acid at position 233.

Additionally, EDA233- or EDA233# designates a deletion of the sequence GluAspAla that begins at position 233.

[0042] By "variant protein" or "protein variant", or "variant" as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification. Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it. Preferably, the protein variant has at least one amino acid modification compared to the parent protein, e.g. from about one to about seventy amino acid modifications, and preferably from about one to about five amino acid modifications compared to the parent. As described below, in some embodiments the parent polypeptide, for example an Fc parent polypeptide, is a human wild type sequence, such as the Fc region from IgGl, IgG2, IgG3 or IgG4, although human sequences with variants can also serve as “parent polypeptides”. The protein variant sequence herein will preferably possess at least about 80% identity with a parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99% identity. Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it. Accordingly, by "antibody variant" or "variant antibody" as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification, "IgG variant" or "variant IgG" as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification, and "immunoglobulin variant" or "variant immunoglobulin" as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. "Fc variant" or "variant Fc" as used herein is meant a protein comprising an amino acid modification in an Fc domain. The Fc variants of the present invention are defined according to the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, where the numbering is according to the EU index. Likewise, M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L/434S. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L/434S is the same Fc variant as M428L/N434S, and so on. For all positions discussed in the present invention that relate to antibodies, unless otherwise noted, amino acid position numbering is according to the EU index. The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference.) The modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include U.S. Pat. 6,586,207; WO 98/48032; WO 03/073238; US2004-0214988A1; WO 05/35727A2; WO 05/74524A2; J. W. Chin et al., (2002), Journal of the American Chemical Society 124:9026-9027; J. W. Chin, & P. G. Schultz, (2002), ChemBioChem 11: 1135-1137;

J. W. Chin, et al., (2002), PICAS United States of America 99: 11020-11024; and, L. Wang,

& P. G. Schultz, (2002), Chem. 1-10, all entirely incorporated by reference.

[0043] As used herein, "protein" herein is meant at least two covalently attached amino acids, which includes proteins, polypeptides, oligopeptides and peptides. The peptidyl group may comprise naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures, i.e. "analogs", such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992), entirely incorporated by reference). The amino acids may either be naturally occurring or synthetic (e.g. not an amino acid that is coded for by DNA); as will be appreciated by those in the art. For example, homo-phenylalanine, citrulline, ornithine and noreleucine are considered synthetic amino acids for the purposes of the invention, and both D- and L-(R or S) configured amino acids may be utilized. The variants of the present invention may comprise modifications that include the use of synthetic amino acids incorporated using, for example, the technologies developed by Schultz and colleagues, including but not limited to methods described by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30, Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566-71, Zhang et al., 2003, 303(5656):371-3, and Chin et al., 2003, Science 301(5635):964-7, all entirely incorporated by reference. In addition, polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0044] By "residue" as used herein is meant a position in a protein and its associated amino acid identity. For example, Asparagine 297 (also referred to as Asn297 or N297) is a residue at position 297 in the human antibody IgGl.

[0045] By “antigen binding domain” or “ABD” herein is meant a set of six Complementary Determining Regions (CDRs) that, when present as part of a polypeptide sequence, specifically binds a target antigen as discussed herein. Thus, a “checkpoint antigen binding domain” binds a target checkpoint antigen as outlined herein. As is known in the art, these CDRs are generally present as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDRl, vhCDR2, vhCDR3 for the heavy chain and vlCDRl, vlCDR2 and vlCDR3 for the light. The CDRs are present in the variable heavy and variable light domains, respectively, and together form an Fv region. Thus, in some cases, the six CDRs of the antigen binding domain are contributed by a variable heavy and a variable light domain. In a “Fab” format, the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (vh or VH; containing the vhCDRl, vhCDR2 and vhCDR3) and the variable light domain (vl or VL; containing the vlCDRl, vlCDR2 and vlCDR3), with the C-terminus of the vh domain being attached to the N-terminus of the CHI domain of the heavy chain and the C- terminus of the vl domain being attached to the N-terminus of the constant light domain (and thus forming the light chain). In a scFv format, the vh and vl domains are covalently attached, generally through the use of a linker (a “scFv linker”) as outlined herein, into a single polypeptide sequence, which can be either (starting from the N-terminus) vh-linker-vl or vl-linker-vh. In general, the C-terminus of the scFv domain is attached to the N-terminus of the hinge in the second monomer.

[0046] By "Fab" or "Fab region" as used herein is meant the polypeptide that comprises the VH, CHI, VL, and CL immunoglobulin domains, as, for example, on two different polypeptide chains (e.g. VH-CH1 on one chain and VL-CL on the other). Fab may refer to this region in isolation, or this region in the context of a bispecific antibody, or this region in the context of a full-length antibody, antibody fragment or Fab fusion protein. In the context of a Fab, the Fab can comprise an Fv region in addition to the CHI and CL domains.

[0047] By "Fv" or "Fv fragment" or "Fv region" as used herein is meant a polypeptide that comprises the VL and VH domains of an ABD. Fv regions can be formatted as both Fabs (as discussed above, generally two different polypeptides that also include the constant regions as outlined above) and scFvs, where the vl and vh domains are combined (generally with a linker as discussed herein) to form an scFv.

[0048] By “single chain Fv” or “scFv” herein is meant a variable heavy domain covalently attached to a variable light domain, generally using a scFv linker as discussed herein, to form a scFv or scFv domain. A scFv domain can be in either orientation from N- to C-terminus (vh-linker-vl or vl-linker-vh). In the sequences depicted in the sequence listing and in the figures, the order of the vh and vl domain is indicated in the name, e.g. H.X_L.Y means N- to C-terminal is vh-linker-vl, and L.Y H.X is vl-linker-vh.

[0049] By "amino acid" and "amino acid identity" as used herein is meant one of the 20 naturally occurring amino acids that are coded for by DNA and RNA.

[0050] By "IgG Fc ligand" as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an IgG antibody to form an Fc/Fc ligand complex. Fc ligands include but are not limited to FcyRIs, FcyRIIs, FcyRIIIs, FcRn, Clq, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcyR. Fc ligands also include Fc receptor homologs (FcRH), which are a family of Fc receptors that are homologous to the FcyRs (Davis et ah, 2002, Immunological Reviews 190:123-136, entirely incorporated by reference). Fc ligands may include undiscovered molecules that bind Fc. Particular IgG Fc ligands are FcRn and Fc gamma receptors. By "Fc ligand" as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc/Fc ligand complex.

[0051] By "Fc gamma receptor", "FcyR" or "FcqammaR" as used herein is meant any member of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcyR gene. In humans this family includes but is not limited to FcyRI (CD64), including isoforms FcyRIa, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-l and FcyRIIb-2). and FcyRIIc; and FcyRIII (CD 16), including isoforms FcyRIIIa (including allotypes V158 and F158) and FcyRIIIb (including allotypes FcyRIIb-NAl and FcyRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, entirely incorporated by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes. An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), F cy R II I (CD 16), and FcyRIII-2 (CD 16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.

[0052] By "FcRn" or "neonatal Fc Receptor" as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene. The FcRn may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. As is known in the art, the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain. The light chain is beta-2 -microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise noted herein, FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2 -microglobulin. A variety of FcRn variants can be used to increase binding to the FcRn receptor, and in some cases, to increase serum half-life.

[0053] By "parent polypeptide" as used herein is meant a starting polypeptide that is subsequently modified to generate a variant. The parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Parent polypeptide may refer to the polypeptide itself, compositions that comprise the parent polypeptide, or the amino acid sequence that encodes it. Accordingly, by "parent immunoglobulin" as used herein is meant an unmodified immunoglobulin polypeptide that is modified to generate a variant, and by "parent antibody" as used herein is meant an unmodified antibody that is modified to generate a variant antibody. It should be noted that "parent antibody" includes known commercial, recombinantly produced antibodies as outlined below.

[0054] By “Fc” or “Fc region” or “Fc domain” as used herein is meant the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgGl, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof. An “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C- termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g. non-denaturing chromatography, size exclusion chromatography, etc.) Human IgG Fc domains are of particular use in the present invention, and can be the Fc domain from human IgGl, IgG2 or IgG4.

[0055] By “heavy chain constant region” herein is meant the CHl-hinge-CH2-CH3 portion of an antibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgGl this is amino acids 118-447. By “heavy chain constant region fragment” herein is meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.

[0056] By "position" as used herein is meant a location in the sequence of a protein. Positions may be numbered sequentially, or according to an established format, for example the EU index for antibody numbering.

[0057] By "target antigen" as used herein is meant the molecule that is bound specifically by the antigen binding domain comprising the variable regions of a given antibody. The two target antigens of the present invention are human CD3 and human CD 123.

[0058] By “strandedness” in the context of the monomers of the heterodimeric antibodies of the invention herein is meant that, similar to the two strands of DNA that “match”, heterodimerization variants are incorporated into each monomer so as to preserve the ability to “match” to form heterodimers. For example, if some pi variants are engineered into monomer A (e.g. making the pi higher) then steric variants that are “charge pairs” that can be utilized as well do not interfere with the pi variants, e.g. the charge variants that make a pi higher are put on the same “strand” or “monomer” to preserve both functionalities. Similarly, for “skew” variants that come in pairs of a set as more fully outlined below, the skilled artisan will consider pi in deciding into which strand or monomer that incorporates one set of the pair will go, such that pi separation is maximized using the pi of the skews as well.

[0059] By "target cell" as used herein is meant a cell that expresses a target antigen.

[0060] By “host cell” in the context of producing a bispecific antibody according to the invention herein is meant a cell that contains the exogenous nucleic acids encoding the components of the bispecific antibody and is capable of expressing the bispecific antibody under suitable conditions. Suitable host cells are discussed herein.

[0061] By "variable region" or “variable domain” as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK, Vk, and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity. Thus, a “variable heavy domain” pairs with a “variable light domain” to form an antigen binding domain (“ABD”). In addition, each variable domain comprises three hypervariable regions (“complementary determining regions,” “CDRs”) (vhCDRl, vhCDR2 and vhCDR3 for the variable heavy domain and vlCDRl, vlCDR2 and vlCDR3 for the variable light domain) and four framework (FR) regions, arranged from amino-terminus to carboxy-terminus in the following order: FR1 -CDR1 -FR2-CDR2-FR3 -CDR3 -FR4.

[0062] Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison Of Biosequences,” Adv. Appl. Math. 2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J. (1988) “Improved Tools For Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) “Basic Local Alignment Search Tool,” J. Mol. Biol. 215:403-10 , the “BLAST” algorithm, see https://blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters.

[0063] By "wild type or WT" herein is meant an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0064] The antibodies of the present invention are generally isolated or recombinant. “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide will be prepared by at least one purification step. An “isolated antibody,” refers to an antibody which is substantially free of other antibodies having different antigenic specificities. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogenous host cells, and they can be isolated as well.

[0065] “Specific binding” or “specifically binds to” or is “specific for” a particular antigen or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0066] Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10⁴ M, at least about 10⁵ M, at least about 10⁶ M, at least about 10⁷ M, at least about 10⁸ M, at least about 10⁹ M, alternatively at least about 10 ¹⁰ M, at least about 10 ¹¹ M, at least about 10 ¹² M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.

[0067] Also, specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction. Binding affinity is generally measured using a Biacore, SPR or BLI assay.

[0068] As used herein, the term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, and effects on particular biomarkers related to CD 123 disorder pathology.

[0069] By "refractory" in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent. A cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (i.e. , non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.

[0070] As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of the biological activity of CD 123, in an assay that measures such response.

[0071] As used herein, EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

[0072] The term “remission” in relation to cancer means a decrease in or disappearance of signs (e.g., tumor size, biomarkers) and/or symptoms of cancer. In some cases, the remission can be partial or complete. For example, remission can lead to the reduction or amelioration or elimination of the progression, severity and/or effect associated with a CD 123 -expressing cancer (e.g., a hematological cancer) and/or an improvement in one or more symptoms associated with a CD 123 -expressing cancer. In some cases, remission can be associated with an increase in the immune system response of the human subject, or the amelioration of one or more symptoms of a CD 123 -expressing cancer, that result from the administration of an antibody described herein. In cases, remission can result in the amelioration of at least one measurable physical parameter of a cancer, such as tumor size, rate of tumor growth, number of tumor cells, tumor invasiveness, presence of metastasis, or extent of metastasis. In other cases, remission can lead to the inhibition of the progression of a CD 123-expressing cancer, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In some cases, remission can be associated with one or more of the following: (1) a reduction in the number of CD123⁺ expressing cancer-associated cells, including CD123⁺ peripheral blood blasts and/or marrow blasts, such as for example a reduction to levels below the detection limits of a MRD (minimal residual disease) assay (/. e. flow cytometry assay, RT-qPCR assay, or next-gen sequencing based MRD assay) (or such as an increase in T cell activation or an increase in IFN pathway upregulation); (2) an increase in CD123⁺ expressing cancer-associated cell death; (3) inhibition of CD123⁺ expressing cancer-associated cell survival; (5) inhibition ( i.e ., slowing to some extent, preferably halting) of CD123⁺ expressing cancer-associated proliferation (such as an increase in T cell activation or an increase in IFN pathway upregulation) (or such as a reduction in the rate of growth of CD 123 -expressing cancer cells); (6) an increased human subject survival rate; (7) improvement in peripheral blood cytopenias associated with the CD 123 -expressing cancer; and (8) any amount of relief (subjective and/or objective) from one or more symptoms of a CD 123-expressing cancer.

[0073] Remission can be determined by standardized response criteria specific to that CD 123-expressing cancer. Examples of such response criteria include the European LeukemiaNet response assessment categories for clinical trials. Examples for AML can be found in Dohner et al. Blood, 2017; 129(4): 424. Examples for ALL, including extrameduallary disease assessment such as cerebrospinal fluid cytology, can be found in Cheson, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-9.

Examples for BPDCN, can be found in Cheson et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. 1999; 17(4): 1244; Cheson et al. Journal of Clinical Oncology. 2007;25(5):579-86; Olsen et al. Journal of Clinical Oncology. 2011;29(18):2598-607; Pagano et al. Haematologica. 2013;98(2):239-46. Examples for chronic myeloid leukemia in blast phase can be found in Cortes et al. Blood. 2007;109(8):3207-13.

[0074] Improvement in one or more symptoms associated with a CD 123 -expressing cancer include feeling less tired, feeling less weak, feeling less dizzy or lightheaded, reduction in shortness of breath, reduction in fever, fewer infections, quicker recovery from infections, reduction in ease of bruising, reduction in bleeding episodes, weight gain, reduction in night sweats, gain of appetite, reduction in abdominal swelling, reduction in lymph node swelling, reduction in bone or joint pain, and reduction in thymus swelling.

[0075] An improvement in the CD 123 -expressing cancer can be characterized as a “complete remission” or “complete response”. The terms “complete remission” or “complete response” in relation to cancer can mean all signs and/or symptoms of cancer have disappeared, although in some cases, a cancer patient may still have cancer cells in the body. Complete remission can result in an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF). In one case, complete remission is defined as <5% bone marrow blasts, no circulating blasts or blasts with Auer rods, absence of extramedullary disease, and normalization of blood counts (absolute neutrophil count >1000/microliter and platelet count > 100000/microliter). In some cases, with regarding to blood cancers such as AML and ALL, complete remission can, in addition to absence of morphologic evidence of leukemia, result in a recovery of normal blood cell counts to a normal range.

[0076] Alternatively, an improvement in the CD 123-expressing cancer can be characterized as a “partial remission” or “partial response”. The term “partial remission” or “partial response” in relation to cancer can mean that some, but not all, signs and/or symptoms of cancer have disappeared. For example, in some cases, partial response can convey that at least about a 5% decrease in at least one measurable tumor burden (i.e.. the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions, which can persist for 4 to 8 weeks, or 6 to 8 weeks. In some cases, partial response can lead to at least about a 10% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 15% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 20% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 25% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 30% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 35% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 40% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 45% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 50% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 60% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 70% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 80% decrease in at least one measurable tumor burden. In some cases, partial response mean at least about a 90% decrease in at least one measurable tumor burden.

[0077] The terms “patent” and “human subject” can be used interchangeably herein.

II. Overview

[0078] Disclosed herein are methods of treating a cancer that include cells expressing CD 123 (“CD 123 -expressing cancer”), for example, a hematologic cancer, such as leukemia, through the administration of certain bispecific anti-CD 123 x anti-CD3 antibodies at particular dosages. The term “CD 123-expressing cancer” can refer to a cancer that expresses CD 123 or a cancer that overexpresses CD 123. The present invention also provides methods of combination therapies, for example, methods of treating a cancer that include cells expressing CD 123 (“CD 123-expressing cancer”), e.g., a hematologic cancer, such as leukemia, through the administration of certain bispecific anti-CD 123 x anti-CD3 antibodies (e.g., XmAb 14045) in combination with one or more therapies that can ameliorate one or more side effects of an anti-CD 123 x anti-CD3 bispecific antibody.

III. Antibodies

[0079] The present invention is directed to the administration of bispecific antibodies, such as anti-CD 123 x anti-CD3 antibodies, for the treatment of CD 123 -expressing cancers, such as particular leukemias. For example, some embodiments of antibodies with bispecific formats of the figures and polynucleotide/polypeptide sequences, are disclosed in U.S. Pat. Appl. Pub. No. 2016/0229924.

[0080] In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibodies have a “bottle opener” format as is generally depicted in FIG. 1. In this embodiment, the anti-CD3 antigen binding domain is the scFv-Fc domain monomer and the anti-CD 123 antigen binding domain is the Fab monomer ( see e.g., U.S. Pat. Appl. Pub. Nos. 2014/0288275; 2014/0294823; and 2016/0355608). [0081] Alternate formats for the bispecific, heterodimeric anti-CD 123 x anti-CD3 antibodies are shown in FIG. 7, which also generally rely on the use of Fabs and scFv domains in different formats.

[0082] In addition, other heterodimeric and non-heterodimeric anti-CD 123 x anti-CD3 bispecific antibodies, can be dosed at the same dosage levels and by the same methods as described therein.

[0083] The anti-CD3 scFv antigen binding domain can have the sequence depicted in FIG. 2, or can be selected from the group consisting of:

1) the set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) from any one of the anti-CD3 antigen binding domain sequence depicted in FIGs. 2 and 6 of U.S. Pat. Appl. Pub. No. 2014/0288275;

2) the variable heavy and variable light chains from any one of the anti-CD3 antigen binding domain sequence depicted in FIGs. 2 and 6 of U.S. Pat. Appl. Pub. No. 2014/0288275;

3) the scFv domains from any one of the anti-CD3 scFv sequence depicted in FIG. 2 of U.S. Pat. Appl. Pub. No. 2014/0288275;

4) other known anti-CD3 variable heavy and variable light chains, that can be combined to form scFvs (or Fabs, when the format is reversed or an alternative format is used); and

5) any one of the anti-CD3 antigen binding domains of FIGs. 2, 3, 4, 5, 6, and 7 of U.S. Pat. Appl. Pub. No. 2016/0229924.

[0084] The anti-CD 123 Fab binding domain can have the sequence depicted in FIG 2 or 5, or can be selected from the group consisting of:

1) The set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) from any one of the anti-CD123 antigen binding domain sequence depicted in U.S.

Pat. Appl. Pub. No. 2016/0229924, including those depicted in FIGs. 2, 3 and 12;

2) The variable heavy and variable light chains from any one of the anti-CD 123 antigen binding domain sequence depicted in U.S. Pat. Appl. Pub. No. 2016/0229924, including those depicted in FIGs. 2, 3 and 12; and 3) Other anti-CD 123 variable heavy and variable light chains as are also known, that can be combined to form Fabs (or scFvs, when the format is reversed or an alternative format is used).

[0085] One bispecific antibody that can be used in the dosing regimens described throughout is XmAb 14045 as shown in FIG 2. The XmAb 14045 bispecific antibody includes a first monomer comprising SEQ ID NO: 1, a second monomer comprising SEQ ID NO: 2, and a light chain comprising SEQ ID NO: 3. In an exemplary embodiment, the bispecific anti- CD123 x anti-CD3 antibody comprises a Heavy Chain 1 (HC1) (Fab-Fc) set forth in SEQ ID NO: 1, a Heavy Chain 2 (HC2) (scFv-Fc) set forth in SEQ ID NO: 2 and a Light Chain set forth in SEQ ID NO: 3. In an exemplary embodiment, the bispecific anti-CD 123 x anti-CD3 antibody consists of a Heavy Chain 1 (HC1) (Fab-Fc) set forth in SEQ ID NO: 1, a Heavy Chain 2 (HC2) (scFv-Fc) set forth in SEQ ID NO: 2 and a Light Chain set forth in SEQ ID NO: 3.

[0086] The bispecific anti-CD 123 x anti-CD3 antibodies as used throughout can be made through known methods. The disclosure further provides polynucleotide compositions encoding the bispecific anti-CD 123 x anti-CD3 antibodies. Further, the polynucleotide compositions will depend on the format and scaffold of the bispecific anti-CD 123 x anti-CD3 antibodies. Thus, for example, when the format requires three amino acid sequences, such as for the triple F format (e.g. a first amino acid monomer comprising an Fc domain and a scFv, a second amino acid monomer comprising a heavy chain and a light chain), three polynucleotides can be incorporated into one or more vectors for expression. Similarly, some formats (e.g. dual scFv formats such as disclosed in FIG. 7) only two polynucleotides are needed; they can also be put into one or two expression vectors.

[0087] The polynucleotides encoding the components of the bispecific antibodies can be incorporated into expression vectors, and depending on the host cells can be used to produce the bispecific anti-CD 123 x anti-CD3 antibodies. Generally the polynucleotides are operably linked to any number of regulatory elements (promoters, origin of replication, selectable markers, ribosomal binding sites, inducers, etc.). The expression vectors can be extra- chromosomal or integrating vectors. [0088] The polynucleotides and/or expression vectors are then transformed into any number of different types of host cells, including but not limited to mammalian, bacterial, yeast, insect and/or fungal cells, with mammalian cells (e.g. CHO cells).

[0089] In some embodiments, polynucleotides encoding each monomer and the optional polynucleotides encoding a light chain, as applicable depending on the format, are each contained within a single expression vector, controlled using different or the same promoter. In some embodiments, each of these two or three polynucleotides are contained on a different expression vector.

[0090] The heterodimeric bispecific anti-CD 123 x anti-CD3 antibodies are made by culturing host cells comprising expression vector(s). Once produced, traditional antibody purification steps are performed, such as an ion exchange chromatography step. As discussed in U.S. Pat. No. 9,650,446 and Int. Publ. No. WO2014/145806, having the pis of the two monomers differ by at least 0.5 can allow separation by ion exchange chromatography or isoelectric focusing, or other methods sensitive to isoelectric point. That is, the inclusion of pi substitutions that alter the isoelectric point (pi) of each monomer so that such that each monomer has a different pi and the heterodimer also has a distinct pi, thus facilitating isoelectric purification of the “triple F” heterodimer (e.g., anionic exchange columns, cationic exchange columns). These substitutions also aid in the determination and monitoring of any contaminating dual scFv-Fc and mAh homodimers post-purification (e.g., IEF gels, cIEF, and analytical IEX columns).

[0091] Once made, the bispecific anti-CD 123 x anti-CD3 antibodies are administered to human subjects in dosages as outlined herein.

IV. Pharmaceutical Compositions and Pharmaceutical Administration [0092] XmAb 14045 can be incorporated into pharmaceutical compositions suitable for administration to a human subject according to a dosage regimen described herein. As used herein, “dosage regimen” refers to a systematic plan of drug administration regarding formulation, route of administration, drug dose, dosing interval and treatment duration. Typically, the pharmaceutical composition comprises XmAb 14045 and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as any combination thereof. In some cases, isotonic agents can be included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of XmAb 14045.

Examples of pharmaceutically acceptable carriers include polysorbates (polysorbate-80).

[0093] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and a preservative or buffer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and histidine. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and an acetate. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium acetate. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and a citrate. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium citrate.

[0094] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and an isotonic agent. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and a polyalcohol. In one embodiment, the pharmaceutical composition comprises XmAbl4045 and mannitol. In one embodiment, the pharmaceutical composition comprises XmAbl4045 and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and potassium chloride.

[0095] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and a wetting or emulsifying agent. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and a polysorbate. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and polysorbate-80.

[0096] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and an intravenous solution stabilizer. In one embodiment, the intravenous solution stabilizer comprises a polysorbate and a citrate. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium citrate and polysorbate-80. [0097] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and a buffer and an isotonic agent. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and a buffer and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and an acetate and an isotonic agent. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and histidine and an isotonic agent. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and an acetate and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium acetate and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and histidine and sorbitol.

[0098] In one embodiment, the pharmaceutical composition comprises XmAbl4045 and a buffer and an isotonic agent and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and a buffer and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and an acetate and an isotonic agent and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and histidine and an isotonic agent and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and an acetate and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium acetate and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and histidine and sorbitol and an intravenous solution stabilizer.

[0099] In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAbl4045 and sodium chloride and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium citrate and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium citrate, sodium chloride, and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAb 14045 and sodium citrate, sodium chloride, sodium acetate, sorbitol and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAbl4045 and sodium citrate, sodium chloride, histidine, sorbitol and polysorbate-80. [0100] The pharmaceutical compositions can be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions. The form depends on the intended mode of administration and therapeutic application. Exemplary compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies. In one embodiment, the mode of administration is intravenous. In one embodiment, the antibody is administered by intravenous infusion or injection.

[0101] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or any combination of ingredients enumerated herein, as required, followed by fdtered sterilization. Generally, dispersions are prepared by incorporating the antibody into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.

[0102] XmAbl4045 can be administered by any known method. In one embodiment, the route/mode of administration is intravenous injection. The route and/or mode of administration can vary depending upon the desired results.

V CD123-Exyressing Cancer Treatment Protocols

[0103] In one embodiment, the antibodies of the invention treat a CD 123 -expressing cancer. In one embodiment, the CD 123 -expressing cancer is a hematologic cancer. In one embodiment, the CD 123 -expressing cancer is a leukemia.

[0104] CD 123 is frequently expressed on hematologic malignancies, such as 96-98% of acute myelogenous leukemia cases; >50% of myelodysplastic syndrome cases; 82-100% of B-cell acute lymphoblastic leukemia cases; 83-100% of Blastic plasmacytoid dendritic cell neoplasm cases; 75-100% of Chronic myelogenous leukemia cases; and 95-100% of Hairy cell leukemia cases.

[0105] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of blood cells, usually leukocytes (white blood cells). Leukemia is a broad term covering a spectrum of diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body.

Acute forms of leukemia are the most common forms of leukemia in children; (ii) chronic leukemia is distinguished by the excessive buildup of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias: (i) lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells; (ii) myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

[0106] In one embodiment, the leukemia is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In one embodiment, the leukemia is acute lymphocytic leukemia (ALL). In one embodiment, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and hairy cell leukemia (HCL). In one embodiment, the leukemia is acute lymphocytic leukemia (ALL).

In one embodiment, the leukemia is acute lymphocytic leukemia, and the acute lymphocytic leukemia is B-cell acute lymphocytic leukemia (B-ALL). In one embodiment, the leukemia is myelodysplastic syndrome. In one embodiment, the leukemia is acute myeloid leukemia (AML). In one embodiment, the leukemia is acute myeloid leukemia (AML), and the AML is blastic plasmacytoid dendritic cell neoplasm (BPDCN). In one embodiment, the leukemia is chronic myeloid leukemia (CML). In one embodiment, the leukemia is chronic phase chronic myeloid leukemia. In one embodiment, the leukemia is accelerated phase chronic myeloid leukemia. In one embodiment, the leukemia is blast phase chronic myeloid leukemia. In one embodiment, the leukemia is hairy cell leukemia (HCL). In one embodiment, the leukemia is classic hairy cell leukemia (HCLc). In one embodiment, the leukemia is acute myeloid leukemia (AML), where the AML is primary acute myeloid leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML), where the AML is secondary acute myeloid leukemia. In one embodiment, the leukemia is erythroleukemia. In one embodiment, the leukemia is eosinophilic leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML), where the AML does not include acute promyelocytic leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML), where the AML is blastic plasmacytoid dendritic cell neoplasm. In one embodiment, the leukemia is B-cell acute lymphocytic leukemia (B-ALL). In one embodiment, the leukemia is T-cell acute lymphocytic leukemia (T-ALL).

[0107] In one embodiment, the leukemia is relapsed acute myeloid leukemia (AML). In one embodiment, the leukemia is refractory acute myeloid leukemia (AML).

[0108] In some embodiments, the cancer is treated according to a method described herein. In one embodiment, the cancer is treated by dispensing XmAb 14045 to the human subject in one or more phases. Each phase comprises dose(s) of XmAb 14045 provided on a per week or per month basis (‘dosage regimen’). Each phase can last for one or more weeks or months, or until remission. In one embodiment, the antibody is administered until partial remission. In one embodiment, the antibody is administered until complete remission.

[0109] In one embodiment, the method of treatment comprises an antibody being dispensed in one to four phases. In one embodiment, a phase has the same dosage regimen that occurs between one (1) and twenty (20) times, or until remission). In one embodiment, the dosage regimen has a dose amount (quantity of an antibody) and an administration time (the length of time in which the dose amount is administered).

[0110] In one embodiment, the method comprises a first phase. In one embodiment, the method comprises a first phase. In one embodiment, the method comprises a first phase and a second phase. In one embodiment, the method comprises a first phase and a second phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase and a third phase. In one embodiment, the method comprises a first phase and a second phase and a third phase. In one embodiment, the method comprises a first phase and a second phase and a third phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where each phase is different. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase. In one embodiment, the method comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where each phase is different. In one embodiment, a dosage regimen continues until the cancer (e.g., hematological cancer) is in remission (e.g., complete or partial).

V a). Dose

[0111] A dose has a specific amount of antibody that is administered to a human subject over a defined time period. The amount of antibody administered to a human subject is also known as the dose amount. The time over which the dose amount is administered to a human subject is also known as the administration time.

V a) i). Dose Amount

[0112] The dose amount may be determined or adjusted by measuring the amount of bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) in the blood upon administration, for instance taking out a biological sample and using anti-idiotypic antibodies which target the antigen binding region of the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045). The dose amount may be determined based upon the weight of the human subject, such as by multiplying the weight (in kg, for example) of the human subject by a dose amount (such as those described herein). Prior to the administering of the first phase of the bispecific anti-CD 123 x anti-CD3 antibody, such as the day before the first phase administration, the weight of the human subject can be assessed. For human subjects whose weight exceeds 100 kg, the dose amount can be calculated based on a weight of 100 kg rather than being calculated based upon the human subject’s actual body weight.

[0113] Following the first dose in the first phase administration, subsequent doses may be modified if the human subject’s weight changes by a certain amount (for example, more than by about 5%, more than by about 10%, from the weight assessment prior to the first phase assessment). At such a point, the weight may be recalculated for that infusion day using the current weight.

[0114] PARAGRAPH A includes the following dose amounts: In one embodiment, the dose amount is between about 350 ng/kg and about 21,000 ng/kg.

[0115] PARAGRAPH B includes any one of the following dose amounts: In one embodiment, the dose amount is between about 350 ng/kg and about 650 ng/kg. In one embodiment, the dose amount is between about 400 ng/kg and about 600 ng/kg. In one embodiment, the dose amount is between about 400 ng/kg and about 500 ng/kg. In one embodiment, the dose amount is between about 425 ng/kg and about 475 ng/kg. In one embodiment, the dose amount is between about 450 ng/kg and about 470 ng/kg. In one embodiment, the dose amount is about 460 ng/kg. In one embodiment, the dose amount is 460 ng/kg. In one embodiment, the dose amount is between about 525 ng/kg and about 600 ng/kg. In one embodiment, the dose amount is between about 550 ng/kg and about 600 ng/kg. In one embodiment, the dose amount is between about 560 ng/kg and about 580 ng/kg. In one embodiment, the dose amount is about 570 ng/kg. In one embodiment, the dose amount is 570 ng/kg. In one embodiment, the dose amount is about 575 ng/kg. In one embodiment, the dose amount is 575 ng/kg. In one embodiment, the dose amount is between about 450 ng/kg and about 550 ng/kg. In one embodiment, the dose amount is between about 475 ng/kg and about 525 ng/kg. In one embodiment, the dose amount is about 500 ng/kg. In one embodiment, the dose amount is 500 ng/kg. [0116] PARAGRAPH C includes any one of the following dose amounts: In one embodiment, the dose amount is between about 600 ng/kg and about 900 ng/kg. In one embodiment, the dose amount is between about 100 ng/kg and about 750 ng/kg. In one embodiment, the dose amount is between about 500 ng/kg and about 750 ng/kg. In one embodiment, the dose amount is between about 600 ng/kg and about 750 ng/kg. In one embodiment, the dose amount is between about 700 ng/kg and about 750 ng/kg. In one embodiment, the dose amount is between about 600 ng/kg and about 700 ng/kg. In one embodiment, the dose amount is between about 625 ng/kg and about 675 ng/kg. In one embodiment, the dose amount is between about 640 ng/kg and about 660 ng/kg. In one embodiment, the dose amount is about 650 ng/kg. In one embodiment, the dose amount is 650 ng/kg. In one embodiment, the dose amount is between about 650 ng/kg and about 700 ng/kg. In one embodiment, the dose amount is between about 660 ng/kg and about 680 ng/kg. In one embodiment, the dose amount is about 667 ng/kg. In one embodiment, the dose amount is 667 ng/kg. In one embodiment, the dose amount is between about 725 ng/kg and about 775 ng/kg. In one embodiment, the dose amount is between about 740 ng/kg and about 780 ng/kg. In one embodiment, the dose amount is between about 760 ng/kg and about 780 ng/kg. In one embodiment, the dose amount is between about 750 ng/kg and about 780 ng/kg. In one embodiment, the dose amount is about 767 ng/kg. In one embodiment, the dose amount is 767 ng/kg. In one embodiment, the dose amount is about 770 ng/kg. In one embodiment, the dose amount is 770 ng/kg. In one embodiment, the dose amount is between about 700 ng/kg and about 900 ng/kg. In one embodiment, the dose amount is between about 750 ng/kg and about 850 ng/kg. In one embodiment, the dose amount is between about 775 ng/kg and about 825 ng/kg. In one embodiment, the dose amount is about 800 ng/kg. In one embodiment, the dose amount is 800 ng/kg. In one embodiment, the dose amount is between about 650 ng/kg and about 850 ng/kg. In one embodiment, the dose amount is between about 700 ng/kg and about 800 ng/kg. In one embodiment, the dose amount is between about 725 ng/kg and about 775 ng/kg. In one embodiment, the dose amount is between about 740 ng/kg and about 760 ng/kg. In one embodiment, the dose amount is about 750 ng/kg. In one embodiment, the dose amount is 750 ng/kg.

[0117] PARAGRAPH D includes any one of the following dose amounts: In one embodiment, the dose amount is between about 700 ng/kg and about 1,900 ng/kg. In one embodiment, the dose amount is between about 1,500 ng/kg and about 1,900 ng/kg. In one embodiment, the dose amount is between about 1,300 ng/kg and about 1,500 ng/kg. In one embodiment, the dose amount is between about 1,350 ng/kg and about 1,450 ng/kg. In one embodiment, the dose amount is about 1,400 ng/kg. In one embodiment, the dose amount is 1,400 ng/kg. In one embodiment, the dose amount is between about 300 ng/kg and about

1,100 ng/kg. In one embodiment, the dose amount is between about 700 ng/kg and about

1,100 ng/kg. In one embodiment, the dose amount is between about 900 ng/kg and about

1,100 ng/kg. In one embodiment, the dose amount is between about 950 ng/kg and about 1,050 ng/kg. In one embodiment, the dose amount is about 1,000 ng/kg. In one embodiment, the dose amount is 1,000 ng/kg. In one embodiment, the dose amount is between about 1,100 ng/kg and about 1,200 ng/kg. In one embodiment, the dose amount is between about 1,125 ng/kg and about 1,175 ng/kg. In one embodiment, the dose amount is about 1,125 ng/kg. In one embodiment, the dose amount is 1,125 ng/kg. In one embodiment, the dose amount is about 1,150 ng/kg. In one embodiment, the dose amount is 1,150 ng/kg. In one embodiment, the dose amount is between about 1,150 ng/kg and about 1,180 ng/kg. In one embodiment, the dose amount is between about 1,160 ng/kg and about 1,175 ng/kg. In one embodiment, the dose amount is about 1,167 ng/kg. In one embodiment, the dose amount is 1,167 ng/kg.

In one embodiment, the dose amount is between about 700 ng/kg and about 1,100 ng/kg. In one embodiment, the dose amount is between about 800 ng/kg and about 1,000 ng/kg. In one embodiment, the dose amount is between about 850 ng/kg and about 950 ng/kg. In one embodiment, the dose amount is between about 875 ng/kg and about 925 ng/kg. In one embodiment, the dose amount is between about 890 ng/kg and about 910 ng/kg. In one embodiment, the dose amount is about 900 ng/kg. In one embodiment, the dose amount is 900 ng/kg. In one embodiment, the dose amount is between about 1,000 ng/kg and about 1,500 ng/kg. In one embodiment, the dose amount is between about 1,000 ng/kg and about 1,250 ng/kg. In one embodiment, the dose amount is between about 1,050 ng/kg and about 1,200 ng/kg. In one embodiment, the dose amount is between about 1,050 ng/kg and about 1,150 ng/kg. In one embodiment, the dose amount is between about 1,075 ng/kg and about 1,125 ng/kg. In one embodiment, the dose amount is between about 1,090 ng/kg and about 1,110 ng/kg. In one embodiment, the dose amount is about 1,100 ng/kg. In one embodiment, the dose amount is 1,100 ng/kg. In one embodiment, the dose amount is between about 1,100 ng/kg and about 1,400 ng/kg. In one embodiment, the dose amount is between about 1,100 ng/kg and about 1,300 ng/kg. In one embodiment, the dose amount is between about 1,150 ng/kg and about 1,250 ng/kg. In one embodiment, the dose amount is between about 1,175 ng/kg and about 1,225 ng/kg. In one embodiment, the dose amount is between about 1,190 ng/kg and about 1,210 ng/kg. In one embodiment, the dose amount is about 1,200 ng/kg. In one embodiment, the dose amount is 1,200 ng/kg. In one embodiment, the dose amount is between about 800 ng/kg and about 1,100 ng/kg. In one embodiment, the dose amount is between about 900 ng/kg and about 1,050 ng/kg. In one embodiment, the dose amount is between about 950 ng/kg and about 1,100 ng/kg. In one embodiment, the dose amount is between about 850 ng/kg and about 1,750 ng/kg. In one embodiment, the dose amount is between about 1,000 ng/kg and about 1,600 ng/kg. In one embodiment, the dose amount is between about 1,000 ng/kg and about 1,400 ng/kg. In one embodiment, the dose amount is between about 1,150 ng/kg and about 1,450 ng/kg. In one embodiment, the dose amount is between about 1,300 ng/kg and about 1,350 ng/kg. In one embodiment, the dose amount is about 1,333 ng/kg. In one embodiment, the dose amount is 1,333 ng/kg. In one embodiment, the dose amount is about 1,300 ng/kg. In one embodiment, the dose amount is 1,300 ng/kg.

[0118] PARAGRAPH E includes any one of the following dose amounts: In one embodiment, the amount is between about 900 ng/kg and about 3,400 ng/kg. In one embodiment, the amount is between about 1,200 ng/kg and about 3,400 ng/kg. In one embodiment, the amount is between about 1,400 ng/kg and about 2,400 ng/kg. In one embodiment, the amount is between about 1,500 ng/kg and about 1,800 ng/kg. In one embodiment, the amount is between about 1,500 ng/kg and about 1,900 ng/kg. In one embodiment, the amount is between about 1,700 ng/kg and about 1,800 ng/kg. In one embodiment, the dose amount is about 1,750 ng/kg. In one embodiment, the dose amount is 1,750 ng/kg. In one embodiment, the amount is between about 1,700 ng/kg and about 1,740 ng/kg. In one embodiment, the amount is between about 1,700 ng/kg and about 1,725 ng/kg. In one embodiment, the dose amount is about 1,714 ng/kg. In one embodiment, the dose amount is 1,714 ng/kg. In one embodiment, the dose amount is between about 1,300 ng/kg and about 1,700 ng/kg. In one embodiment, the dose amount is between about 1,350 ng/kg and about 1,650 ng/kg. In one embodiment, the dose amount is between about 1,400 ng/kg and about 1,600 ng/kg. In one embodiment, the dose amount is between about 1,450 ng/kg and about 1,550 ng/kg. In one embodiment, the dose amount is between about 1,475 ng/kg and about 1,525 ng/kg. In one embodiment, the dose amount is between about 1,490 ng/kg and about 1,510 ng/kg. In one embodiment, the dose amount is about 1,500 ng/kg. In one embodiment, the dose amount is 1,500 ng/kg. In one embodiment, the dose amount is between about 1,600 ng/kg and about 1,800 ng/kg. In one embodiment, the dose amount is between about 1,650 ng/kg and about 1,750 ng/kg. In one embodiment, the dose amount is between about 1,675 ng/kg and about 1,725 ng/kg. In one embodiment, the dose amount is between about 1,690 ng/kg and about 1,710 ng/kg. In one embodiment, the dose amount is about 1,700 ng/kg. In one embodiment, the dose amount is 1,700 ng/kg. In one embodiment, the dose amount is between about 1,600 ng/kg and about 2,000 ng/kg. In one embodiment, the dose amount is between about 1,650 ng/kg and about 1,950 ng/kg. In one embodiment, the dose amount is between about 1,700 ng/kg and about 1,900 ng/kg. In one embodiment, the dose amount is between about 1,750 ng/kg and about 1,850 ng/kg. In one embodiment, the dose amount is between about 1,775 ng/kg and about 1,825 ng/kg. In one embodiment, the dose amount is between about 1,790 ng/kg and about 1,810 ng/kg. In one embodiment, the dose amount is about 1,800 ng/kg. In one embodiment, the dose amount is 1,800 ng/kg.

In one embodiment, the amount is between about 1,400 ng/kg and about 3,200 ng/kg. In one embodiment, the amount is between about 1,600 ng/kg and about 3,000 ng/kg. In one embodiment, the dose amount is between about 1,800 ng/kg and about 2,200 ng/kg. In one embodiment, the dose amount is between about 1,900 ng/kg and about 2,100 ng/kg. In one embodiment, the dose amount is about 2,000 ng/kg. In one embodiment, the dose amount is 2,000 ng/kg. In one embodiment, the dose amount is between about 1,800 ng/kg and about 2,800 ng/kg. In one embodiment, the dose amount is between about 2,000 ng/kg and about 2,600 ng/kg. In one embodiment, the dose amount is between about 2,250 ng/kg and about 2,500 ng/kg. In one embodiment, the dose amount is between about 2,300 ng/kg and about 2,350 ng/kg. In one embodiment, the dose amount is about 2,333 ng/kg. In one embodiment, the dose amount is 2,333 ng/kg. In one embodiment, the dose amount is about 2,400 ng/kg.

In one embodiment, the dose amount is 2,400 ng/kg. In one embodiment, the dose amount is between about 2,200 ng/kg and about 2,400 ng/kg. In one embodiment, the dose amount is about 2,300 ng/kg. In one embodiment, the dose amount is 2,300 ng/kg.

[0119] PARAGRAPH F includes any one of the following dose amounts: In one embodiment, the dose amount is between about 2,000 ng/kg and about 5,000 ng/kg. In one embodiment, the dose amount is between about 2,000 ng/kg and about 4,000 ng/kg. In one embodiment, the dose amount is between about 3,000 ng/kg and about 4,000 ng/kg. In one embodiment, the dose amount is between about 3,250 ng/kg and about 3,750 ng/kg. In one embodiment, the dose amount is between about 3,400 ng/kg and about 3,600 ng/kg. In one embodiment, the dose amount is about 3,500 ng/kg. In one embodiment, the dose amount is 3,500 ng/kg. In one embodiment, the dose amount is between about 3,500 ng/kg and about 3,700 ng/kg. In one embodiment, the dose amount is about 3,600 ng/kg. In one embodiment, the dose amount is 3,600 ng/kg. In one embodiment, the dose amount is between about 3,000 ng/kg and about 5,000 ng/kg. In one embodiment, the dose amount is between about 3,400 ng/kg and about 3,600 ng/kg. In one embodiment, the dose amount is about 3,500 ng/kg. In one embodiment, the dose amount is 3,500 ng/kg. In one embodiment, the dose amount is between about 2,500 ng/kg and about 3,500 ng/kg. In one embodiment, the dose amount is between about 2,750 ng/kg and about 3,250 ng/kg. In one embodiment, the dose amount is about 3,000 ng/kg. In one embodiment, the dose amount is 3,000 ng/kg. In one embodiment, the dose amount is between about 2,750 ng/kg and about 3,000 ng/kg. In one embodiment, the dose amount is between about 2,800 ng/kg and about 2,900 ng/kg. In one embodiment, the dose amount is between about 2,830 ng/kg and about 2,880 ng/kg. In one embodiment, the dose amount is about 2,857 ng/kg. In one embodiment, the dose amount is 2,857 ng/kg.

In one embodiment, the dose amount is between about 2,000 ng/kg and about 3,000 ng/kg. In one embodiment, the dose amount is between about 2, 100 ng/kg and about 2,900 ng/kg. In one embodiment, the dose amount is between about 2,200 ng/kg and about 2,800 ng/kg. In one embodiment, the dose amount is between about 2,300 ng/kg and about 2,700 ng/kg. In one embodiment, the dose amount is between about 2,350 ng/kg and about 2,650 ng/kg. In one embodiment, the dose amount is between about 2,400 ng/kg and about 2,600 ng/kg. In one embodiment, the dose amount is between about 2,425 ng/kg and about 2,575 ng/kg. In one embodiment, the dose amount is between about 2,450 ng/kg and about 2,550 ng/kg. In one embodiment, the dose amount is between about 2,475 ng/kg and about 2,525 ng/kg. In one embodiment, the dose amount is between about 2,490 ng/kg and about 2,510 ng/kg. In one embodiment, the dose amount is about 2,500 ng/kg. In one embodiment, the dose amount is 2,500 ng/kg. In one embodiment, the dose amount is between about 2,500 ng/kg and about 3,500 ng/kg. In one embodiment, the dose amount is between about 2,600 ng/kg and about 3,300 ng/kg. In one embodiment, the dose amount is between about 2,700 ng/kg and about 3,200 ng/kg. In one embodiment, the dose amount is between about 2,800 ng/kg and about 3,100 ng/kg. In one embodiment, the dose amount is between about 2,850 ng/kg and about 3,000 ng/kg. In one embodiment, the dose amount is between about 2,850 ng/kg and about 2,950 ng/kg. In one embodiment, the dose amount is between about 2,875 ng/kg and about 2,925 ng/kg. In one embodiment, the dose amount is between about 2,890 ng/kg and about 2,910 ng/kg. In one embodiment, the dose amount is about 2,900 ng/kg. In one embodiment, the dose amount is 2,900 ng/kg. In one embodiment, the dose amount is between about 3,500 ng/kg and about 4,000 ng/kg. In one embodiment, the dose amount is between about 3,600 ng/kg and about 3,900 ng/kg. In one embodiment, the dose amount is between about 3,700 ng/kg and about 3,900 ng/kg. In one embodiment, the dose amount is between about 3,750 ng/kg and about 3,850 ng/kg. In one embodiment, the dose amount is between about 3,775 ng/kg and about 3,825 ng/kg. In one embodiment, the dose amount is between about 3,790 ng/kg and about 3,810 ng/kg. In one embodiment, the dose amount is about 3,800 ng/kg. In one embodiment, the dose amount is 3,800 ng/kg. In one embodiment, the dose amount is between about 3,200 ng/kg and about 3,400 ng/kg. In one embodiment, the dose amount is between about 3,300 ng/kg and about 3,350 ng/kg. In one embodiment, the dose amount is about 3,333 ng/kg. In one embodiment, the dose amount is 3,333 ng/kg.

In one embodiment, the dose amount is between about 4,000 ng/kg and about 5,000 ng/kg. In one embodiment, the dose amount is between about 4, 100 ng/kg and about 4,900 ng/kg. In one embodiment, the dose amount is between about 4,200 ng/kg and about 4,800 ng/kg. In one embodiment, the dose amount is between about 4,300 ng/kg and about 4,700 ng/kg. In one embodiment, the dose amount is between about 4,400 ng/kg and about 4,600 ng/kg. In one embodiment, the dose amount is about 4,500 ng/kg. In one embodiment, the dose amount is 4,500 ng/kg. In one embodiment, the dose amount is between about 2,500 ng/kg and about 5,000 ng/kg. In one embodiment, the dose amount is between about 3,000 ng/kg and about 5,000 ng/kg. In one embodiment, the dose amount is between about 3,500 ng/kg and about 4,500 ng/kg. In one embodiment, the dose amount is between about 3,750 ng/kg and about 4,250 ng/kg. In one embodiment, the dose amount is about 4,000 ng/kg. In one embodiment, the dose amount is 4,000 ng/kg.

[0120] PARAGRAPH G includes any one of the following dose amounts: In one embodiment, the dose amount is between about 3,000 ng/kg and about 11,000 ng/kg. In one embodiment, the dose amount is between about 4,000 ng/kg and about 10,000 ng/kg. In one embodiment, the dose amount is between about 6,000 ng/kg and about 7,000 ng/kg. In one embodiment, the dose amount is between about 6,500 ng/kg and about 6,750 ng/kg. In one embodiment, the dose amount is about 6,667 ng/kg. In one embodiment, the dose amount is 6,667 ng/kg. In one embodiment, the dose amount is about 6,700 ng/kg. In one embodiment, the dose amount is 6,700 ng/kg. In one embodiment, the dose amount is between about 4,000 ng/kg and about 6,000 ng/kg. In one embodiment, the dose amount is between about 4,500 ng/kg and about 5,500 ng/kg. In one embodiment, the dose amount is between about 4,750 ng/kg and about 5,250 ng/kg. In one embodiment, the dose amount is between about 4,900 ng/kg and about 5,100 ng/kg. In one embodiment, the dose amount is about 5,000 ng/kg. In one embodiment, the dose amount is 5,000 ng/kg. In one embodiment, the dose amount is between about 4,000 ng/kg and about 8,000 ng/kg. In one embodiment, the dose amount is between about 5,000 ng/kg and about 7,000 ng/kg. In one embodiment, the dose amount is between about 5,500 ng/kg and about 6,000 ng/kg. In one embodiment, the dose amount is between about 5,500 ng/kg and about 5,700 ng/kg. In one embodiment, the dose amount is about 5,600 ng/kg. In one embodiment, the dose amount is 5,600 ng/kg. In one embodiment, the dose amount is between about 5,750 ng/kg and about 5,900 ng/kg. In one embodiment, the dose amount is about 5,833 ng/kg. In one embodiment, the dose amount is 5,833 ng/kg.

In one embodiment, the dose amount is between about 5,600 ng/kg and about 5,900 ng/kg. In one embodiment, the dose amount is between about 5,600 ng/kg and about 5,800 ng/kg. In one embodiment, the dose amount is between about 5,650 ng/kg and about 5,750 ng/kg. In one embodiment, the dose amount is between about 5,675 ng/kg and about 5,725 ng/kg. In one embodiment, the dose amount is between about 5,690 ng/kg and about 5,710 ng/kg. In one embodiment, the dose amount is about 5,700 ng/kg. In one embodiment, the dose amount is 5,700 ng/kg. In one embodiment, the dose amount is between about 6,000 ng/kg and about 11,000 ng/kg. In one embodiment, the dose amount is between about 6,500 ng/kg and about 10,500 ng/kg. In one embodiment, the dose amount is between about 7,000 ng/kg and about 10,000 ng/kg. In one embodiment, the dose amount is between about 7,500 ng/kg and about 9,500 ng/kg. In one embodiment, the dose amount is between about 8,000 ng/kg and about 9,000 ng/kg. In one embodiment, the dose amount is between about 8,100 ng/kg and about 8,900 ng/kg. In one embodiment, the dose amount is between about 8,200 ng/kg and about 8,800 ng/kg. In one embodiment, the dose amount is between about 8,300 ng/kg and about 8,700 ng/kg. In one embodiment, the dose amount is between about 8,350 ng/kg and about 8,650 ng/kg. In one embodiment, the dose amount is between about 8,400 ng/kg and about 8,600 ng/kg. In one embodiment, the dose amount is between about 8,425 ng/kg and about 8,575 ng/kg. In one embodiment, the dose amount is between about 8,450 ng/kg and about 8,550 ng/kg. In one embodiment, the dose amount is between about 8,475 ng/kg and about 8,525 ng/kg. In one embodiment, the dose amount is between about 8,490 ng/kg and about 8,510 ng/kg. In one embodiment, the dose amount is about 8,500 ng/kg. In one embodiment, the dose amount is 8,500 ng/kg. In one embodiment, the dose amount is between about 5,500 ng/kg and about 6,500 ng/kg. In one embodiment, the dose amount is between about 5,900 ng/kg and about 6,100 ng/kg. In one embodiment, the dose amount is about 6,000 ng/kg. In one embodiment, the dose amount is 6,000 ng/kg. In one embodiment, the dose amount is between about 5,000 ng/kg and about 9,000 ng/kg. In one embodiment, the dose amount is between about 6,000 ng/kg and about 8,000 ng/kg. In one embodiment, the dose amount is between about 6,500 ng/kg and about 7,500 ng/kg. In one embodiment, the dose amount is about 7,000 ng/kg. In one embodiment, the dose amount is 7,000 ng/kg.

[0121] PARAGRAPH H includes any one of the following dose amounts: In one embodiment, the dose amount is between about 7,000 ng/kg and about 17,000 ng/kg. In one embodiment, the dose amount is between about 8,000 ng/kg and about 16,000 ng/kg. In one embodiment, the dose amount is between about 8,000 ng/kg and about 14,000 ng/kg. In one embodiment, the dose amount is between about 8,000 ng/kg and about 12,000 ng/kg. In one embodiment, the dose amount is between about 9,000 ng/kg and about 11,000 ng/kg. In one embodiment, the dose amount is between about 9,500 ng/kg and about 10,500 ng/kg. In one embodiment, the dose amount is about 10,000 ng/kg. In one embodiment, the dose amount is 10,000 ng/kg. In one embodiment, the dose amount is between about 8,000 ng/kg and about 9,500 ng/kg. In one embodiment, the dose amount is between about 8,250 ng/kg and about 9,250 ng/kg. In one embodiment, the dose amount is between about 8,500 ng/kg and about 9,000 ng/kg. In one embodiment, the dose amount is about 8,750 ng/kg. In one embodiment, the dose amount is 8,750 ng/kg. In one embodiment, the dose amount is between about 9,000 ng/kg and about 15,000 ng/kg. In one embodiment, the dose amount is between about 10,000 ng/kg and about 14,000 ng/kg. In one embodiment, the dose amount is between about 11,250 ng/kg and about 12,500 ng/kg. In one embodiment, the dose amount is between about 11,250 ng/kg and about 12,000 ng/kg. In one embodiment, the dose amount is between about 11,500 ng/kg and about 11,750 ng/kg. In one embodiment, the dose amount is about 11,667 ng/kg.

In one embodiment, the dose amount is 11,667 ng/kg. In one embodiment, the dose amount is about 11,700 ng/kg. In one embodiment, the dose amount is 11,700 ng/kg. In one embodiment, the dose amount is between about 11,000 ng/kg and about 13,000 ng/kg. In one embodiment, the dose amount is about 12,000 ng/kg. In one embodiment, the dose amount is 12,000 ng/kg. In one embodiment, the dose amount is between about 10,500 ng/kg and about 13,500 ng/kg. In one embodiment, the dose amount is between about 11,000 ng/kg and about 13,000 ng/kg. In one embodiment, the dose amount is between about 12,500 ng/kg and about 13,000 ng/kg. In one embodiment, the dose amount is between about 12,600 ng/kg and about

12,950 ng/kg. In one embodiment, the dose amount is between about 12,650 ng/kg and about

12,950 ng/kg. In one embodiment, the dose amount is between about 12,700 ng/kg and about

12,950 ng/kg. In one embodiment, the dose amount is between about 12,700 ng/kg and about 12,900 ng/kg. In one embodiment, the dose amount is between about 12,750 ng/kg and about 12,850 ng/kg. In one embodiment, the dose amount is between about 12,775 ng/kg and about 12,825 ng/kg. In one embodiment, the dose amount is between about 12,790 ng/kg and about 12,810 ng/kg. In one embodiment, the dose amount is about 12,800 ng/kg. In one embodiment, the dose amount is 12,800 ng/kg.

[0122] PARAGRAPH I includes any one of the following dose amounts: In one embodiment, the dose amount is between about 12,000 ng/kg and about 28,000 ng/kg. In one embodiment, the dose amount is between about 14,000 ng/kg and about 26,000 ng/kg. In one embodiment, the dose amount is between about 16,000 ng/kg and about 24,000 ng/kg. In one embodiment, the dose amount is between about 16,000 ng/kg and about 20,000 ng/kg. In one embodiment, the dose amount is between about 17,000 ng/kg and about 19,000 ng/kg. In one embodiment, the dose amount is between about 17,000 ng/kg and about 18,000 ng/kg. In one embodiment, the dose amount is between about 17,250 ng/kg and about 17,750 ng/kg. In one embodiment, the dose amount is about 17,750 ng/kg. In one embodiment, the dose amount is 17,750 ng/kg. In one embodiment, the dose amount is between about 18,000 ng/kg and about 22,000 ng/kg. In one embodiment, the dose amount is between about 19,000 ng/kg and about 21,000 ng/kg. In one embodiment, the dose amount is about 20,000 ng/kg. In one embodiment, the dose amount is 20,000 ng/kg. In one embodiment, the dose amount is between about 18,000 ng/kg and about 20,000 ng/kg. In one embodiment, the dose amount is between about 18,500 ng/kg and about 20,000 ng/kg. In one embodiment, the dose amount is between about 18,750 ng/kg and about 19,750 ng/kg. In one embodiment, the dose amount is between about 19,000 ng/kg and about 19,500 ng/kg. In one embodiment, the dose amount is between about 19,100 ng/kg and about 19,400 ng/kg. In one embodiment, the dose amount is between about 19,100 ng/kg and about 19,300 ng/kg. In one embodiment, the dose amount is between about 19,150 ng/kg and about 19,250 ng/kg. In one embodiment, the dose amount is between about 19,175 ng/kg and about 19,225 ng/kg. In one embodiment, the dose amount is between about 19,190 ng/kg and about 19,210 ng/kg. In one embodiment, the dose amount is about 19,200 ng/kg. In one embodiment, the dose amount is 19,200 ng/kg.

[0123] PARAGRAPH J includes any one of the following dose amounts: In one embodiment, the dose amount is between about 20,000 ng/kg and about 50,000 ng/kg. In one embodiment, the dose amount is between about 25,000 ng/kg and about 45,000 ng/kg. In one embodiment, the dose amount is between about 28,000 ng/kg and about 30,000 ng/kg. In one embodiment, the dose amount is between about 28,500 ng/kg and about 29,500 ng/kg. In one embodiment, the dose amount is about 28,800 ng/kg. In one embodiment, the dose amount is 28,800 ng/kg. In one embodiment, the dose amount is between about 30,000 ng/kg and about 40,000 ng/kg. In one embodiment, the dose amount is between about 31,000 ng/kg and about 38,000 ng/kg. In one embodiment, the dose amount is between about 34,000 ng/kg and about 36,000 ng/kg. In one embodiment, the dose amount is about 35,000 ng/kg. In one embodiment, the dose amount is 35,000 ng/kg.

V a) ii). Administration Time

[0124] In one embodiment, the dose to the human subject is administered between about 5 minutes and about 10 hours. In one embodiment, the dose to the human subject is administered between about 5 minutes and about 5 hours. In one embodiment, the dose to the human subject is administered between about 5 minutes and about 60 minutes. In one embodiment, the dose to the human subject is administered between about 5 minutes and about 30 minutes. In one embodiment, the dose to the human subject is administered between about 30 minutes and about 60 minutes. In one embodiment, the dose to the human subject is administered between about 60 minutes and about 90 minutes. In one embodiment, the dose to the human subject is administered between about 90 minutes and about 2 hours.

In one embodiment, the dose to the human subject is administered between about one hour and about three hours. In one embodiment, the dose to the human subject is administered between about two hours and about four hours. In one embodiment, the dose to the human subject is administered between about three hours and about five hours. In one embodiment, the dose to the human subject is administered between about four hours and about six hours. In one embodiment, the dose to the human subject is administered between about five hours and about seven hours. In one embodiment, the dose to the human subject is administered between about six hours and about eight hours. In one embodiment, the dose to the human subject is administered between about seven hours and about nine hours. In one embodiment, the dose to the human subject is administered between about eight hours and about ten hours. In one embodiment, the dose to the human subject is administered over about one hour or about three hours or about four hours or about five hours or about six hours or about seven hours or about eight hours or about nine hours or about ten hours. In one embodiment, the dose to the human subject is administered between about 90 minutes and about 150 minutes. In one embodiment, the dose to the human subject is administered between about 105 minutes and about 135 minutes. In one embodiment, the dose to the human subject is administered over about two hours. In one embodiment, the dose to the human subject is administered over two hours.

V b). Dosage regimen

[0125] In one embodiment, each dosage regimen comprises at least one dose of the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) provided to the human subject (per week or per month/over a set period of day(s) or week(s)). Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). The efficient dosages and the dosage regimens for the bispecific anti-CD 123 x anti-CD3 antibodies used in the present invention depend on the disease or condition to be treated.

Daily Dosage Re si men

[0126] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once a day, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Every other day Dosase Resimen

[0127] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once every other day, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof.

The administration time can be any described throughout the specification.

Six Times a Week Dosage Regimen

[0128] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided six times a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Five Times a Week Dosage Regimen

[0129] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided five times a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Four Times a Week Dosage Regimen

[0130] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided four times a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Three Times a Week Dosage Resimen

[0131] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided three times a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Two Times a Week Dosage Regimen

[0132] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided two times a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Once a Week Dosage Regimen

[0133] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once a week, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

[0134] In an exemplary embodiment, the dose is administered once between about 5 and about 10 days. In an exemplary embodiment, the dose is administered once every 5-10 days. In an exemplary embodiment, the dose is administered once between about 5 and about 9 days. In an exemplary embodiment, the dose is administered once every 5-9 days. In an exemplary embodiment, the dose is administered once between about 6 and about 8 days. In an exemplary embodiment, the dose is administered once every 6-8 days. In an exemplary embodiment, the dose is administered once between about 6 and about 10 days. In an exemplary embodiment, the dose is administered once every 6-10 days. In an exemplary embodiment, the dose is administered once between about 7 and about 9 days. In an exemplary embodiment, the dose is administered once every 7-9 days. In an exemplary embodiment, the intravenous dose of XmAb 14045 is administered once about every 7 days.

In an exemplary embodiment, the dose is administered once every 7 days. In an exemplary embodiment, the dose is administered about once a week. In an exemplary embodiment, the intravenous dose of XmAbl4045 is administered once a week.

Every Two Weeks Dosage Regimen

[0135] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once every two weeks, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof.

The administration time can be any described throughout the specification.

Every Three Weeks Dosage Regimen

[0136] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once every three weeks, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Every Four Weeks Dosage Regimen

[0137] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once every four weeks, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof.

The administration time can be any described throughout the specification.

Two times a Month Dosage Regimen

[0138] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided two times a month, in a dose amount selected from the from the group consisting of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Three times a Month Dosage Resimen

[0139] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided three times a month, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

Monthly Dosage Regimen

[0140] In one embodiment, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) dose is provided once a month, in a dose amount disclosed in any one of Paragraph A or Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J, or any combination thereof. The administration time can be any described throughout the specification.

[0141] In an exemplary embodiment, the dose is administered once between about 12 and about 17 days. In an exemplary embodiment, the dose is administered once between about 13 and about 15 days. In an exemplary embodiment, the dose is administered once every 13- 15 days. In an exemplary embodiment, the dose is administered once between about 12 and about 16 days. In an exemplary embodiment, the dose is administered once every 12-16 days. In an exemplary embodiment, the dose is administered once every 14-16 days. In an exemplary embodiment, the dose is administered once about every 14 days. In an exemplary embodiment, the dose is administered once every 14 days. In an exemplary embodiment, the dose is administered once about every two weeks. In an exemplary embodiment, the dose is administered once every two weeks. In an exemplary embodiment, the dose is administered once between about 13 and about 17 days. In an exemplary embodiment, the dose is administered once every 13-17 days. In an exemplary embodiment, the dose is administered once about every 15 days. In an exemplary embodiment, the dose is administered once every 15 days.

V c). Phase

[0142] In one embodiment, a phase comprises a certain number of occurrences of a dosage regimen. In one embodiment, a dosage regimen occurs one time in a phase. In one embodiment, a dosage regimen occurs two times in a phase. In one embodiment, a dosage regimen occurs three times in a phase. In one embodiment, a dosage regimen occurs four times in a phase. In one embodiment, a dosage regimen occurs five times in a phase. In one embodiment, a dosage regimen occurs six times in a phase. In one embodiment, a dosage regimen occurs seven times in a phase. In one embodiment, a dosage regimen occurs eight times in a phase. In one embodiment, a dosage regimen occurs nine times in a phase. In one embodiment, a dosage regimen occurs ten times in a phase. In one embodiment, a dosage regimen occurs eleven times in a phase. In one embodiment, a dosage regimen occurs twelve times in a phase. In one embodiment, a dosage regimen occurs thirteen times in a phase. In one embodiment, a dosage regimen occurs fourteen times in a phase. In one embodiment, a dosage regimen occurs fifteen times in a phase. In one embodiment, a dosage regimen occurs sixteen times in a phase. In one embodiment, a dosage regimen occurs seventeen times in a phase. In one embodiment, a dosage regimen occurs eighteen times in a phase. In one embodiment, a dosage regimen occurs nineteen times in a phase. In one embodiment, a dosage regimen occurs twenty times in a phase. In one embodiment, a dosage regimen continues until the cancer (e.g., hematological cancer) is in remission (e.g., complete or partial). [0143] In one embodiment, the phase is a once a week dosage regimen described herein, with a duration of one week. In one embodiment, the phase is a once a week dosage regimen described herein, with a duration of two weeks. In one embodiment, the phase is a once a week dosage regimen described herein, with a duration of three weeks. In one embodiment, the phase is a once a week dosage regimen described herein, with a duration of four weeks.

[0144] In one embodiment, the phase is a two times a week dosage regimen described herein, with a duration of one week. In one embodiment, the phase is a two times a week dosage regimen described herein, with a duration of two weeks. In one embodiment, the phase is a two times a week dosage regimen described herein, with a duration of three weeks. In one embodiment, the phase is a two times a week dosage regimen described herein, with a duration of four weeks.

[0145] In one embodiment, the phase is a three times a week dosage regimen described herein, with a duration of one week. In one embodiment, the phase is a three times a week dosage regimen described herein, with a duration of two weeks. In one embodiment, the phase is a three times a week dosage regimen described herein, with a duration of three weeks. In one embodiment, the phase is a three times a week dosage regimen described herein, with a duration of four weeks.

[0146] In one embodiment, the phase is a four times a week dosage regimen described herein, with a duration of one week. In one embodiment, the phase is a four times a week dosage regimen described herein, with a duration of two weeks. In one embodiment, the phase is a four times a week dosage regimen described herein, with a duration of three weeks. In one embodiment, the phase is a four times a week dosage regimen described herein, with a duration of four weeks.

[0147] In one embodiment, the phase is a five times a week dosage regimen described herein, with a duration of one week. In one embodiment, the phase is a five times a week dosage regimen described herein, with a duration of two weeks. In one embodiment, the phase is a five times a week dosage regimen described herein, with a duration of three weeks. In one embodiment, the phase is a five times a week dosage regimen described herein, with a duration of four weeks. V d). Maintenance

[0148] In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) treats a refractory leukemia or lymphoma. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) is amaintenance therapy. In one embodiment, for any method described herein, when the CD 123 -expressing cancer is in remission, such as partial remission and/or complete remission, the method further includes providing the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) according to a dosage regimen described herein, at a maintenance dose, which is the same dose amount for remission, such as partial remission and/or complete remission, or within about 10% of the dose amount (plus or minus), or within about 20% of the dose amount (plus or minus), of within about 30% of the dose amount (plus or minus), for at least one dose, and until non- efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. In one embodiment, for any method described herein, when the CD 123- expressing cancer is in remission, such as partial remission and/or complete remission, the method further includes providing the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) according to a once a week dosage regimen described herein or a once every three weeks dosage regimen described herein or a once every four weeks dosage regimen described herein or a two times a month dosage regimen described herein or a three times a month dosage regimen described herein or a monthly dosage regimen described herein, at a maintenance dose, which is the same dose amount for remission, such as partial remission and/or complete remission, or within about 10% of the dose amount (plus or minus), or within about 20% of the dose amount (plus or minus), of within about 30% of the dose amount (plus or minus), for at least one dose, and until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. In one embodiment, for any method described herein, when the CD 123-expressing cancer is in remission, such as partial remission and/or complete remission, the method further includes providing the bispecific anti-CD 123 x anti-CD3 antibody (e.g, XmAb 14045) according to a once every two weeks dosage regimen described herein , at a maintenance dose, which is the same dose amount for remission, such as partial remission and/or complete remission, or within about 10% of the dose amount (plus or minus), or within about 20% of the dose amount (plus or minus), of within about 30% of the dose amount (plus or minus), for at least one dose, and until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject.

VI. Embodiments Four phases

[0149] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase. In the first phase, the antibody can be provided according to a first dosage regimen, with a first dose amount. In the second phase, the antibody can be provided according to a second dosage regimen, with a second dose amount. In the third phase, the antibody can be provided according to a third dosage regimen, with a third dose amount. In the fourth phase, the antibody can be provided according to a fourth dosage regimen, with a fourth dose amount. The administration times can independently be any described throughout the specification. In some embodiments, the fourth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Four phases, no dosage regimen

[0150] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase. In the first phase, the antibody can be provided according to a daily or an every other day or a six times a week or a five times a week or a four times a week or a three times a week or a two times a week dosage regimen described herein, for up to four weeks (e.g. , one, two, three, or four weeks), wherein the dose amount(s) is/are described within Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F. In the second phase, the antibody can be provided according to a second dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a second dose amount described within Paragraph E or Paragraph F or Paragraph G. In the third phase, the antibody can be provided according to a third dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a third dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fourth phase, the antibody can be provided according to a fourth dosage regimen described herein, in a fourth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In one embodiment, the fourth phase continues until the cancer (e.g., a CD 123- expressing cancer) is in remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Two Phases, w/the first phase being dosed three times a week [0151] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week in three different dose amounts, and where during the second phase the antibody is provided once a week in a second dose amount. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0152] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 400 ng/kg and about 500 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 430 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and the dose amount in the second phase is greater than any dose amount in the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0153] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is found in Paragraph B, such as between about 400 ng/kg and about 450 ng/kg, such as about 430 ng/kg, and the second dose amount in the first phase is between about 100% and about 180%, such as between about 140% and about 180%, such as between about 170% and about 180%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0154] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0155] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 1,500 ng/kg and about 1,900 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0156] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is about 750 ng/kg, and the third dose amount in the first phase is about 1,100 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of about 1,700 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

De-escalation Cohort:

[0157] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 400 ng/kg and about 500 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph D, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 430 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph D, and the dose amount in the second phase is greater than any dose amount in the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0158] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is found in Paragraph B, such as between about 400 ng/kg and about 450 ng/kg, such as about 430 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, and where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0159] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose amount in the first phase is between about 624 ng/kg and about 732 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0160] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose amount in the first phase is between about 624 ng/kg and about 732 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 900 ng/kg and about 1,238 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0161] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week, where the first dose amount in the first phase is about 430 ng/kg, and the second dose amount in the first phase is about 542 ng/kg, and the third dose amount in the first phase is about 678 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of about 848 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Four Phases, w/the first phase being dosed three times a week [0162] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In one embodiment, the fourth phase continues until the cancer (e.g., a CD 123 -expressing cancer) is in remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0163] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In one embodiment, the fourth phase continues until the cancer (e.g., a CD 123 -expressing cancer) is in remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0164] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount.

The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In one embodiment, the fourth phase continues until the cancer (e.g., a CD 123 -expressing cancer) is in remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0165] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In one embodiment, the fourth phase continues until the cancer (e.g., a CD 123 -expressing cancer) is in remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0166] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0167] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 2,400 ng/kg and about 2,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0168] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 2,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 3,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of about 5,700 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0169] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0170] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0171] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0172] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,400 ng/kg and about 1,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0173] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 1,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of about 2,300 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission.

In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. Five phases

[0174] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase. In the first phase, the antibody can be provided according to a first dosage regimen, with a first dose amount. In the second phase, the antibody can be provided according to a second dosage regimen, with a second dose amount. In the third phase, the antibody can be provided according to a third dosage regimen, with a third dose amount. In the fourth phase, the antibody can be provided according to a fourth dosage regimen, with a fourth dose amount. In the fifth phase, the antibody can be provided according to a fifth dosage regimen, with a fifth dose amount. The administration times can independently be any described throughout the specification. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Five phases, no dosage regimen

[0175] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase. In the first phase, the antibody can be provided according to a daily or an every other day or a six times a week or a five times a week or a four times a week or a three times a week or a two times a week dosage regimen described herein, for up to four weeks (e.g. , one, two, three, or four weeks), wherein the dose amount(s) is/are described within Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F. In the second phase, the antibody can be provided according to a second dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a second dose amount described within Paragraph E or Paragraph F or Paragraph G. In the third phase, the antibody can be provided according to a third dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a third dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fourth phase, the antibody can be provided according to a fourth dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a fourth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fifth phase, the antibody can be provided according to a fifth dosage regimen described herein, in a fifth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Five Phases, w/the first phase being dosed three times a week [0176] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0177] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0178] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph G or Paragraph H, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount as described in Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount as described in Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount as described in Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount as described in Paragraph G or Paragraph H, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0179] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0180] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 130% and about 160% of the second dose amount and where during the fourth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0181] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 2,400 ng/kg and about 2,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0182] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 2,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 3,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 5,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of about 8,500 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0183] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0184] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0185] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0186] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,400 ng/kg and about 1,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0187] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 1,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,300 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of about 2,900 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Six phases

[0188] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase. In the first phase, the antibody can be provided according to a first dosage regimen, with a first dose amount. In the second phase, the antibody can be provided according to a second dosage regimen, with a second dose amount. In the third phase, the antibody can be provided according to a third dosage regimen, with a third dose amount. In the fourth phase, the antibody can be provided according to a fourth dosage regimen, with a fourth dose amount.

In the fifth phase, the antibody can be provided according to a fifth dosage regimen, with a fifth dose amount. In the sixth phase, the antibody can be provided according to a sixth dosage regimen, with a sixth dose amount. The administration times can independently be any described throughout the specification. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Six phases, no dosage regimen

[0189] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase. In the first phase, the antibody can be provided according to a daily or an every other day or a six times a week or a five times a week or a four times a week or a three times a week or a two times a week dosage regimen described herein, for up to four weeks (e.g., one, two, three, or four weeks), wherein the dose amount(s) is/are described within Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F. In the second phase, the antibody can be provided according to a second dosage regimen described herein for up to four weeks (e.g. , one, two, three, or four weeks), in a second dose amount described within Paragraph E or Paragraph F or Paragraph G. In the third phase, the antibody can be provided according to a third dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a third dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fourth phase, the antibody can be provided according to a fourth dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a fourth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fifth phase, the antibody can be provided according to a fifth dosage regimen described herein, in a fifth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I. In the sixth phase, the antibody can be provided according to a sixth dosage regimen described herein, in a sixth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Six Phases, w/the first phase being dosed three times a week

[0190] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0191] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0192] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph G or Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph G or Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount as described in Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount as described in Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount as described in Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount as described in Paragraph G or Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount as described in Paragraph G or Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0193] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0194] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 130% and about 160% of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0195] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 2,400 ng/kg and about 2,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 12,500 ng/kg and about 13,000 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0196] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 2,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 3,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 5,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 8,500 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of about 12,800 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0197] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0198] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0199] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0200] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,400 ng/kg and about 1,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 3,500 ng/kg and about 3,700 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0201] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,500 ng/kg, and where during the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 1,800 ng/kg, and where during the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,300 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 2,900 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of about 3,600 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Seven phases

[0202] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase. In the first phase, the antibody can be provided according to a first dosage regimen, with a first dose amount. In the second phase, the antibody can be provided according to a second dosage regimen, with a second dose amount. In the third phase, the antibody can be provided according to a third dosage regimen, with a third dose amount. In the fourth phase, the antibody can be provided according to a fourth dosage regimen, with a fourth dose amount. In the fifth phase, the antibody can be provided according to a fifth dosage regimen, with a fifth dose amount. In the sixth phase, the antibody can be provided according to a sixth dosage regimen, with a sixth dose amount. In the seventh phase, the antibody can be provided according to a seventh dosage regimen, with a seventh dose amount. The administration times can independently be any described throughout the specification. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Seven phases, no dosage regimen

[0203] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase. In the first phase, the antibody can be provided according to a daily or an every other day or a six times a week or a five times a week or a four times a week or a three times a week or a two times a week dosage regimen described herein, for up to four weeks (e.g. , one, two, three, or four weeks), wherein the dose amount(s) is/are described within Paragraph B or Paragraph C or Paragraph D or Paragraph E or Paragraph F. In the second phase, the antibody can be provided according to a second dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a second dose amount described within Paragraph E or Paragraph F or Paragraph G. In the third phase, the antibody can be provided according to a third dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a third dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fourth phase, the antibody can be provided according to a fourth dosage regimen described herein for up to four weeks (e.g., one, two, three, or four weeks), in a fourth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H. In the fifth phase, the antibody can be provided according to a fifth dosage regimen described herein, in a fifth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I. In the sixth phase, the antibody can be provided according to a sixth dosage regimen described herein, in a sixth dose amount described within Paragraph E or Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J. In the seventh phase, the antibody can be provided according to a seventh dosage regimen described herein, in a seventh dose amount described within Paragraph F or Paragraph G or Paragraph H or Paragraph I or Paragraph J. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Seven Phases, w/the first phase being dosed three times a week [0204] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0205] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0206] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph G or Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph G or Paragraph H or Paragraph I, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph G or Paragraph H or Paragraph I or Paragraph H, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount as described in Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount as described in Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount as described in Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount as described in Paragraph G or Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount as described in Paragraph G or Paragraph H or Paragraph I, and where during the seventh phase the antibody is provided once a week in a seventh dose amount as described in Paragraph G or Paragraph H or Paragraph I or Paragraph J, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0207] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti- CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 130% and about 160% of the fifth dose amount and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the sixth dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0208] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0209] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 2,400 ng/kg and about 2,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 12,500 ng/kg and about 13,000 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 19,000 ng/kg and about 19,500 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0210] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1, 100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, where during the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 2,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 3,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 5,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 8,500 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of about 12,800 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of about 19,200 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0211] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph F or Paragraph G, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided three times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph F or Paragraph G, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0212] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti- CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, and where during the seventh phase the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0213] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0214] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,400 ng/kg and about 1,600 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 3,500 ng/kg and about 3,700 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 4,400 ng/kg and about 4,600 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0215] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject three times a week for one week in a first, second, and third dose amounts, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,500 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 1,800 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,300 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 2,900 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of about 3,600 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of about 4,500 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. Two Phases, w/the first phase being dosed four times a week

[0216] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week in four different dose amounts, and where during the second phase the antibody is provided once a week in a second dose amount. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0217] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 400 ng/kg and about 500 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 433 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and the dose amount in the second phase is greater than any dose amount in the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0218] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph B, such as between about 400 ng/kg and about 450 ng/kg, such as about 433 ng/kg, and the second dose amount in the first phase is between about 100% and about 180%, such as between about 140% and about 180%, such as between about 170% and about 180%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 160%, such as between about 140% and about 160%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0219] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the fourth dose amount in the first phase is between about 1,500 ng/kg and about 1,900 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0220] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the fourth dose amount in the first phase is between about 1,500 ng/kg and about 1,900 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 2,000 ng/kg and about 3,000 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0221] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is about 750 ng/kg, and the third dose amount in the first phase is about 1, 100 ng/kg, and the fourth dose amount in the first phase is about 1,700 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of about 2,500 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

De-escalation Cohort:

[0222] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 400 ng/kg and about 500 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and the dose amount in the second phase is greater than any dose amount in the first phase. The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 433 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and the dose amount in the second phase is greater than any dose amount in the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0223] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph B, such as between about 400 ng/kg and about 450 ng/kg, such as about 433 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount in the first phase, and where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase. In some embodiments, the second phase has a duration of between one and four weeks. In some embodiments, the second phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0224] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose amount in the first phase is between about 624 ng/kg and about 732 ng/kg, and the fourth dose amount in the first phase is between about 750 ng/kg and about 952 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0225] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose amount in the first phase is between about 624 ng/kg and about 732 ng/kg, and the fourth dose amount in the first phase is between about 750 ng/kg and about 952 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of between about 900 ng/kg and about 1,238 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0226] The method of treatment disclosed herein can comprise a first phase and a second phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 433 ng/kg, and the second dose amount in the first phase is about 542 ng/kg, and the third dose amount in the first phase is about 678 ng/kg, and the fourth dose amount in the first phase is about 848 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week in a second dose amount of about 1,060 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Four Phases, w/the first phase being dosed four times a week

[0227] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0228] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0229] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E or Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph F, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0230] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, and fourth dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount in the first phase, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0231] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0232] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 8,400 ng/kg and about 8,600 ng/kg until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0233] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, and the fourth dose amount in the first phase is about 2,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 3,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 5,700 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of about 8,500 ng/kg until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0234] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E or Paragraph F, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E or Paragraph F, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0235] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount in the first phase, and where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount. In some embodiments, the fourth phase has a duration of between one and four weeks. In some embodiments, the fourth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0236] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0237] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0238] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase, where during the first phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, and the fourth dose amount in the first phase is about 1,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 2,300 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fourth dose amount of about 2,900 ng/kg until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Five Phases, w/the first phase being dosed four times a week

[0239] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0240] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0241] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent two dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph G or Paragraph H, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount as described in Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount as described in Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount as described in Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount as described in Paragraph G or Paragraph H, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0242] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti- CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0243] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0244] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the third dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 12,500 ng/kg and about 13,000 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0245] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1, 100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, and the fourth dose amount in the first phase is about 2,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 3,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 5,700 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 8,500 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of about 12,800 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0246] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0247] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, and fourth dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount. In some embodiments, the fifth phase has a duration of one or two weeks. In some embodiments, the fifth phase has a duration of between one and four weeks. In some embodiments, the fifth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0248] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0249] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, where during the second phase, the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of between about 3,500 ng/kg and about 3,700 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0250] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, where during the second phase, the fourth dose amount in the first phase is about 1,500 ng/kg, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 2,300 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a fifth dose amount of about 3,600 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. Six Phases, w/the first phase being dosed four times a week

[0251] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0252] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0253] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0254] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0255] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0256] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 12,500 ng/kg and about 13,000 ng/kg, and where during the sixth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 19,000 ng/kg and about 19,500 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0257] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, and the fourth dose amount in the first phase is about 2,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti- CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 3,800 ng/kg, and where during the third phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 5,700 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 8,500 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 12,800 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, until remission (e.g., complete or partial), or for as long as the cancer is in remission.

In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0258] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0259] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount. In some embodiments, the sixth phase has a duration of one or two weeks. In some embodiments, the sixth phase has a duration of between one and four weeks. In some embodiments, the sixth phase continues until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0260] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 120% and about 130% of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0261] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 3,500 ng/kg and about 3,700 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of between about 4,400 ng/kg and about 4,600 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0262] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, and the fourth dose amount in the first phase is about 1,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti- CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,800 ng/kg, and where during the third phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 2,300 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 3,600 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a sixth dose amount of about 4,500 ng/kg until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

Seven Phases, w/the first phase being dosed four times a week [0263] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week in a first dose amount, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0264] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph B, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0265] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is described in Paragraph C, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount, and where during the third phase the antibody is provided once a week in a third dose amount, and where during the fourth phase the antibody is provided once a week in a fourth dose amount, and where during the fifth phase the antibody is provided once a week in a fifth dose amount, and where during the sixth phase the antibody is provided once a week in a sixth dose amount, and where during the seventh phase the antibody is provided once a week in a seventh dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph I or Paragraph J, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph F, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph G, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph G, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph H, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph H or Paragraph I, and where during the seventh phase the antibody is provided once a week in a seventh dose amount as described in Paragraph I or Paragraph J, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0266] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount in the first phase, and the fourth dose amount in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount in the first phase, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0267] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fourth dose amount, and where during the sixth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the fifth dose amount, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 160%, such as between about 130% and about 160%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0268] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose amount in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose amount in the first phase is between about 2,400 ng/kg and about 2,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 3,600 ng/kg and about 3,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 5,600 ng/kg and about 5,900 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 8,300 ng/kg and about 8,700 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 12,500 ng/kg and about 13,000 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 19,000 ng/kg and about 19,500 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 28,000 ng/kg and about 30,000 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification. [0269] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 1,100 ng/kg, and the third dose amount in the first phase is about 1,700 ng/kg, and the fourth dose amount in the first phase is about 2,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 3,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 5,700 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 8,500 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 12,800 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of about 19,200 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of about 28,800 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0270] The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is between about 600 ng/kg and about 900 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph F or Paragraph G, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. The method of treatment disclosed herein can comprise a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase the antibody is provided four times a week for a duration of one week, where the first dose amount in the first phase is about 750 ng/kg, and the subsequent three dose amounts are greater than the first dose amount and are each independently selected from Paragraph D or Paragraph E, and where during the second phase the antibody is provided once a week in a second dose amount which is selected from Paragraph E, and where during the third phase the antibody is provided once a week in a third dose amount which is selected from Paragraph E, and where during the fourth phase the antibody is provided once a week in a fourth dose amount which is selected from Paragraph E, and where during the fifth phase the antibody is provided once a week in a fifth dose amount which is selected from Paragraph F, and where during the sixth phase the antibody is provided once a week in a sixth dose amount which is selected from Paragraph F, and where during the seventh phase the antibody is provided once a week in a seventh dose amount which is selected from Paragraph F or Paragraph G, and the seventh dose amount is greater than the sixth dose amount, and the sixth dose amount is greater than the fifth dose amount, and the fifth dose amount is greater than the fourth dose amount, and the fourth dose amount is greater than the third dose amount, and the third dose amount is greater than the second dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0271] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is found in Paragraph C, such as between about 600 ng/kg and about 900 ng/kg, such as about 750 ng/kg, and the second dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the first dose amount in the first phase, and the third dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount in the first phase, where during the second phase, and the fourth dose amount in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount in the first phase, where during the second phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, and where during the seventh phase the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the sixth dose amount. In some embodiments, the seventh phase has a duration of between one and four weeks. In some embodiments, the seventh phase continues until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123- expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAbl4045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0272] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount of the first phase, where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the second dose amount and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the third dose amount, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fourth dose amount, and where during the sixth phase, the bispecific anti- CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the fifth dose amount, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 100% and about 130%, such as between about 120% and about 130%, of the sixth dose amount, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0273] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is between about 800 ng/kg and about 1,000 ng/kg, and the third dose amount in the first phase is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose amount in the first phase is between about 1,400 ng/kg and about 1,600 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of between about 1,700 ng/kg and about 1,900 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of between about 2,200 ng/kg and about 2,400 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of between about 2,800 ng/kg and about 3,000 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of between about 3,500 ng/kg and about 3,700 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of between about 4,400 ng/kg and about 4,600 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of between about 5,500 ng/kg and about 5,700 ng/kg, until remission (e.g. , complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123 -expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0274] In one embodiment, the method of treatment comprises a first phase and a second phase and a third phase and a fourth phase and a fifth phase and a sixth phase and a seventh phase, where during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject four times a week for one week, where the first dose amount in the first phase is about 750 ng/kg, and the second dose amount in the first phase is about 900 ng/kg, and the third dose amount in the first phase is about 1,200 ng/kg, and the fourth dose amount in the first phase is about 1,500 ng/kg, where during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week in a second dose amount of about 1,800 ng/kg, and where during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a third dose amount of about 2,300 ng/kg, and where during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fourth dose amount of about 2,900 ng/kg, and where during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a fifth dose amount of about 3,600 ng/kg, and where during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week for one week, in a sixth dose amount of about 4,500 ng/kg, and where during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered to the human subject once a week, in a seventh dose amount of about 5,600 ng/kg, until remission (e.g., complete or partial), or for as long as the cancer is in remission. In one embodiment, once the CD 123-expressing cancer is in remission, the method further comprises providing the antibody (e.g., XmAb 14045) as a maintenance therapy, according to a weekly dosage regimen described herein or an every two weeks dosage regimen described herein, at a maintenance dose, which is about the same dose amount for remission, or within about 10% or about 20% or about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated by the human subject. The administration times can independently be any described throughout the specification.

[0275] In some embodiments, the antibody comprises a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) that is administered intravenously. In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody is administered via continuous infusion. In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody is administered intravenously, continuous infusion, or both. Should there be more than two treatments, any combination of intravenous administration or continuous infusion can be used. In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) is administered until non- efficacy is determined, an unacceptable level of toxicity is observed, or is voluntary terminated by the human subject.

[0276] In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.

[0277] In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody (e.g.,

XmAb 14045) treats a refractory leukemia. In some embodiments, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) is a maintenance therapy. In one embodiment, for any method described herein, when the CD 123-expressing cancer is in remission, such as partial remission and/or complete remission, the method further includes providing the bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) according to an every other week dosage regimen described herein, at the same dose amount for remission, such as partial remission and/or complete remission, until non-efficacy is determined, an unacceptable level of toxicity is observed, or is voluntary terminated by the human subject. In one embodiment, for any method described herein, when the CD 123 -expressing cancer is in remission, such as partial remission and/or complete remission, the method further includes providing the bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) according to a once a week dosage regimen described herein or a once every three weeks dosage regimen described herein or a once every four weeks dosage regimen described herein or a two times a month dosage regimen described herein or a three times a month dosage regimen described herein or a monthly dosage regimen described herein, at the same dose amount for remission, such as partial remission and/or complete remission, or within about 10% of the dose amount (plus or minus), or within about 20% of the dose amount (plus or minus), of within about 30% of the dose amount (plus or minus), until non-efficacy is determined, an unacceptable level of toxicity is observed, or is voluntary terminated by the human subject.

[0278] A medical professional can readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

VII. Treatment Informed By Blast Cell Percentage

[0279] In another aspect, the invention provides a method of treating certain populations of human subjects with a CD 123-expressing cancer. In an exemplary embodiment, prior to the first phase administration of any CD 123 expressing cancer treatment protocol described herein, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 35% or lower, or about 30% or lower, or about 25% or lower, or about 20% or lower, or about 15% or lower, or about 10% or lower, or about 5% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described herein, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD 123-expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123 -expressing cancer treatment protocol described in the “Two Phases, w/the first phase being dosed three times a week” section, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD 123-expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described in the “Four Phases, w/the first phase being dosed three times a week” section, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123 -expressing cancer treatment protocol described in the “Two Phases, w/the first phase being dosed four times a week” section, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD123- expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described in the “Four Phases, w/the first phase being dosed four times a week” section, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 25% or lower.

[0280] In an exemplary embodiment, the invention provides a method of improving therapeutic efficacy for treatment of a CD 123 -expressing cancer, comprising: determining the percentage of blast cells in the bone marrow of a human subject (such as one having a CD 123 -expressing cancer); wherein a percentage 25% or lower indicates the efficacy of a bispecific anti-CD 123 x anti-CD3 antibody.

[0281] In an exemplary embodiment, the invention provides a method of determining susceptibility to treatment of a CD 123-expressing cancer, comprising: determining the percentage of blast cells in the bone marrow of a human subject (such as one having a CD 123 -expressing cancer); wherein a percentage 25% or lower indicates efficacy of a bispecific anti-CD 123 x anti-CD3 antibody. [0282] In an exemplary embodiment, the invention provides a method of selecting one or more human subjects with increased responsiveness to treatment of a CD 123 -expressing cancer, comprising: determining the percentage of blast cells in the bone marrow of a human subject (such as one having a CD 123 -expressing cancer); wherein a percentage 25% or lower corresponds to an increase in responsiveness in a subject.

[0283] The percentage of blast cells in the bone marrow in the human subject can be determined by through standard methods of AML diagnosis, such as bone marrow aspirate or bone marrow biopsy.

VIII. Treatment Informed By CD 8+ PD-1 + Percentage

[0284] In another aspect, the invention provides a method of treating certain populations of human subjects with a CD 123-expressing cancer. In an exemplary embodiment, prior to the first phase administration of any CD 123 expressing cancer treatment protocol described herein, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 35% or lower, or about 30% or lower, or about 25% or lower, or about 20% or lower, or about 15% or lower, or about 10% or lower, or about 5% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described herein, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123 -expressing cancer treatment protocol described in the “Two Phases, w/the first phase being dosed three times a week” section, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD 123-expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described in the “Four Phases, w/the first phase being dosed three times a week” section, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123 -expressing cancer treatment protocol described in the “Two Phases, w/the first phase being dosed four times a week” section, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD123- expressing cancer treatment protocol if the percentage is about 25% or lower. In an exemplary embodiment, prior to the first phase administration of any CD 123-expressing cancer treatment protocol described in the “Four Phases, w/the first phase being dosed four times a week” section, determining the percentage of CD8+ T-cells which are PD-1+ in the human subject, and proceeding with the CD 123 -expressing cancer treatment protocol if the percentage is about 25% or lower.

[0285] In an exemplary embodiment, the invention provides a method of improving therapeutic efficacy for treatment of a CD 123 -expressing cancer, comprising: determining the percentage of CD8+ T cells which are PD-1+ in a human subject (such as one having a CD 123 -expressing cancer); wherein a percentage 25% or lower indicates the efficacy of a bispecific anti-CD 123 x anti-CD3 antibody.

[0286] In an exemplary embodiment, the invention provides a method of determining susceptibility to treatment of a CD 123-expressing cancer, comprising: determining the percentage of CD8+ T cells which are PD-1+ in a human subject (such as one having a CD 123 -expressing cancer); wherein a percentage 25% or lower indicates the efficacy of a bispecific anti-CD 123 x anti-CD3 antibody.

[0287] In an exemplary embodiment, the invention provides a method of selecting one or more human subjects with increased responsiveness to treatment of a CD 123 -expressing cancer, comprising: determining the percentage of CD8+ T cells which are PD-1+ in a human subject (such as one having a CD 123-expressing cancer); wherein a percentage 25% or lower corresponds to an increase in responsiveness in a subject.

[0288] The percentage of CD8+ T-cells which are PD-1+ in the human subject can be determined by standard methods, such as flow cytometric assessment of peripheral blood and bone marrow aspirate.

Combination Therapy

[0289] In certain instances, a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with one or more (such as another) therapeutic agent. Administered “in combination”, as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces one or more symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0290] The bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be administered first, and the additional agent can be administered second, or vice versa.

[0291] The bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and/or one or more additional therapeutic agents, procedures or modalities can be administered during periods of active disorder, or during a period of remission or less active disease. The bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) can be administered before the other treatment, concurrently with the treatment, post-treatment, or during remission of the disorder.

[0292] When administered in combination, the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and the one or more additional agents (e.g., second or third agent) can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually, e.g., as a monotherapy. In some embodiments, the administered amount or dosage of the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and the one or more additional agents (e.g., second or third agent), is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and the one or more additional agents (e.g., second or third agent, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%) than the amount or dosage of each agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect.

[0293] In some embodiments, the antibodies are combined with other therapeutic agents, such as anti -cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, or any combination thereof. In some embodiments, the antibodies are combined with other therapeutic agents, such as anti-allergic agents, anti nausea agents (or anti-emetics), pain relievers, cytoprotective agents, or any combination thereof.

[0294] In some embodiments, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is administered to a human subject in combination with one or more of the following: an anti-TNF or anti-IL6 receptor antibody, a steroid, or an antihistamine (e.g., Benadryl).

[0295] In some embodiments, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is administered to a human subject in combination with an antihistamine. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the antihistamine is a first generation Hi antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine or carbinoxamine or doxylamine or orphenadrine or bromazine or clemastine or dimenhydrinate. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the Hi antagonist is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelennamine, and triprolidine, or any combination thereof. In one embodiment, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is Benadryl®. In one embodiment, the antihistamine is an Hi inverse agonist. In one embodiment, the Hi inverse agonist is acrivastine, cetirizine, levocetirizine, desloratadine, pyrilamine, or any combination thereof. In one embodiment, the antihistamine is an H2 antihistamine. In one embodiment, the H2 antihistamine is an H2 antagonist. In one embodiment, the H2 antihistamine is an H2 inverse agonist. In one embodiment, the H2 antihistamine is cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, and tiotidine, or any combination thereof.

[0296] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein may be administered in combination with at least one therapeutic agent which is an anti-cancer agent and/or a side effect ameliorating agent.

Combination Therapy. Anti-cancer agent

[0297] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein may be administered in combination with at least one therapeutic agent which is an anti-cancer agent. In an embodiment, the anti-cancer agent is a chemotherapeutic, radiation, or antibody (for example antibodies directed against checkpoint inhibitors). In an embodiment, the anti-cancer agent is an immunoablative agent such as alemtuzumab, anti-TIM-3 antibody (e.g., MBG45), other antibody therapies, BCL-2 inhibitors (e.g., venetoclax), cytoxan, fludarabine, rapamycin, mycophenolic acid, steroids, FR90165, cytokines, irradiation, or peptide vaccine, such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971. In an embodiment, the anti-cancer agent is an immunosuppressive agent. In an embodiment, the immunosuppressive agent is cyclosporin, azathioprine, methotrexate, mycophenolate, or FK506.

Combination Therapy anti-cancer agent. Radiation

[0298] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with radiation. Combination Therapy anti-cancer agent. Chemotherapeutics

[0299] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with an anti-cancer agent.

[0300] In an embodiment, the anti-cancer agent is a chemotherapeutic. In an embodiment, the chemotherapeutic is selected from the group consisting of alkylating agent, anti metabolite, kinase inhibitor, proteasome inhibitor, vinca alkaloid, anthracy cline, antitumor antibiotic, aromatase inhibitor, topoisomerase inhibitor, mTOR inhibitor, and retinoid.

Combination Therapy, anti-cancer agent. Alkylating agents

[0301] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an alkylating agent. In an embodiment, the alkylating agent is a nitrogen mustard, nitrosourea, alkyl sulfonate, triazine, aziridine, platinum complex, or non-classical alkylating agent.

[0302] In an embodiment, the alkylating agent is a nitrogen mustard. In an exemplary embodiment, the alkylating agent is a nitrogen mustard, which is mechlorethamine (mechlorethamine HC1), ifosfamide (IFEX), melphalan (Alkeran), chlorambucil, cyclophosphamide, or a derivative thereof. In an embodiment, the alkylating agent is a nitrogen mustard, which is trofosfamide, estramustine, or a derivative thereof.

[0303] In an embodiment, the alkylating agent is a nitrosourea. In an embodiment, the alkylating agent is a nitrosourea, which is N-Nitroso-N-methylurea (MNU), streptozocin, carmustine (BCNU), lomustine (CCNU), bendamustine (such as bendamustine HC1), or a derivative thereof. In an embodiment, the alkylating agent is a nitrosourea, which is semustine, fotemustine, nimustine, ranimustine, or a derivative thereof.

[0304] In an embodiment, the alkylating agent is an alkyl sulfonate. In an embodiment, the alkylating agent is an alkyl sulfonate, which is busulfan, or a derivative thereof. In an embodiment, the alkylating agent is an alkyl sulfonate, which is treosulfan, mannosulfan, or a derivative thereof.

[0305] In an embodiment, the alkylating agent is a triazine. In an embodiment, the alkylating agent is a triazine, which is dacarbazine, mitozolomide, temozolomide (Temodar), or a derivative thereof.

[0306] In an embodiment, the alkylating agent is an aziridine. In an embodiment, the alkylating agent is an aziridine, which is thiotepa, altretamine, or a derivative thereof. In an embodiment, the alkylating agent is an aziridine, which is triaziquone, carboquone, mytomycin, or a derivative thereof.

[0307] In an embodiment, the alkylating agent is a platinum complex. In an embodiment, the alkylating agent is a platinum complex, which is cisplatin, carboplatin, oxaliplatin, or a derivative thereof.

[0308] In an embodiment, the alkylating agent is a non-classical alkylating agent. In an embodiment, the non-classical alkylating agent is procarbazine, hexamethylmelamine, or a derivative thereof. In an embodiment, the alkylating agent is trabectedin, or a derivative thereof.

Combination Therapy, anti-cancer agent. Anti-metabolites

[0309] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an anti- metabolite. In an embodiment, the anti-metabolite is a pyrimidine analog, purine analog, or folate antagonist.

[0310] In an embodiment, the anti-metabolite is a pyrimidine analog. In an embodiment, the anti-metabolite is a pyrimidine analog which is a fluoropyrimidine. In an embodiment, the fluoropyrimidine is 5-fluorouracil, capecitabine, carmofur, floxuridine, doxifluridine, tegafur, or a derivative thereof. In an embodiment, the anti-metabolite is a pyrimidine analog which is cytarabine, gemcitabine, decitabine, azacitidine, or a derivative thereof. In an embodiment, the anti-metabolite is an adenosine deaminase inhibitor.

[0311] In an embodiment, the anti -metabolite is a purine analog. In an embodiment, the anti- metabolite is a purine analog, which is fludarabine (also known as 2-fluoro-ara-amp), nelarabine, clofarabine, or a derivative thereof. In an embodiment, the purine analog is an adenosine analog. In an embodiment, the adenosine analog is fludarabine (such as fludarabine phosphate), cladribine, pentostatin, or a derivative thereof. In an embodiment, the purine analog is a guanine analog. In an embodiment, the guanine analog is thioguanine, 6-mercaptopurine (6-MP), or a derivative thereof.

[0312] In an embodiment, the anti-metabolite is a folate antagonist, which is methotrexate, pemetrexed, or a derivative thereof. Combination Therapy anti-cancer agent. Kinase inhibitors

[0313] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a kinase inhibitor. In an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor. In an embodiment, the kinase inhibitor is a Src kinase inhibitor. In an embodiment, the kinase inhibitor is a Bcr-Abl tyrosine kinase inhibitor. In an embodiment, the kinase inhibitor is asciminib, imatinib (Gleevec), nilotinib (Tasinga), ponatinib (Iclusig), bosutinib (Pfizer), or dasatinib (Sprycel). In an embodiment, the kinase inhibitor is a spleen tyrosine kinase (syk) inhibitor. In an embodiment, the kinase inhibitor is fostamatinib (Tavalisse)(Rigel). In an embodiment, the kinase inhibitor is a Bruton’s tyrosine kinase (Btk) inhibitor. In an embodiment, the kinase inhibitor is zanubrutinib also known as BGB-3111 (BeiGene), ibrutinib (e.g., Imbruvica), evobrutinib (EMD Serono), or acalabrutinib (Acerta/AstraZeneca). In an embodiment, the kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor. In an embodiment, the kinase inhibitor inhibits the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In an embodiment, the kinase inhibitor inhibits the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In an embodiment, the kinase inhibitor is gefitinib (Iressa), erlotinib (Tarceva), pyrotinib, also known as HTI-1001 (Hengrui Therapeutics), afatinib (Gilotrif), or lapatinib (Tykerb). In an embodiment, the kinase inhibitor is a platelet-derived growth factor receptor (PDGF-R) inhibitor. In an embodiment, the kinase inhibitor is a vascular endothelial growth factor receptor (VEGFR) inhibitor. In an embodiment, the kinase inhibitor is sunitinib (Sutent), lenvatinib (Lenvima), or axitinib, formerly known as AGO 13736 (Inlyta). In an embodiment, the kinase inhibitor is a vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor. In an embodiment, the kinase inhibitor is apatinib, also known as YN968D1 (Jiangsu Hengrui) vatalanib, cabozantinib (Cabometyx), golvatinib also known as E7050, or regorafenib (BAY 73-4506, Stivarga). In an embodiment, the kinase inhibitor is a Raf kinase inhibitor. In an embodiment, the kinase inhibitor is sorafenib (Nexavar). In an embodiment, the kinase inhibitor is an Axl receptor tyrosine kinase. In an embodiment, the kinase inhibitor is bemcentinib, also known as BGB324 also known as R428 (Rigel), gilteritinib (Astellas). In an embodiment, the tyrosine kinase inhibitor is neratinib (HER2 Herl Her4), toceranib, or a derivative thereof. In an embodiment, the kinase inhibitor is a phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K(s)). In an embodiment, the kinase inhibitor is idelalisib (e.g., Zydelig) (Gilead) or alpelisib. In an embodiment, the kinase inhibitor is a Chkl inhibitor. In an embodiment, the kinase inhibitor is rabusertib also known as LY2603618 (Eli Lilly).

Combination Therapy, anti-cancer agent, Proteosome inhibitors

[0314] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a proteasome inhibitor. In an embodiment, the proteasome inhibitor is bortezomib (Velcade), carfilzomib, ixazomid, or a derivative thereof.

Combination Therapy, anti-cancer agent. Vinca alkaloids

[0315] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a vinca alkaloid. In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a monoterpenoid indole alkaloid. In an embodiment, the anti-cancer agent is a vinca alkaloid, which is vinblastine, vinorelbine, vincristine, vindesine, or a derivative thereof.

Combination Therapy, anti-cancer agent, Anthracvclines

[0316] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an anthracy cline. In an embodiment, the anthracy cline is daunorubicin, also known as daunomycin, doxorubicin (Adriamycin) (e.g., liposomal doxorubicin), epirubicin, idarubicin (Idamycin), valrubicin, or a derivative thereof.

Combination Therapy, anti-cancer agent. Other antitumor antibiotics [0317] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an antitumor antibiotic. In an embodiment, the antitumor antibiotic is actinomycin, bleomycin, dactinomycin, mytomycin, or a derivative thereof. In an embodiment, the antitumor antibiotic is actinomycin-D or mytomycin-C, or a derivative thereof.

[0318] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a microtubule agent. In an embodiment, the microtubule agent is docetaxel, paclitaxel, or a derivative thereof.

Combination Therapy, anti-cancer agent, Aromatase inhibitors

[0319] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an aromatase inhibitor. In an embodiment, the aromatase inhibitor is a steroidal inhibitor. In an embodiment, the aromatase steroidal inhibitor is exemestane (Aromasin), formestane, or a derivative thereof. In an embodiment, the aromatase inhibitor is a non-steroidal inhibitor. In an embodiment, the aromatase non-steroidal inhibitor is anastrozole (Arimidex), letrozole (Femara), or a derivative thereof. Combination Therapy anti-cancer agent. Topoisomerase inhibitors [0320] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a topoisomerase inhibitor. In an embodiment, the topoisomerase inhibitor is a topoisomerase I inhibitor. In an embodiment, the topoisomerase I inhibitor is camptothecin, or a derivative thereof. In an embodiment, the topoisomerase I inhibitor is irinotecan, topotecan, or a derivative thereof. In an embodiment, the topoisomerase inhibitor is a topoisomerase II inhibitor. In an embodiment, the topoisomerase II inhibitor is etoposide, teniposide, mitoxantrone (Novantrone), or a derivative thereof.

Combination Therapy, anti-cancer agent, mTOR inhibitors

[0321] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is an mTOR inhibitor. In an embodiment, the mTOR inhibitor is rapamycin or a rapalog. In an embodiment, the mTOR inhibitor is temsirolimus (Torisel), everolimus (Afmitor), ridaforolimus, or a derivative thereof. In an embodiment, the mTOR inhibitor is a dual PI3K/mTOR inhibitor. In an embodiment, the dual PI3K/mTOR inhibitor is dactolisib, GSK2126458, or a derivative thereof. In an embodiment, the mTOR inhibitor is ATP- competitive mTORCl/mTORC2 inhibitor. In an embodiment, the ATP-competitive mTORCl/mTORC2 inhibitor is sapanisertib, or a derivative thereof.

Combination Therapy, anti-cancer agent. Retinoids

[0322] In an embodiment, the anti-cancer agent is a chemotherapeutic, which is a retinoid. In an embodiment, the retinoid is all-trans retinoic acid (tretinoin), alitretinoin (9-cis RA), bexarotene (Targretin), or a derivative thereof.

[0323] Exemplary chemotherapeutics include an anthracenedione derivative (e.g., mitoxantrone), an immune cell antibody (e.g., gemtuzumab, gemtuzumab ozogamicin, rituximab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, brentuximab), an anti-CD52 Ab such as alemtuzumab (Campath). In an embodiment, the chemotherapeutic agent is tositumomab or aclacinomycin A or gliotoxin or pegaspargase.

[0324] General chemotherapeutic agents considered for use in combination therapies include bleomycin sulfate (Blenoxane), busulfan (Myleran), capecitabine (Xeloda), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), cyclophosphamide (Cytoxan orNeosar), cytarabine liposome injection (DepoCyt), dacarbazine (DTIC-Dome), dactinomycin (Actinomycin D, Cosmegan), daunorubicin HCl(Cerubidine), daunorubicin citrate liposome injection (DaunoXome), dexamethasone, docetaxel (Taxotere), doxorubicin HCl(Adriamycin, Rubex), etoposide (Vepesid), fludarabine phosphate (Fludara), 5- fluorouracil (Adrucil, Eftidex), gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea), idarubicin (Idamycin), irinotecan (Camptosar), L-asparaginase (ELSPAR), leucovorin calcium, 6-mercaptopurine (Purinethol), methotrexate (Folex), paclitaxel (Taxol), teniposide (Vumon), tirapazamine (Tirazone), topotecan HC1 for injection (Hycamptin), vinblastine (Velban), vincristine (Oncovin), and vinorelbine (Navelbine). In an embodiment, the chemotherapeutic agent is selected from the group consisting of anastrozole (Arimidex), bicalutamide (Casodex), busulfan injection (Busulfex), cytosine arabinoside (Cytosar-U), flutamide (Eulexin), tezacitibine, phoenix (Y ttrium90/MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel), and tamoxifen citrate (Nolvadex).

[0325] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein is administered to a subject in combination with one or more of the following therapeutic agents: methotrexate (e.g., Abitrexate, Methotrexate LPF, Mexate, Mexate-AQ, Folex, Folex PFS), nelarabine (e.g., Arranon), doxorubicin HC1, daunorubicin in combination with cytarabine and anthracy cline, or idararubicin, clofarabine (e.g., Clofarex or Clolar), cyclophosphamide (e.g., Cytoxan, Neosar, Clafen), cytarabine (e.g., Cytosar-U, Tarabine PFS), dasatinib (e.g., Sprycel), or other BCR-ABL and SRC tyrosine kinase inhibitors, Erwinaze (e.g., Asparaginase Erwinia Chrysanthemi), imatinib mesylate (e.g., Gleevec), ponatinib HC1 (e.g., Iclusig), mercaptopurine (e.g., Purinethol, Purixan), pegaspargase (e.g., Oncaspar), ponatinib HC1, prednisone, vincristine sulfate, vincristine sulfate liposome (e.g., Marqibo), vincasar PFS, and Hyper-CVAD. In an embodiment, the subject in the previous sentence has ALL.

[0326] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein is administered to a subject in combination with one or more of the following therapeutic agents: daunorubicin HC1 (e.g., Cerubidine or Rubidomycin) (optionally in combination with cytarabine and an anthracycline, such as daunorubicin or idararubicin), idarubicin HC1 (e.g., Idamycin), Bcl2 inhibitor (e.g., ABT-737, venetoclax (e.g., Venclexta)), cyclophosphamide (e.g., Cytoxan, Clafen, Neosar), cytarabine (e.g., Cytosar-U, Tarabine PFS), doxorubicin HC1, decitabine (hypomethylating agent), fludarabine (fludara), FLT3 inhibitors (e.g., sunitinib, sorafenib, midostaurin, lestaurtinib, quizartinib, crenolanib, PLX3397), GCSF (Granulocyte-colony stimulating factor), IDH inhibitors (e.g., IDH1 inhibitors, e.g., AG120 or IDH305); IDH2 inhibitors, e.g., AG221; pan IGH1/IGH2 inhibitors, e.g., AG881), mitoxantrone HC1, thioguanine (e.g., Tabloid), azacitidine or decitabine (e.g., hypomethylating agent), vincristine sulfate (e.g., Vincasar PFS). In an embodiment, the subject in the previous sentence has AML.

[0327] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein is administered to a subject in combination with one or more of the following therapeutic agents: G100 (Immune Design), bosutinib (e.g., Bosulif), busulfan (e.g., Busulfex, Myleran), cyclophosphamide (e.g., Clafen, Cytoxan, Neosar), cytarabine (e.g., Cytosar-U, Tarabine PFS), dasatinib (e.g., Sprycel), imatinib mesylate (e.g., Gleevec), hydroxyurea (e.g., Hydrea), ponatinib HC1 (e.g., Iclusig), mechlorethamine HC1 (e.g., Mustargen), nilotinib, omacetaxine mepesuccinate (e.g., Synribo), and interferon-alpha. In an embodiment, the subject in the previous sentence has CML.

[0328] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein is administered to a subject in combination with CVP (a combination of cyclophosphamide, vincristine, and prednisone) and/or CHOP (a combination of cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone) with or without etoposide (e.g., VP- 16) and/or a combination of cyclophosphamide and pentostatin and/or a combination of chlorambucil and prednisone and/or a combination of fludarabine and cyclophosphamide and an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide).

Combination Therapy anti-cancer agent. Inhibitors such as antibodies [0329] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a PD1 inhibitor, a PDL1 inhibitor, a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In an embodiment, the PD1 inhibitor, PDL1 inhibitor, PDL2 inhibitor, TIM3 inhibitor, LAG3 inhibitor, CTLA4 inhibitor, TIGIT inhibitor, BTLA inhibitor, CD47 inhibitor, or IDO inhibitor is a small molecule. In an embodiment, the PD1 inhibitor, PDL1 inhibitor, PDL2 inhibitor, TIM3 inhibitor, LAG3 inhibitor, CTLA4 inhibitor, TIGIT inhibitor, BTLA inhibitor, CD47 inhibitor, or IDO inhibitor is an antibody. [0330] In an embodiment, the anti-cancer agent is an antibody, such as an immuno-oncology agent.

Combination Therapy, anti -cancer agent, PD 1

[0331] In an embodiment, abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with a PD 1 inhibitor. In an embodiment, the PD1 inhibitor is a small molecule inhibitor. In an embodiment, the PD1 inhibitor is CA-170 (Curis), AUNP-12 (Aurigene), or a compound described in WO 2015/034820 — in particular, BMS-1, BMS-2, BMS-79, and BMS-196.

[0332] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with an anti -PD 1 antibody. In an embodiment, the PD 1 inhibitor is nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab (Medivation/Pfizer), spartalizumab also known as PDR001, JNJ-63723283 (J&J), TSR-042 (Tesaro), cemiplimab also known as REGN2810 (Sanofi), AMP-224 (Amplimmune/GSK), MEDI0680 also known as AMP-514 (AstraZeneca), MGA012 (MacroGenics/Incyte), MGD013 (MacroGenics), MGD019 (MacroGenics), SHR-1210 (Shanghai Hengrui Pharma/Incyte), GLS-010 (Gloria Pharma/WuXi Biologies), JS001 (Shanghai Junshi Biosciences), tislelizumab also known as BGB-A317 (BeiGene/Celgene), sintilimab also known as IBI308 (Innovent), CX-188 (CytomX Therapeutics), or CS1003 (CStone Pharmaceuticals) .

[0333] Exemplary non-limiting anti-PDl antibody molecules are disclosed in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD1 and Uses Thereof,” incorporated by reference in its entirety.

[0334] In an embodiment, the anti -PD 1 antibody molecule includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1 of US 2015/0210769, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. The anti-PDl antibody molecule, optionally, comprises a leader sequence from a heavy chain, a light chain, or both, as shown in Table 4 of US 2015/0210769; or a sequence substantially identical thereto.

[0335] In an embodiment, the anti -PD 1 antibody molecule includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-huml0, BAP049-huml 1, BAP049-huml2, BAP049-huml3, BAP049-huml4, BAP049-huml5, BAP049-huml6, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0336] In an embodiment, the anti-PD 1 antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0337] In an embodiment, the anti-PD 1 antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, the anti-PD 1 antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain. In one embodiment, the anti-PD 1 antibody molecule includes a substitution in the light chain CDR3 at position 102 of the light variable region, e.g., a substitution of a cysteine to tyrosine, or a cysteine to serine residue, at position 102 of the light variable region according to Table 1 (e.g., SEQ ID NO: 16 or 24 for murine or chimeric, unmodified; or any of SEQ ID NOs: 34, 42, 46, 54, 58, 62, 66, 70, 74, or 78 for a modified sequence).

[0338] In an embodiment, the anti -PD 1 antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0339] In an embodiment, the anti -PD 1 antibody molecule includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32, each disclosed in Table 1 of US 2015/0210769;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769; or

(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32, each disclosed in Table 1 of US 2015/0210769. [0340] In an embodiment, the anti -PD 1 antibody molecule comprises (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 5; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769.

[0341] In an embodiment, the PD1 inhibitor is an anti -PD 1 antibody chosen from nivolumab, pembrolizumab, or pidilizumab. In other embodiments, the PD1 inhibitor is spartalizumab (PDR001).

[0342] In an embodiment, the anti -PD 1 antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In an embodiment, the anti-PDl antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in US 8,008,449 and W02006/121168. In an embodiment, the inhibitor of PD 1 is nivolumab, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0343] The heavy and light chain amino acid sequences of nivolumab are as follows:

Heavy chain

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDG

SKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVT

V S SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWN SGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPE

FLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT

KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP

QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS

FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Light chain

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP ARFSGSGSGTDFTFTISSFEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIF PPSDEQFKSGTASWCFFN FYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTYS FS STFTFSKADYEKHKVYACEVTHQGFS SPVTKSFNRGEC

[0344] In an embodiment, the anti -PD 1 antibody is pembrolizumab. Pembrolizumab (also referred to as lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA; Merck) is a humanized IgG4 monoclonal antibody that binds to PD 1. Pembrolizumab and other humanized anti-PDl antibodies are disclosed in Hamid, O. etal. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509 and W02009/114335. The heavy and light chain amino acid sequences of pembrolizumab are as follows:

Heavy chain

QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50 INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD 100 YRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT 200 YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT 350 LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447

Fight chain

EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50 LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100 TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTY SLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218'

[0345] In an embodiment, the inhibitor of PD1 is pembrolizumab disclosed in, e.g., US 8,354,509 and WO 2009/114335, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0346] In an embodiment, the anti-PDl antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgGlk monoclonal antibody that binds to PD 1. Pidilizumab and other humanized anti-PDl monoclonal antibodies are disclosed in W02009/101611. [0347] Other anti-PDl antibodies include AMP 514 (Amplimmune), among others, e.g., anti- PD1 antibodies disclosed in US 8,609,089, US 2010028330, and/or US 20120114649.

[0348] In an embodiment, the PD1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD 1 binding portion of PDU1 or PDU2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In an embodiment, the PD1 inhibitor is AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in W02010/027827 and WO2011/066342), is a PDU2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[0349] In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises another anti-cancer agent. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises a chemotherapeutic. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises a pyrimidine analog. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises cytarabine. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti- CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises anthracycbne. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises idarubicin. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises daunorubicin. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises anthracenedione. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises gemtuzumab. In an embodiment, for any of the combinations of abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises a FUT3 inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises a topoisomerase inhibitor. In an embodiment, for any of the combinations of a bispecific anti- CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises a topoisomerase II inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises etoposide. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises mitoxantrone. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises an adenosine analog. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises fludarabine. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises cladribine. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises a kinase inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PD1 inhibitor described herein, this combination further comprises a Bcr-Abl inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises imatinib or nilotinib or dasatinib or bosutinib or ponatinib or a combination thereof. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PD1 inhibitor described herein, this combination further comprises omacetaxine. In an embodiment, for any of the combinations described in this paragraph, the PD1 inhibitor is spartalizumab.

Combination Therapy anti -cancer agent PDLl orPDL2

[0350] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a PDL1 inhibitor. In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with a PDL2 inhibitor. [0351] In an embodiments, the PDL1 inhibitor is an antibody molecule. In an embodiment, the anti-PDLl inhibitor is atezolizumab (Tecentriq) formerly known as YW243.55.S70 or MPDL3280A, avelumab (Bavencio (EMD Serono) formerly known as MSB-0010718C, durvalumab (Imfinzi; Medlmmune/AstraZeneca) formerly known as MEDI-4736, FAZ053, LY3300054 (Lilly), ABBV-181 (Abb Vie), MSB2311 (MabSpace Biosciences), MDX-1105 also known as BMS-936559, CSIOOI formerly known as WBP3155 (CStone Pharmaceuticals), KN035 (Alphamab), CA-327 (Curis), CX-072 (CytomX Therapeutics), M7824 (EMD Serono), HTI-1316 (Hengrui Therapeutics), or JS003 (Shanghai Junshi Biosciences).

[0352] Exemplary non-limiting PDL1 inhibitors are disclosed in US 2016/0108123, published on April 21, 2016, entitled “Antibody Molecules to PDL1 and Uses Thereof,” incorporated by reference in its entirety.

[0353] In an embodiment, the PDL1 inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum 10, BAP058-huml 1, BAP058-huml2, BAP058-huml3, BAP058-huml4, BAP058-huml5, BAP058-huml6, BAP058-huml7, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical ( e.g ., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0354] In an embodiment, the PDL1 inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-huml0, BAP058-hum 11, BAP058-huml2, BAP058-huml3, BAP058-huml4, BAP058-huml5, BAP058-hum 16, BAP058-huml7, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058-Clone-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0355] In an embodiment, the PDL1 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2016/0108123, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0356] In an embodiment, the PDL1 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2016/0108123, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, the PDU1 inhibitor includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain.

[0357] In an embodiment, the PDU1 inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1 of US 2016/0108123. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0358] In an embodiment, the PDU1 inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2016/0108123; and (ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence ofSEQ ID NO: 11, each disclosed in Table 1 ofUS 2016/0108123.

[0359] In an embodiment, the PDL1 inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2016/0108123; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence ofSEQ ID NO: 14, each disclosed in Table 1 of US 2016/0108123.

[0360] In an embodiment, the PDL1 inhibitor comprises the VHCDR1 amino acid sequence of SEQ ID NO: 1. In an embodiment, the anti-PDLl antibody molecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 4. In an embodiment, the PDL1 inhibitor comprises the VHCDR1 amino acid sequence of SEQ ID NO: 195, each disclosed in Table 1 of US 2016/0108123.

[0361] In an embodiment, the PDL1 inhibitor is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PDL1. Pembrolizumab and other humanized anti-PDLl antibodies are disclosed in WO2013/079174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified). The heavy and light chain amino acid sequences of MSB0010718C include at least the following:

Heavy chain (SEQ ID NO: 24 as disclosed in WO2013/079174)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGI

TFYADKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTL

VTVSS

Light chain (SEQ ID NO: 25 as disclosed in WO2013/079174)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN

RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL. [0362] In an embodiment, the PDL1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PDLl described in WO 2010/077634 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively), and having a sequence disclosed therein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0363] In an embodiment, the PDL1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PDLl antibody described in W02007/005874, and having a sequence disclosed therein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0364] In an embodiment, the PDL1 inhibitor is MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc optimized IgGl monoclonal antibody that binds to PDL1. MDPL3280A and other human monoclonal antibodies to PDL1 are disclosed in U.S. Patent No.: 7,943,743 and U.S. Publication No.: 20120039906.

[0365] In an embodiment, the PDL2 inhibitor is AMP-224. AMP-224 is a PDL2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg;

Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342).

[0366] In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises another anti-cancer agent. In an embodiment, for any of the combinations of a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a chemotherapeutic. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) and PDL1 inhibitor described herein, this combination further comprises a pyrimidine analog. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises cytarabine. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti- CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises anthracycline. In an embodiment, for any of the combinations of a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises idarubicin. In an embodiment, for any of the combinations of abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises daunorubicin. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises anthracenedione. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises gemtuzumab. In an embodiment, for any of the combinations of abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a FLT3 inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a topoisomerase inhibitor. In an embodiment, for any of the combinations of a bispecific anti- CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a topoisomerase II inhibitor. In an embodiment, for any of the combinations of abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises etoposide. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises mitoxantrone. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises an adenosine analog. In an embodiment, for any of the combinations of a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises fludarabine. In an embodiment, for any of the combinations of abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises cladribine. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a kinase inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises a Bcr-Abl inhibitor. In an embodiment, for any of the combinations of a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises imatinib or nilotinib or dasatinib or bosutinib or ponatinib or a combination thereof. In an embodiment, for any of the combinations of a bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) and PDL1 inhibitor described herein, this combination further comprises omacetaxine. In an embodiment, for any of the combinations described in this paragraph, this combination further comprises a PD 1 inhibitor. In an embodiment, for any of the combinations described in this paragraph, the PD 1 inhibitor is spartalizumab.

Combination Therapy, anti-cancer agent, TIM3

[0367] In an embodiment, a bispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a TIM3 inhibitor. In an embodiment, the TIM3 inhibitor is MGB453, INCAGN2390 (Incyte), Sym023, TSR-022 (Tesaro), and LY3321367 (Lilly).

[0368] Exemplary non-limiting TIM3 inhibitors are disclosed in US 2015/0218274, published on August 6, 2015, entitled “Antibody Molecules to TIM3 and Uses Thereof,” incorporated by reference in its entirety.

[0369] In an embodiment, the TIM3 inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3- hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3- hum09, ABTIM3-huml0, ABTIM3-huml 1, ABTIM3-huml2, ABTIM3-huml3, ABTIM3- huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3- huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. The TIM3 inhibitor, optionally, comprises a leader sequence from a heavy chain, a light chain, or both, as shown in US 2015/0218274; or a sequence substantially identical thereto.

[0370] In an embodiment, the TIM3 inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3 -humO 1 , ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-huml0, ABTIM3-huml 1, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0371] In an embodiment, the TIM3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1-4. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Table 1-4.

[0372] In an embodiment, the TIM3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1-4. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4. In an embodiment, the TIM3 inhibitor includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain.

[0373] In an embodiment, the TIM3 inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1-4. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4. [0374] In an embodiment, the TIM3 inhibitor includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274; or

(f) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274.

[0375] Exemplary TIM3 inhibitor are disclosed in U.S. Patent No.: 8,552,156, WO 2011/155607, EP 2581113 and U.S. Publication No.: 2014/044728.

Combination Therapy anti-cancer agent. LAG3

[0376] In an embodiment, abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with a LAG3 inhibitor. In an embodiment, the LAG3 Inhibitor is LAG525, TSR-033 (Tesaro), REGN3767 (Sanofi), eftilagimod alpha also known as IMP321 (Prima BioMed), MGD013 (MacroGenics), FS118 (F-star/Merck), INCAGN2385 (Incyte), orGSK2831781 (GSK).

[0377] Exemplary non-limiting LAG3 inhibitors are disclosed in US 2015/0259420 published on September 17, 2015, entitled “Antibody Molecules to LAG3 and Uses Thereof,” incorporated by reference in its entirety.

[0378] In an embodiment, the LAG3 inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum 10, BAP050-huml 1, BAP050-huml2, BAP050-huml3, BAP050-huml4, BAP050-huml5, BAP050-huml6, BAP050-huml7, BAP050-huml8, BAP050-huml9, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050- hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050- hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum 10-Ser, BAP050- humll-Ser, BAP050-hum 12-Ser, BAP050-huml3-Ser, BAP050-hum 14-Ser, BAP050- huml5-Ser, BAP050-huml8-Ser, BAP050-hum 19-Ser, or BAP050-hum20-Ser), BAP050- Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone- J; or as described in Table 1 of US 2015/0259420, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0379] In an embodiment, the LAG3 inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-huml0, BAP050-hum 11, BAP050-huml2, BAP050-huml3, BAP050-huml4, BAP050-huml5, BAP050-hum 16, BAP050-huml7, BAP050-huml8, BAP050-huml9, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum 10-Ser, BAP050-hum 11-Ser,

BAP050-hum 12-Ser, BAP050-huml3-Ser, BAP050-hum 14-Ser, BAP050-huml5-Ser, BAP050-huml8-Ser, BAP050-hum 19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1 of US 2015/0259420, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0380] In an embodiment, the LAG3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0259420, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0381] In an embodiment, the UAG3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0259420, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In an embodiment, the anti-PDUl antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain. [0382] In an embodiment, the LAG3 inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1 of US 2015/0259420. In an embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0383] In an embodiment, the LAG3 inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2015/0259420; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12, each disclosed in Table 1 of US 2015/0259420.

[0384] In another embodiment, the anti-LAG3 antibody molecule includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2015/0259420; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15, each disclosed in Table 1 of US 2015/0259420.

[0385] In an embodiment, the anti-LAG3 antibody molecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 1. In an embodiment, the anti-LAG3 antibody molecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 4. In an embodiment, the anti- LAG3 antibody molecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 286, each disclosed in Table 1 of US 2015/0259420.

[0386] In an embodiment, the anti-LAG3 antibody is relatlimab. Relatlimab (also referred to as BMS-986016 or BMS986016; Bristol-Myers Squibb) is a monoclonal antibody that binds to LAG3. Relatlimab and other humanized anti-LAG3 antibodies are disclosed in US 2011/0150892, W02010/019570, and W02014/008218.

Combination Therapy, anti-cancer agent, CTLA4

[0387] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a CTLA4 inhibitor.

[0388] Exemplary anti-CTLA4 antibodies include tremelimumab (IgG2 monoclonal antibody available from Medlmmune, a subsidiary of AstraZeneca, formerly known as ticilimumab, CP-675,206); and ipilimumab (Y ervoy) (CTLA4 antibody, also known as MDX-010, CAS No. 477202-00-9). Other exemplary anti-CTLA4 antibodies are disclosed, e.g., in U.S. Pat. No. 5,811,097. Other exemplary anti-CTLA4 antibodies include abatacept (Orencia), IBI310 (Innovent), BMS-986249 (BMS/CytomX Therapeutics), or CS1002 (CStone Pharmaceuticals) .

[0389] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with an anti-PDl antibody molecule, e.g., as described herein, and an anti-CTLA4 antibody, e.g., ipilimumab.

Combination Therapy, anti-cancer agent, TIGIT

[0390] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a TIGIT inhibitor. In an embodiment, the TIGIT inhibitor is OMP-313M32 (OncoMed).

Combination Therapy anti-cancer agent. BTLA

[0391] In an embodiment, abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with a BTLA inhibitor.

Combination Therapy, anti-cancer agent, CD47

[0392] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a CD47 inhibitor. In an embodiment, the CD47 inhibitor is TTI-621 (Trillium Therapeutics), TTI-622 (Trillium Therapeutics), Hu5F9- G4 (Forty-Seven), or CC-90002 (InhibRx/Celgene).

Combination Therapy anti-cancer agent. IDO

[0393] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with an IDO inhibitor. In an embodiment, the IDO inhibitor is navoximod also known as GDC-0919 (Genetech/NewLink Genetics), indoximod or prodrugs of indoximod such as NLG802 (NewLink Genetics), epacadostat also known as INCB024360 (Incyte), HTI-1090 also known as SHR9146 (Hengrui Therapeutics), BMS-986205 (BMS), or LY3381916 (Lilly).

Combination Therapy anti-cancer agent GITR agonist

[0394] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a GITR agonist.

[0395] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a GITR agonist. In an embodiment, the GITR inhibitor is TRX518-001, GWN323, MEDI1873 (Medlmmune), OMP-336B11 (OncoMed), or ICAGN01876 (Incyte).

[0396] Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Patent No.: 6,111,090, European Patent No.: 0920505B1, U.S. PatentNo.: 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. PatentNo.: 7,025,962, European PatentNo.: 1947183B1, U.S. Patent No.: 7,812,135, U.S. PatentNo.: 8,388,967, U.S. PatentNo.: 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683, U.S. Patent No.: 8,709,424, PCT Publication No.: WO 2013/039954, International Publication No.: WO2013/039954, U.S. Publication No.: US2014/0072566, International Publication NO.: WO2015/026684, PCT Publication No.: W02005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: W02005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO99/20758, U.S. PatentNo.: 6,689,607, PCT Publication No.: W02006/083289, PCT Publication No.: WO 2005/115451, U.S. PatentNo.: 7,618,632, PCT Publication No.: WO 2011/051726, International Publication No.: W02004060319, and International Publication No.: WO2014012479.

[0397] In an embodiment, abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with a GITR agonist and a PD1 inhibitor, e.g., as described in WO2015/026684. [0398] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a GITR agonist and a TLR agonist, e.g., as described in W02004060319, and International Publication No.: WO2014012479.

[0399] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a GITR agonist and a PD1 inhibitor, e.g., as described in WO2015/026684.

[0400] In an embodiment, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAb 14045) described herein can be used in combination with a GITR agonist and a TLR agonist, e.g., as described in W02004060319, and International Publication No.: WO2014012479.

Combination Therapy anti-cancer agent ICOS agonist

[0401] In an embodiment, abispecific anti-CD123 x anti-CD3 antibody (e.g., XmAbl4045) described herein can be used in combination with an ICOS agonist.

Combination Therapy administration to human subject who has ALL [0402] In some embodiments, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is administered to a human subject who has ALL, in combination with one or more of: Methotrexate (e.g., Abitrexate, Methotrexate LPF, Mexate, Mexate-AQ, Folex,

Folex PFS), Nelarabine (e.g., Arranon), Doxorubicin Hydrochloride, Daunorubicin Hydrochloride (e.g., Cerubidine, Rubidomycin) (in combination with cytarabine and anthracycline (daunorubicin or idararubicin), mitoxantrone, fludarabine, cladribine, Clofarabine (e.g., Clofarex or Clolar), Cyclophosphamide (e.g, Cytoxan, Neosar, Clafen), Cytarabine (e.g., Cytosar-U, Tarabine PFS), Dasatinib (e.g, Sprycel), other Brc tyrosine kinase inhibitor, Erwinaze (e.g., Asparaginase Erwinia Chrysanthemi), Imatinib Mesylate (e.g., Gleevec), Ponatinib Hydrochloride (e.g., Ichisig), inotuzumab ozogamicin, https://www.cancer.gov/about-cancer/treatment/drugs/vincristine-sulfate-liposome, Mercaptopurine (e.g., Purinethol, Purixan), Pegaspargase (e.g., Oncaspar), Ponatinib Hydrochloride, Prednisone, Vincristine Sulfate, Vincristine Sulfate Liposome (e.g.,

Marqibo), Vincasar PFS, Hyper-CVAD, or any combination thereof. The bispecific antibody can be given to human subjects who are undergoing tisagenlecleucel therapy, or additional donor lymphocyte infusions in human subjects that have previously had an allogeneic stem cell transplantation. Combination Therapy administration to human subject who has AML [0403] In some embodiments, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is administered to a human subject who has AML, in combination with one or more of: Daunorubicin Hydrochloride (e.g, Cerubidine or Rubidomycin) (optionally in combination with cytarabine and anthracycline -daunorubicin or idararubicin), Vyxeos, Idarubicin Hydrochloride (e.g., Idamycin), BCL2 inhibitor (e.g., Venclextra), Cyclophosphamide (e.g., Cytoxan, Clafen, Neosar), Cytarabine (e.g., Cytosar-U, Tarabine PFS), Doxorubicin Hydrochloride, Decitabine (hypomethylating agent), Fludarabine (fludara), Flt3 inhibitors (e.g., sunitinib, sorafenib, midostaurin, lestaurtinib, quizartinib, crenolanib, PLX3397), GCSF (Granulocyte-colony stimulating factor), IDH inhibitors (e.g., IDH1 inhibitors, e.g, AG120 or IDH305); IDH2 inhibitors, e.g, AG221; pan IGH1/IGH2 inhibitors, e.g., AG881), Mitoxantrone Hydrochloride, Thioguanine (e.g., Tabloid), azacitidine (e.g, Vidaza, hypomethylating agent), Vincristine Sulfate (e.g., Vincasar PFS), gemtuzumab ozogamicin, etoposide, enasidenib, or any combination thereof.

Combination Therapy administration to human subject who has CML [0404] In some embodiments, abispecific anti-CD 123 x anti-CD3 antibody (e.g., XmAbl4045) is administered to a human subject who has CML, in combination with one or more of: Bosutinib (e.g., Bosulif), Busulfan (e.g., Busulfex), Cyclophosphamide (e.g., Clafen, Cytoxan, Neosar), Cytarabine (e.g., Cytosar-U, Tarabine PFS), Dasatinib (e.g., Sprycel), Imatinib Mesylate (e.g, Gleevec), Hydroxyurea (e.g., Hydrea), Ponatinib Hydrochloride (e.g., Iclusig), Mechlorethamine Hydrochloride (e.g., Mustargen), Busulfan (e.g., Myleran), Nilotinib, Omacetaxine Mepesuccinate (e.g., Synribo), and interferon-alpha, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent

[0405] In some embodiments, a bispecific antibody is administered to a human subject in combination with one or more side-effect ameliorating agent(s). In an exemplary embodiment, the one or more side-effect ameliorating agent(s) is administered prior to the first administration of the bispecific antibody. In an exemplary embodiment, the one or more side-effect ameliorating agent(s) is administered prior to each administration of the bispecific antibody. [0406] Side effects associated with the administration of the CD 123 x CD3 bispecific antibody, include, but are not limited to cytokine release syndrome (“CRS”). Other possible side effects include lymphopenia (lymphocyte count decreased), increased amounts of gamma-glutamyl transpeptidase (GGT) in the blood, increased amounts of alanine transaminase (ALT) in the blood, increased amounts of aspartate transaminase (AST) in the blood, fever, vomiting, nausea, diarrhea, hypotension, hypoxia, rash, dysphagia, gastroparesis, capillary leak syndrome, hypophosphatemia, anemia, fatigue, and increased lipase in the blood.

[0407] Symptoms of CRS can include high fevers, nausea, transient hypotension, hypoxia, and the like. CRS can include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, and headache. CRS can include clinical skin signs and symptoms such as rash. CRS can include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. CRS can include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. CRS can include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potentially diminished cardiac output. CRS can include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. CRS can include clinical renal signs and symptoms such as azotemia. CRS can include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. CRS can include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dymetria, altered gait, and seizures.

[0408] In an exemplary embodiment, the administration of XmAbl4045 described herein to the human subject produces a low rate of one or more CRS symptoms described herein. In an exemplary embodiment, the administration of XmAb 14045 described herein to the human subject produces a low level of one or more CRS symptoms described herein. In an exemplary embodiment, the administration of XmAb 14045 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of one or more CRS symptoms described herein. In an exemplary embodiment, the administration of XmAb 14045 described herein to the human subject produces a low Grade (such as Grade 1 or Grade 2) of CRS. [0409] In one embodiment, the one or more side-effect ameliorating agent(s) include steroids, antihistamines, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agents, antipyretic agents, cytoprotective agents, vasopressor agents, anticonvulsant agents, antiinflammatories, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. Steroid [0410] In one embodiment, the side-effect ameliorating agent is a steroid. In one embodiment, the steroid is a corticosteroid. In one embodiment, the corticosteroid is a glucocorticoid. In one embodiment, the corticosteroid is betamethasone, dexamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone, or any combination thereof. In one embodiment, the corticosteroid is hydrocortisone, cortisone, ethamethasoneb, or any combination thereof. In one embodiment, the steroid is fludrocortisone. In one embodiment, the steroid is dexamethasone.

Combination Therapy: Side-effect ameliorating agent. Antihistamine [0411] In one embodiment, the side-effect ameliorating agent is an antihistamine. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the Hi antagonist is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelennamine, triprolidine, or any combination thereof.

[0412] In one embodiment, the antihistamine is acrivastine. In one embodiment, the antihistamine is cetirizine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is Benadryl®.

[0413] In one embodiment, the antihistamine is an Hi inverse agonist. In one embodiment, the Hi inverse agonist is acrivastine, cetirizine, levocetirizine, desloratadine, pyrilamine, or any combination thereof. [0414] In one embodiment, the antihistamine is an Eh antihistamine. In one embodiment, the Eh antihistamine is an Eh antagonist. In one embodiment, the Eh antihistamine is an Eh inverse agonist. In one embodiment, the Eh antihistamine is cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. Anti-allergy agent [0415] In one embodiment, the side-effect ameliorating agent is an antiallergy agent. In one embodiment, the side-effect ameliorating agent is antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, antileukotriene agents, anti-cholinergics, decongestants, or any combination thereof. In one embodiment, the side-effect ameliorating agent is a decongestant. In one embodiment, the side-effect ameliorating agent is an adrenaline releasing agent. In one embodiment, the side-effect ameliorating agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), loratadine, or any combination thereof. In one embodiment, the side-effect ameliorating agent is an a- adrenergic receptor agonist. In one embodiment, the side-effect ameliorating agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetryzoline, tramazoline, xylometazoline, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. Antinausea agents (or anti-emetic) [0416] In one embodiment, the side-effect ameliorating agent is an antinausea agent. In one embodiment, the side-effect ameliorating agent is an antiemetic agent. In one embodiment, the side-effect ameliorating agent is a 5-HT₃ receptor antagonist. In one embodiment, the side-effect ameliorating agent is a dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofiran®), tropisetron (Setrovel®, Navoban®), palonosetron (Aloxi®), mirtazapine (Remeron®), or any combination thereof. In one embodiment, the side-effect ameliorating agent is a dopamine antagonist. In one embodiment, the side-effect ameliorating agent is a 5-HT₃ receptor antagonist. In one embodiment, the side-effect ameliorating agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®), or any combination thereof. In one embodiment, the side-effect ameliorating agent is a NK1 receptor antagonist. In one embodiment, the side-effect ameliorating agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®), or any combination thereof. In one embodiment, the side-effect ameliorating agent is an anticholinergic. In one embodiment, the side-effect ameliorating agent is scopolamine.

Combination Therapy: Side-effect ameliorating agent. Analgesic and/or antipyretic agent [0417] In one embodiment, the side-effect ameliorating agent is an analgesic agent. In one embodiment, the side-effect ameliorating agent is an antipyretic agent. In one embodiment, the side-effect ameliorating agent is a salicylate, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, salicylic acid, any derivative thereof, or any combination thereof. In one embodiment, the salicylate is choline salicylate, magnesium salicylate, sodium salicylate, or any combination thereof. In one embodiment, the side-effect ameliorating agent is aspirin.

In one embodiment, the side-effect ameliorating agent is acetaminophen, any derivative thereof. In one embodiment, the side-effect ameliorating agent is an NSAID, any derivative thereof. In one embodiment, the NSAID is a propionic acid derivative. In one embodiment, the NSAID is ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, any derivative thereof, or any combination thereof. In one embodiment, the NSAID is ibuprofen. In one embodiment, the NSAID is naproxen. In one embodiment, the NSAID is an acetic acid derivative. In one embodiment, the NSAID is indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, any derivative thereof, or any combination thereof. In one embodiment, the NSAID is an enolic acid derivative. In one embodiment, the NSAID is piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, phenylbutazone, any derivative thereof, or any combination thereof.

In one embodiment, the NSAID is an anthranilic acid derivative. In one embodiment, the NSAID is mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, any derivative thereof, or any combination thereof. In one embodiment, the side-effect ameliorating agent is phenazone, metamizole, nabumetone, any derivative thereof, or any combination thereof. In one embodiment, the side-effect ameliorating agent is an opiate. In one embodiment, the side-effect ameliorating agent is codeine, morphine, thebaine, fentanyl, or any combination thereof. In one embodiment, the side-effect ameliorating agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon, or any combination thereof. Combination Therapy: Side-effect ameliorating agent. Cvtoprotective agent

[0418] In one embodiment, the side-effect ameliorating agent is a cytoprotective agent. In one embodiment, the side-effect ameliorating agent is an aminothiol compound. In one embodiment, the side-effect ameliorating agent is amifostine. In one embodiment, the side- effect ameliorating agent is bleomycin, dexrazoxane, coenzyme M, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. Vasopressor agent [0419] In one embodiment, the side-effect ameliorating agent is a vasopressor agent. In one embodiment, the vasopressor agent is norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or any combination thereof. In one embodiment, the vasopressor agent is dobutamine, midodrine, amezinium, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. Anticonvulsant agent [0420] In one embodiment, the side-effect ameliorating agent is an anticonvulsant agent. In one embodiment, the anticonvulsant is an aldehyde. In one embodiment, the aldehyde is paraldehyde. In one embodiment, the anticonvulsant is an aromatic allylic alcohol. In one embodiment, the aromatic allylic alcohol is stiripentol. In one embodiment, the anticonvulsant is a barbiturate. In one embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, barbexaclone, or any combination thereof. In one embodiment, the anticonvulsant is a benzodiazepine. In one embodiment, the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, nimetazepam, or any combination thereof. In one embodiment, the anticonvulsant is a carboxamide. In one embodiment, the carboxamide is carbamazepine, oxcarbazepine, eslicarbazepine acetate or any combination thereof. In one embodiment, the anticonvulsant is a fatty acid. In one embodiment, the fatty acid is a valproate. In one embodiment, the valproate is valproic acid, sodium valproate, divalproex sodium, or any combination thereof. In one embodiment, the valproate is vigabatrin, progabide, and tiagabine. In one embodiment, the anticonvulsant is a fructose derivative. In one embodiment, the fructose derivative is topiramate. In one embodiment, the anticonvulsant is a GABA analog. In one embodiment, the GABA analog is gabapentin, pregabalin, or any combination thereof. In one embodiment, the anticonvulsant is a hydantoin. In one embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, fosphenytoin, or any combination thereof. In one embodiment, the anticonvulsant is an oxazolidinedione. In one embodiment, the oxazolidinedione is paramethadione, trimethadione, ethadione, or any combination thereof. In one embodiment, the anticonvulsant is a propionate. In one embodiment, the anticonvulsant is a pyrimidinedione. In one embodiment, the anticonvulsant is a pyrrolidine. In one embodiment, the pyrrolidine is brivaracetam, etiracetam, levetiracetam, seletracetam, or any combination thereof. In one embodiment, the anticonvulsant is levetiracetam. In one embodiment, the anticonvulsant is a succinimide. In one embodiment, the succinimide is ethosuximide, phensuximide, mesuximide, or any combination thereof. In one embodiment, the anticonvulsant is a sulfonamide. In one embodiment, the succinimide is acetazolamide, sultiame, methazolamide, zonisamide, or any combination thereof. In one embodiment, the anticonvulsant is a triazine. In one embodiment, the triazine is lamotrigine. In one embodiment, the anticonvulsant is a urea. In one embodiment, the urea is pheneturide, phenacemide, or any combination thereof. In one embodiment, the anticonvulsant is a valproylamide. In one embodiment, the anticonvulsant is a valproylamide. In one embodiment, the valproylamide is valpromide, valnoctamide, or any combination thereof. In one embodiment, the anticonvulsant is perampanel, stiripentol, pyridoxine, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent, TNFa inhibitor

[0421] In one embodiment, the side-effect ameliorating agent is an anti-inflammatory agent.

In one embodiment, the side-effect ameliorating agent is a TNF-a inhibitor. In one embodiment, the TNF-a inhibitor is an antibody. Examples of an anti-TNFa antibody molecule such as, infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), or any combination thereof. Another example of a TNFa inhibitor is a fusion protein such as entanercept (Enbrel®). In one embodiment, the TNF-a inhibitor is a small molecule. Small molecule inhibitor of TNFa include, but are not limited to, xanthine derivatives (e.g. pentoxifylline), bupropion, or any combination thereof.

Combination Therapy: Side-effect ameliorating agent. IL6 inhibitor

[0422] In one embodiment, the side-effect ameliorating agent is an anti-inflammatory agent.

In one embodiment, the side-effect ameliorating agent is a IL-6 inhibitor. An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toe), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, FM101, or any combination thereof. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab.

[0423] The methods described herein can comprise administering a bispecific antibody described herein to a human subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a bispecific antibody. In one embodiment, the soluble factor elevated in the human subject is one or more of IFN-g, TNFa, IL-2 and IL-6. In an embodiment, the factor elevated in the human subject is one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine. Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFa, and inhibitor of IL-1R, and an inhibitor of IL-6. Examples include anakinra or rilonacept or canakinumab.

[0424] In one embodiment, the side-effect ameliorating agent is one that reduces an immune- mediated side effect. Exemplary immune-mediated side effects include, but are not limited to pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and endocrinopathies (e.g., hypophysitis, Type 1 diabetes mellitus and thyroid disorders such as hypothyroidism and hyperthyroidism). In one embodiment, the side-effect ameliorating agent reduces embryofetal toxicity.

[0425] In an embodiment, the human subject can be administered an antipyretic agent. In an embodiment, the human subject can be administered an analgesic agent.

Side-effect combinations and amounts

[0426] In one embodiment, a steroid is administered prior to the bispecific antibody. In one embodiment, the steroid is administered in an amount of between about 5 mg and about 30 mg. In one embodiment, the steroid described herein is administered in an amount of between about 5 mg and about 25 mg. In one embodiment, the steroid is administered in an amount of between about 5 mg and about 15 mg. In one embodiment, the steroid is administered in an amount of between about 8 mg and about 12 mg. In one embodiment, the steroid is administered in an amount of between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg. In one embodiment, the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount of between about 18 mg and about 22 mg. In one embodiment, the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount of between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 20 mg. In one embodiment, the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of XmAb 14045. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of XmAb 14045. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before each administration of XmAb 14045.

[0427] In one embodiment, an antihistamine is administered prior to the bispecific antibody. In one embodiment, the antihistamine is an Hi antagonist. In one embodiment, the Hi antagonist is a first generation Hi antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is administered in an amount of between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount of between about 20 mg and 30 mg. In one embodiment, the antihistamine is administered in an amount of about 25 mg. In one embodiment, the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount of between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount of between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount of between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg. In one embodiment, the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of XmAb 14045. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of XmAb 14045. In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes before each administration of XmAb 14045.

[0428] In one embodiment, acetaminophen is administered prior to the bispecific antibody.

In one embodiment, acetaminophen is administered in an amount of between about 100 mg and 1000 mg. In one embodiment, acetaminophen is administered in an amount of between about 400 mg and 600 mg. In one embodiment, acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount of between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount of between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount of between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg. In one embodiment, the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of XmAb 14045. In one embodiment, the acetaminophen is administered about 30 minutes before each administration of XmAb 14045. In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of XmAb 14045.

[0429] In one embodiment, a steroid, an Hi antagonist, and acetaminophen are administered prior to the bispecific antibody. In one embodiment, dexamethasone, an Hi antagonist, and acetaminophen are administered prior to the bispecific antibody. In one embodiment, a steroid, diphenhydramine, and acetaminophen are administered prior to the bispecific antibody. In one embodiment, dexamethasone, diphenhydramine, and acetaminophen are administered prior to the bispecific antibody. In one embodiment, dexamethasone is administered in an amount of about 10 mg or about 20 mg, diphenhydramine is administered in an amount of about 25 mg, and acetaminophen is administered in an amount of about 650 mg prior to the bispecific antibody.

[0430] In one embodiment, an antinausea agent is administered prior to the bispecific antibody. In one embodiment, the antinausea agent is a 5-HT₃ receptor antagonist. In one embodiment, the 5-HT₃ receptor antagonist is administered in an amount of between about 5 mg and 30 mg. In one embodiment, the 5-HT₃ receptor antagonist is administered in an amount of between about 5 mg and 15 mg. In one embodiment, the 5-HT₃ receptor antagonist is administered in an amount of between about 5 mg and 10 mg. In one embodiment, the 5-HT₃ receptor antagonist is administered in an amount of about 8 mg. In one embodiment, the 5-HT₃ receptor antagonist is administered in an amount of 8 mg. In one embodiment, the 5-HT₃ receptor antagonist is ondansetron.

[0431] In one embodiment, an NK1 receptor antagonist is administered prior to the bispecific antibody. In one embodiment, the NK1 receptor antagonist is administered in an amount of between about 100 mg and 300 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of between about 125 mg and 200 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of between about 125 mg and 175 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of about 150 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount of 150 mg. In one embodiment, the NK1 receptor antagonist is aprepitant, fosaprepitant, or combination thereof. In one embodiment, the NK1 receptor antagonist is fosaprepitant dimeglumine.

[0432] Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details can be made without departing from the invention as described in the appended claims.

[0433] Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details can be made without departing from the invention as described in the appended claims.

EXAMPLES

[0434] Examples are provided below to illustrate the methods described throughout. These examples are not meant to constrain the methods to any particular application or theory of operation. For all constant region positions discussed, numbering is according to the EU index as in Kabat (Kabat etal., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference). A skilled artisan will appreciate that this convention consists of nonsequential numbering in specific regions of an immunoglobulin sequence, enabling a normalized reference to conserved positions in immunoglobulin families. Accordingly, the positions of any given immunoglobulin as defined by the EU index will not necessarily correspond to its sequential sequence.

[0435] General and specific scientific techniques are outlined in U.S. Pat. Appl. Pubs. 2015/0307629, 2014/0288275, 2014/294823, 2016/0229924, and 2016/0355608.

EXAMPLE 1

XmAbl4045 Treatment Plan

[0436] This is a multicenter, open-label, multi-dose, single-arm, Phase 1, dose-escalation study of XmAb 14045. The dose of XmAb 14045 will be administered IV over a 2-hr infusion period. Modifications of the dose infusion period can occur based on any observed infusion toxicity.

[0437] XmAb 14045 is a humanized bsAb that binds both CD 123 and CD3. The XmAb 14045 pharmaceutical composition is a sterile liquid supplied in single-use glass vials. Each vial is filled with 1.1 mL of pharmaceutical composition that contains 1.0 mg/mL (± 5%) of XmAbl4045, in lOmM sodium citrate, 150mM sodium chloride, and 0.04% (w/v) polysorbate-80 at pH 5.5. Each product vial is intended to deliver 1.0 mL of drug solution.

[0438] IV Solution Stabilizer will be supplied in single-use glass vials. Each vial is filled with 10.5 mL of a solution containing 250 mM sodium citrate, and 1.0% (w/v) polysorbate- 80 at pH 5.5. Each product vial is intended to deliver 10.0 mL of drug solution.

[0439] Prior to administration, XmAb 14045 will be diluted to the required final concentration in one or more ethylene/polypropylene copolymer infusion bags (Excel™, B. Braun) containing 250 mL 0.9% Sodium Chloride Injection, USP after replacement of 10 mL with 10.0 mL IV Solution Stabilizer. After dilution, the bag containing XmAbl4045 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.

[0440] Prior to each dose of XmAb 14045, human subjects should receive:

• Dexamethasone 10-20 mg IV, approximately 1 hour prior to each weekly dose of XmAb 14045 in Parts A and B. In Part C, dexamethasone should be administered before the C1D1 and C1D15 dose and may be omitted on subsequent doses, unless significant CRS symptoms occur. • Acetaminophen 650 mg orally, approximately 30 min before infusion

• Diphenhydramine 25 mg PO or IV, approximately 30-60 min before infusion

[0441] This study will be conducted in 5 parts: Part A, dosing cohorts that establish a MTD/RD for the first infusion; Part B, dosing cohorts that establish a MTD/RD for the second (and subsequent infusions) after human subjects receive their first infusion at the dose determined in Part A; Part C, dosing cohorts that establish an MTD/RD for a dosing schedule of 3 times per week for the 1^st 2 weeks of therapy (Induction), followed by weekly dosing (Consolidation); and Parts D and E, dosing cohorts that establish an MTD/RD for a dosing schedule of 3 (Part D) or 4 (Part E) times per week for the first week of therapy (Induction) followed by weekly dosing (Consolidation) using continuous step-up dose increases during Cycle 1 (Days 1-28), and, if tolerated and desired, into Cycle 2.

[0442] Part A: Human subjects will be enrolled in up to 15 consecutive dose cohorts (0.003, 0.01, 0.03, 0.075, 0.15, 0.3, 0.5, 0.75, 1.3, 2.3, 4.0, 7.0, 12.0, 20.0, and 35.0 pg/kg) with initial accelerated titration for the first 3 cohorts. The first 3 cohorts will consist of 1 human subject each until there is evidence of a > Grade 2 toxicity, and the remaining cohorts will enroll at least 3 human subjects each in a classic 3+3 dose escalation scheme. Human subjects will be admitted for 3 days for the first and fourth doses (and 2 days for the second dose, if admission is necessary to collect serum cytokines and inflammatory factors for the 8-hr post infusion time point) for observation, PK, PD, and laboratory assessment. Within each ascending dose cohort (Cohorts 1A-8A), human subjects will be given XmAb 14045 IV over 2-hr, once every 7 days, for a total of 4 doses in each 28-day cycle. The initial treatment period will include 2 cycles.

[0443] Part B: An attempt will be made to escalate to higher doses for the second and subsequent drug infusions. Human subjects will be admitted for the first and fourth dose as in Part A, but also for the escalated second dose (Day 8) for observation, PK, PD, and cytokine assessment.

[0444] Part C: Human subjects will be enrolled in up to 8 consecutive dose cohorts, with the initial dose level based on the highest tolerable dose level achieved in Part A or B at that point in time. Administration of XmAb 14045 will be divided into Induction (C1D1-C1D14) and Consolidation phases (C1D15 and after). Induction will consist of 62-hour infusions (Days 1, 3, 5, 8, 10, and 12) starting at a dose one-third of the highest weekly dose level from Part A, that has been assessed as tolerable/safe by the DERC at the time Part C was initiated, and Consolidation will consist of weekly 2-hour infusions (C1D15 and C1D22, as well as all subsequent infusions) at the full highest weekly dose level from Part A, that has been assessed as tolerable/safe by the DERC at the time Part C was initiated.

[0445] Part C cohorts will enroll at least 3 human subjects each in a classic 3+3 dose escalation scheme. Human subjects will be admitted for 3 days during the first through second doses, as well as for the eighth dose for observation, PK, PD, and laboratory assessment.

[0446] If all 3 human subjects tolerate the initial Part C dosing cohort without experiencing DLT (and the DERC agrees), enrollment will begin on the next higher cohort, as defined in Table 4. The initial treatment period will include 2 cycles. After the MTD and/or RD dose is reached, the cohort can be expanded by up to an additional 12 human subjects to obtain additional safety data. If a MTD/RD is identified in the Consolidation phase, escalation in the Induction phase can continue until an MTD/RD is also identified.

[0447] Parts D and E: Human subjects may be enrolled in Parts D and E dosing cohorts per Table 5 and Table 6, respectively. The treatment will be divided into Induction (C1D1-C1D7) and Consolidation phases (C1D8 and after). Induction will consist of either 3 (Part D) or 4 (Part E) two-hour infusions during the first week of Cycle 1 (Days 1, 3, and 5 or Days 1, 3, 4, and 5) starting at a C1D1 dose of 0.75 pg/kg, and Consolidation will consist of weekly 2-hour infusions (Days 8, 15, and 22) as well as all subsequent infusions. During Cycle 1 (Days 1-28), each dose will increase by 50% over the previous dose, unless Grade 3 CRS is observed. Enrollment of Part D cohorts may occur in parallel with Parts A, B, C, and E. Enrollment of Part E cohorts may occur in parallel with Parts A, B, C, and D, with the exception that Cohort IE may not open until Cohort ID has been found to be tolerable by the DERC.

[0448] If all 3 human subjects tolerate Cohort ID without experiencing a DLT (and the DERC agrees), enrollment will begin on the next higher Part D cohort (2D), or alternatively Cohort IE, as defined in Table 5 and Table 6. The initial treatment period will include 2 cycles. After the MTD and/or RD dose is reached for either Part D or E, the cohort may be expanded by up to an additional 12 human subjects to obtain additional safety data. If an MTD/RD is identified in the Consolidation phase, escalation in the Induction phase may continue until an MTD/RD is also identified.

[0449] The dose to be administered to the human subject for all cohorts will be calculated based on baseline (Day -1) weight measurement in kg. Following the first dose, subsequent doses will only be modified if the human subject’s weight changes by more than 10% from the Day - 1 weight at which point it will be recalculated for that infusion day using the current weight. For human subjects whose weight exceeds 100 kg, the dose of XmAb 14045 will be calculated based on a weight of 100 kg and will NOT be calculated based upon the human subject’s actual body weight.

[0450] A dose escalation schema will be employed in single dose level cohorts for Part A and sequentially increasing second and subsequent infusion dosing cohorts for Part B. Dose escalation will continue in both Parts A and B until the MTD and/or RD for further study has been identified or until a dose of 35.0 pg/kg has been reached, whichever comes first.

[0451] Human subjects will receive two 28-day cycles of therapy (8 weekly doses in Part A and B; 3 doses per week ^c 2 weeks followed by 6 weekly doses for Part C; 3 doses per week x 1 week followed by 7 weekly doses for Part D; or 4 doses per week ^c 1 week followed by 7 weekly doses for Part E). In the absence of unacceptable study drug -related toxicity, human subjects may receive additional cycles of therapy if there is clinical benefit (as assessed by the Investigator). Doses will be administered on Days 1, 8, 15, and 22 of each cycle, except as noted for Parts C, D, and E. Dosing may be delayed in the presence of drug-related toxicities. Human subjects who complete 4 doses for Parts A and B; 8 doses for Part C; 6 doses for Part D; or 7 doses for Part E of XmAb 14045 and undergo the planned safety evaluations through Day 22 (+ up to 2 days to allow for minor scheduling changes and dosing delays) will be considered to have sufficient safety data/follow-up for identification of DLTs. If the MTD and/or RD are not reached, dose escalation to the next dose cohort will occur following review by the DERC. Human subjects will be followed for at least 4 weeks after treatment is discontinued or until disease progression requiring therapy, stem cell transplantation or the occurrence of death, whichever comes first. Following the last study visit, information regarding disease status and survival will be collected by the investigational sites by either clinic visit, email, or telephone contact at 6 and 12 months, or until the occurrence of death. Dose Escalation Scheme Part A

[0452] In Part A, dose level increases will initially proceed according to an accelerated titration design (see Table 1). This design allows for more efficient dose escalation while maintaining safety standards by implementing conservative triggers for cohort expansion during the accelerated escalation phase, and can limit the number of human subjects exposed to potentially sub-therapeutic doses of XmAb 14045.

Table 1. Study Cohorts - Part A

MTD = maximum tolerated dose. [0453] During the initial accelerated dose escalation phase (Cohorts 1A, 2A, and 3A), dose escalation can occur after treatment of 1 human subject per cohort provided that there is no > Grade 2 toxicity during Cycle 1 and the human subject has met minimum safety assessment requirements (see Table 2). When a human subject experiences a > Grade 2 toxicity during the dose escalation safety assessment period, the accelerated escalation phase will end, the standard dose escalation phase will begin, and the cohort in which the event(s) occurred will be expanded to a total of at least 3 human subjects (2 additional human subjects will be enrolled).

Table 2. Dose Escalation Scheme

DLT= dose-limiting toxicity; MTD= maximum tolerated dose

[0454] From this cohort forward (or beginning with Cohort 4A [0.075 mg/kg], whichever comes first) the standard 3+3 dose escalation rules will apply:

[0455] If zero of 3 human subjects have a DLT, then dose escalation to the next level will occur.

[0456] If 1 of 3 human subjects has a DLT, then the cohort will be further expanded to a total of 6 human subjects or until a second human subject in the cohort experiences a DLT. If there are no additional human subjects with a DLT, then dose escalation to the next higher dose level will occur.

[0457] The MTD is defined as the highest dose level at which no more than 1 human subject experiences DLT out of 6 human subjects assessable for toxicity at that dose level. Any cohort with 2 or more human subjects experiencing a DLT will have exceeded the MTD and there will be no further dose escalation. The dose level below the cohort at which 2 or more human subjects with DLT occurred will be expanded to at least 6 to delineate the MTD.

[0458] Before a dose-escalation decision can be reached, at least 1 human subject (in the accelerated dose escalation phase of the study) or 3 human subjects (in the standard escalation phase of the study) must meet all requirements for dose escalation safety assessment.

[0459] For the purpose of determining the incidence of DLT and defining the MTD and/or recommended dosing of XmAb 14045 for future study, only human subjects who experience DLT and those with sufficient safety data/follow-up will be evaluated. Human subjects who complete 4 doses of XmAb 14045 and undergo the planned safety evaluations through Day 22 (up to +2 days to account for minor scheduling changes and dosing delays) will be considered to have sufficient safety data/follow-up. Human subjects who withdraw from study before completing Day 22 of treatment for reasons unrelated to study drug toxicity will be considered to have inadequate data to support dose escalation. In such cases, replacement human subjects will be enrolled to receive the same dose of XmAbl4045 as the human subjects who withdraw prematurely.

[0460] The decision to advance dosing to the next cohort level will be made by the DERC after review of all required dose escalation safety assessment data from human subjects in a cohort. PK and ADA data cannot be routinely available during the safety assessment period as these samples can be batched for analysis so that a more uniform drug exposure analysis and ADA analysis can be performed across all study samples. However, if a human subject safety issue arises and the treating physician feels that information around drug exposure and/or ADA analysis would be useful information in determining the treatment plan for the human subjects, PK and ADA analysis can be performed on the human subject samples that have been collected to date.

[0461] Once the MTD (or RD for further study) is identified, the MTD/RD dose level can be further expanded up to an additional 12 human subjects (up to a total MTD/RD cohort of 18 human subjects) to further assess safety and PK.

[0462] The dose escalation scheme can be modified (e.g., smaller increases or decreases in dose level can be permitted, additional human subjects in a cohort can be enrolled, infusion duration and scheduling can be modified) based on available PK and PD data, and the type and severity of toxicities observed in this trial, upon agreement of the DERC. Dose Escalation Scheme- Part B—

[0463] In Part B, the Day 1 dose will be fixed at the level determined in Part A. The second dose will be escalated and maintained for subsequent doses. Dosing cohorts will be defined relative to the MTD/RD determined in Part A.

Table 3: Study Cohorts- Part B

MTD= maximum tolerated dose; RD= recommended dose; X= Part A MTD/RD

[0464] Dose escalation will proceed as described for the standard 3+3 scheme noted in Part A and with the same dosing levels (0.003, 0.01, 0.03, 0.075, 0.15, 0.3, 0.5, 0.75, 1.3, 2.3, 4.0, 7.0, 12.0, 20.0, and 35.0 pg/kg) however the Day 1 infusion dose will always be the MTD/RD determined in Part A (denoted as “X” in Table 3). Dose escalation on each Part B cohort will be based on this starting point. For example, if the MTD/RD from Part A is 0.03 pg/kg, the first infusion in Cohort IB will be 0.03 pg/kg and the second and subsequent infusions will be at 0.075 pg/kg (i.e. X+l).

[0465] A minimum of 3 human subjects will be enrolled in each cohort. As in Part A, no two human subjects will start treatment with XmAb 14045 on the same day. If all 3 human subjects tolerate a cohort without experiencing DLT (and the DERC agrees), enrollment will begin on the next higher cohort. If at any time through Day 22 (up to + 2 days to account for minor scheduling changes and dosing delays) a DLT occurs, or if the Medical Monitor determines that additional safety data is needed for a given dose cohort, 3 additional human subjects will be added to the cohort. If there is an additional DLT among the 6 human subjects on the cohort, the previous dosing cohort will be expanded to 6 to establish a MTD and/or RD. If this occurs on Cohort IB, the next 3 human subjects will be enrolled on Cohort -IB. If there are no further DLTs among the 3 additional human subjects, another 3 human subjects will be added to the cohort. If there is an additional DLT, then the MTD/RD and schedule established in Part A will be recommended for further study.

[0466] The dose escalation scheme can be modified (e.g., smaller increases or decreases in dose level can be permitted, additional human subjects in a cohort can be enrolled, infusion duration and scheduling can be modified) based on available PK and PD data, and the type and severity of toxicities observed, upon agreement of the DERC.

Dose Escalation Scheme- Part C

[0467] Accrual into Part C cohorts will begin as soon as feasible. Administration of XmAbl4045 will be divided into Induction (C1D1-C1D14) and Consolidation phases (C1D15 and after). Induction will be 3 infusions per week (Cycle 1, Days 1, 3, 5, 8, 10 and 12) (Induction dose), given IV over 2 hours. From C ID 15 on, administration will be once a week (Consolidation), also administered over 2 hours. The Induction phase of the first Part C cohort will start at a dose of one-third of the highest once a week dose level from Part A (not to exceed a C1D1 dose of 0.75 pg/kg). that has been assessed as tolerable/safe by the DERC (0.43 pg/kg) and Consolidation will consist of once a week 2-hour infusions (C1D15 and C1D22, as well as all subsequent infusions) at the full highest once a week dose level from Part A, that has been assessed as tolerable/safe by the DERC (1.3 pg/kg).

[0468] See Table 4 for specific doses and planned cohort dose escalation.

Table 4: Study Cohorts- Part C

[0469] A minimum of 3 human subjects will be enrolled in each cohort. As in Part A and B, no two human subjects will start treatment with XmAb 14045 on the same day. If all 3 human subjects tolerate a cohort without experiencing DLT (and the DERC agrees), enrollment will begin on the next higher cohort. If at any time through Day 22 (up to +2 days to account for minor scheduling changes and dosing delays) a DLT occurs, or if the Medical Monitor determines that additional safety data is needed for a given dose cohort, 3 additional human subjects will be added to the cohort. If there is an additional DLT among the 6 human subjects on the cohort, the previous dosing cohort will be expanded to 6 to establish a MTD and/or RD.

[0470] The dose escalation scheme can be modified (e.g., smaller increases or decreases in dose level can be permitted, additional human subjects in a cohort can be enrolled, infusion duration and scheduling can be modified) based on available PK and PD data, and the type and severity of toxicities observed, upon agreement of the DERC.

[0471] Changes that can only be made with a protocol amendment will include:

• Dose escalation in either the Induction or Consolidation phases that are more rapid than shown in Table 4.

• Administration of more than 4 infusions per week

• Administration of more than 2 weeks of greater than once a week dosing • Exceeding the highest tolerable C ID 1 dose achieved in Part A as the C ID 1 induction dose in Part C.

Dose Escalation Scheme- Parts D and E

[0472] Parts D and E incorporate the decreased C1D1 dose to improve safety; increase drug exposure early in treatment while limiting the duration of frequent dosing from 2 weeks to 1 week to address practical administration concerns; and limit step-up dosing to 50% or smaller increases. Accrual to Part D will begin immediately, accrual to Part E may begin after Cohort ID or Mod ID has been found to be tolerable by the DERC, and accrual to Parts D and E may occur concurrently. Accrual to Parts A, B, and C are currently suspended.

[0473] Human subjects will be initially enrolled in Cohort ID (Table 5). The treatment will be divided into Induction (C1D1-C1D7) and Consolidation phases (C1D8 and after). Induction will consist of either 3 doses (Part D) or 4 doses (Part E; Table 6) per week infused over 2 hours during the first week of Cycle 1 (Days 1, 3, and 5 or Days 1, 3, 4, and 5) starting at a C1D1 dose of 0.75 pg/kg. and Consolidation for either Part D or E will consist of weekly 2-hour infusions (Days 8, 15, and 22) as well as all subsequent infusions. During Cycle 1 (Days 1-28), each dose will increase by 50% over the previous dose. Human subjects may be enrolled in Modfied ID.

Table 5: Study Cohorts- Part D

Escalation Cohorts (Dose-Escalation Increments of 50%)

Note: Step-up dosing in Part D may continue beyond Cohort 4D in dose increments of approximately 50%.

De-escalation Cohort (Dose-Escalation Increments of 25% if Grade 3 CRS is Observed)

CRS = cytokine release syndrome. All doses are in pg/kg. Modified Part D Escalation Cohorts

CRS = cytokine release syndrome. All doses are in mg/kg.

Table 6: Study Cohorts- Part E

Escalation Cohorts (Dose-Escalation Increments of 50%)

Note: Step-up dosing in Part E may continue beyond Cohort 3E in dose increments of approximately 50%.

CRS = cytokine release syndrome. All doses are in pg/kg. Modified Part E Escalation Cohorts

CRS = cytokine release syndrome. All doses are in mg/kg.

[0474] A minimum of 3 human subjects will be enrolled in each cohort. As in Parts A, B, and C, no 2 human subjects will start treatment with XmAb 14045 on the same day. If all 3 human subjects tolerate Cohort ID without experiencing a DLT, and the DERC agrees that further dose escalation is warranted, enrollment will begin on either Cohort 2D or IE or Mod IE, as desired.

[0475] If Cohorts ID and/or IE are tolerated, further escalation may be considered by the DERC. This would occur in the following manner:

• Dose escalation would occur on C2D1 and would be an additional 50% escalation beyond the previous cohort found acceptable by the DERC.

• A minimum of 3 human subjects will be enrolled in each cohort, and no 2 human subjects will start treatment with the increased dose of XmAb 14045 on the same day.

• The DLT period would be extended to include the day of the escalated dose plus 2 additional days.

• If all 3 human subjects tolerate a cohort without experiencing a DLT, and the DERC agrees that further dose escalation is warranted, then C2D8 will be escalated by 50% over the C2D1 dose, and the DLT period would again be extended to the day of escalated dosing plus 2 days (C2D10).

• Escalation may continue in this manner as found acceptable by the DERC, but may not continue past a dose of 35 pg/kg. [0476] If Cohort ID or IE are not tolerated, the DERC may consider several options:

• If excess CRS is observed with the C1D1 dose, it may be administered as a split dose (ie, the total dose of 0.75 pg/kg may be given as two 2-hour infusions on C ID 1 and C1D2).

• If excess CRS is seen with doses after C1D1, enrollment to the de-escalation Cohort -ID may begin. If excess toxicity continues, de-escalation to Cohort -2D may occur.

• The DERC may make additional changes to the dose and schedule in accordance with the guidelines below.

[0477] If at any time through Day 22 (up to + 2 days to account for minor scheduling changes and dosing delays) a DLT occurs, or if the Medical Monitor determines that additional safety data are needed for a given dose cohort, 3 additional human subjects will be added to the cohort. If an additional DLT occurs among the 6 human subjects on the cohort, the previous dosing cohort will be expanded to 6 human subjects to establish an MTD and/or RD.

[0478] The dose-escalation scheme may be modified (eg, smaller increases or decreases in dose level may be permitted; up to an additional 12 human subjects may be enrolled to a cohort to obtain additional safety data; infusion duration and scheduling may be modified, including split dosing as defined above) based on available PK and PD data, and the type and severity of toxicities observed, upon agreement of the DERC.

[0479] Changes that can only be made with a protocol amendment include the following:

• Dose escalation in either the Induction or Consolidation phases that are more rapid than shown in Table 5 or Table 6

• Administration of more than 4 infusions per week

• Administration of more than 2 weeks of greater-than-weekly dosing

Results:

[0480] At data cut-off, 95 human subjects have been treated, 94 with relapsed/refractory AML and 1 with B-ALL. Human subjects had a median age of 62 years (range of 18-85 yrs) and were heavily pretreated (median of 3 prior therapies [range 1-8]). CRS or its component symptoms were the most common treatment-emergent adverse event (TEAE). CRS episodes began within approximately 1-4 hours of the start of drug infusion and occurred in 76 of 95 human subjects (80%). Grade >3 CRS was only seen at doses of 1,300 ng/kg or 2,300 ng/kg, and on the first dose, with one exception. No myelosuppression requiring dose modification was observed. Two human subjects had evidence of mild tumor lysis syndrome. [0481] Based on published data from Dec. 2018, from a subset of these human subjects administered according to Cohorts 9 A, 10A, IB and 2B, single agent antileukemic activity was documented with a best response of CR (2) or CRi (3) in 5/18 human subjects (CR/CRi rate 27.8%) treated at the two highest dose levels studied to date (1,300 ng/kg or 2,300 ng/kg once a week); no CR, CRi, or morphologic leukemia-free state (MLFS) responses were seen at lower doses. Antileukemic activity occurred quickly; all responders had achieved at least an MLFS response after 4 doses (1 cycle). Stable disease lasting for greater than 3 months occurred in an additional 3 human subjects. Reduction of marrow blasts occurred in 56% of human subjects. Three responders were bridged to stem cell transplantation. Median duration of response is 15.4 weeks(range 9.1-20.3+) . Excluding CRS-related events, additional TEAEs occurring in >10% of human subjects included chills (39%), fever (27%), tachycardia (21%), increased ALT (18%), anemia (17%), hypotension (17%), fatigue (15%), hypertension (14%), increased AST (12%), lymphopenia (11%), nausea (11%), and vomiting (11%). Recurrent infusion-related back or head pain occurred in 4 human subjects and were managed with analgesics. Grade 3 transaminase elevation occurring within 24 hours of XmAbl4045 infusion was seen in 5 human subjects with all resolved within 7 days, and most often occurring with the first dose of XmAb 14045. Only one human subject developed hyperbilirubinemia (Grade 1). The Dec. 2018 published data subset had 66 human subjects; the median age was 61 years (range 18-85); 46% were female; 100% had an AML diagnosis; median time since initial diagnosis was 49 weeks (range 3-879); the median number of prior therapies is 3 (range 1-8); 30% of human subjects had a history of hematopoietic stem cell transplantation; 86% were refractory to last therapy; 5% of human subjects had an ELN Risk Category of Favorable; 33% of human subjects had an ELN Risk Category of Intermediate; 53% of human subjects had an ELN Risk Category of Adverse; 9% of human subjects had an ELN Risk Category of Unknown. 11% of human subjects had secondary leukemia. From the data, it can be seen that XmAb 14045 at the dose and schedule studied was well tolerated and had clinical activity in relapsed AML. The Antibody construct with full-length Fc region permitted weekly dosing. Cytokine release syndrome was the primary toxicity of XmAb 14045; management with premedication and the use of a priming dose and step-up dosing was effective in limiting its severity. No clear evidence of myelosuppression was observed even after prolonged administration. Clinically significant responses were achieved in relapsed/refractory AML allowing allogeneic stem cell transplant. [0482] Based on published data from Dec. 2018, from a subset of these human subjects, CRS severity by infusion (Cohorts 9A-2B) is described in FIG. 17. No premedication was given for Cohorts 1A-3A. Standard premedications were added for Cohort 4A (75 ng/kg): Dexamethasone 10-20 mg IV; Diphenhydramine 50 mg po; Acetaminophen 500 mg po. All episodes of CRS began within 1-4 hours of the start of drug infusion and usually resolved within 1-4 hours. CRS was generally more severe on the initial dose, accounting for most > Grade 3 episodes.

[0483] Based on published data from Dec. 2018, from a subset of these human subjects, Peak Serum IL-6 by infusion is described in FIG. 18. Based on published data from Dec. 2018, from a subset of these human subjects, percentage change in bone marrow blasts from pretreatment baseline is described in FIG. 19. Based on published data from Dec. 2018, from a subset of these human subjects, the time to treatment discontinuation is described in FIG. 20. Based on published data from Dec. 2018, from a subset of these human subjects, CR and CRi responder data is described in FIG. 21. Based on published data from Dec.

2018, from a subset of these human subjects, blast CD 123 expression, for responders versus non-responders, is described in FIG. 22.

[0484] Based on data cutoff of (October 28, 2020), 112 subjects have been dosed. Human subjects had a median age of 64 years (range of 18-85 yrs) and were heavily pretreated (median of 3 prior therapies [range 0-8]). 53% of the human subjects are female. The time since initial diagnosis is 48 weeks [range 3-896 weeks]. Primary toxicity is cytokine release syndrome (CRS) and occurred in 60.7% of human subjects. Efficacy analysis includes all patients who have: a) have completed at least the first cycle (4 doses for Parts A and B; 8 doses for Part C; 6 doses for Part D; and 7 doses for Part E); and b) had at least one post treatment disease assessment (occurs at the end of odd-numbered cycles). 54 human subjects across Cohorts 8A-1D are evaluable. The objective response rate (CR + CRi+MLFS+PR) dosed at >0.75 pg/kg = 14.8% (8/54 human subjects). ORR in blast count < 25% population = 25.9% (7/27 human subjects). Stable Disease occurred in an additional 38 human subjects (70.4%). Reduction of marrow blasts occurred in 52% of human subjects.

[0485] IL-6 levels in human subjects can be used as a predictive biomarker of CRS, in particular when IL-6 levels are greater than 1000 pg/mL. In cohorts with a priming dose of 0.75 microg/kg and weekly step-up dosing, IL-6 peaks were observed at the priming dose and at the weekly step up dose. In cohorts with a priming dose of 0.75 microg/kg and every other day dosing, CRS was observed at the priming dose.

[0486] In cohorts with a priming dose of 0.75 microg/kg or less, an IL-6 inhibtor (tocilizumab) was administered to approximately half of the patients after that priming dose. An IL-6 inhibtor (tocilizumab) was not administered to patients in cohorts with a priming dose of 0.5 microg/kg or less after that priming dose.

[0487] Based on data cutoff of (October 28, 2020), 19 human subjects have been enrolled in Cohort ID. Efficacy is evaluable for 10 of those 19 human subjects. Efficacy & DLTs are provided in the following table:

Cohort ID

CR+CRi+MLFS+PR (I CR)

Evaluable (<=25% blast) 2

CR+CRi+MLFS+PR (<=25 %) (1)

Gr 3 DIC; LFTs; Amylase; Extravasation;

DLTs ARDS

Amylase/Lipase

Xencor Presents Updated Data from the Phase 1 Study of Vibecotamab in Acute Myeloid Leukemia at the 2020 ASH Annual Meeting

[0488] MONROVIA, Calif. -(BUSINESS WIRE)- Xencor, Inc. (NASDAQ :XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune disease, today announced updated data from its ongoing Phase 1 dose-escalation study of vibecotamab (XmAb®14045), a CD123 x CD3 bispecific antibody, in patients with relapsed or refractory acute myeloid leukemia (AML). The data were presented in an oral session at the 62nd American Society of Hematology (ASH) Annual Meeting by Farhad Ravandi, M.D., Professor of Medicine and Chief of the Section of Acute Myeloid Leukemia in the Department of Leukemia at the University of Texas - MD Anderson Cancer Center.

[0489] "Vibecotamab has meaningful clinical activity in relapsed AML, and responses appear to be associated with lower baseline disease burden, indicated by patients with lower blast percentages and lower PD1 expression on CD8+ and CD4+ T cells. This suggests possible strategies to select patients most likely to respond," said Dr. Ravandi. "Responses including CRs and CRis have been durable, lasting many months, in several patients."

[0490] "Additionally, we continue to observe that vibecotamab's primary toxicity, CRS, is generally mild-to-moderate in severity when observed, and our mitigation strategy, which includes a combination of dose-modifying measures, has been effective in limiting its severity," said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer.

"With a manageable profile and encouraging potential in certain patient populations, such as myelodysplastic syndromes and AML with minimal residual disease, we are now planning our next steps to develop vibecotamab for these patients, along with our partner Novartis."

Key Highlights from the Presentation

[0491] At data cut off on October 28, 2020, 112 patients with relapsed or refractory AML had received vibecotamab. Patients were a median of 64 years old and were heavily pretreated, having had a median of three prior therapies and 30% (n=34) with a history of allogeneic hematopoietic stem cell transplantation. 86% of patients (n=96) were refractory to their last therapy, and 62% (n=69) were categorized as adverse risk at diagnosis by the European LeukemiaNet (ELN 2017) system. The study is ongoing, and additional patients are being enrolled.

[0492] Cytokine release syndrome (CRS) was the most common toxicity occurring in 61% of patients (n=68), and 9% of patients (n=10) experienced CRS at Grade 3 or higher. The majority of CRS was observed in the first dose and was generally manageable with premedication. Additional mitigation measures included selecting a lower priming dose, avoiding weekly dose step-up, and more frequent dosing in the first week to allow a higher cumulative exposure and to avoid the potential CD 123 antigen sink. There was no evidence of drug related myelosuppression. Neurological events were infrequent and primarily Grade 1 and Grade 2 headaches.

[0493] The efficacy analysis included 54 evaluable patients who received a dose of at least 0.75 mcg/kg, completed at least the first cycle of treatment and had at least one post treatment disease assessment. Two patients achieved complete remission (CR), and three patients achieved a CR with incomplete hematologic recovery. Additionally, two patients reached a morphologic leukemia-free state, and one patient experienced partial remission, as assessed by the investigator. The overall response rate (ORR) was 15% (n=8/54). [0494] Biomarker analyses suggest that low baseline leukemic burden and low PD- 1 expression on CD4+ and CD8+ T cells are independent predictors of response. Seven responders had a baseline blast count less than or equal to 25% blasts in bone marrow. The ORR increased to 26% (n=7/27) when using this threshold to define the population with low disease burden for the analyses.

[0495] The presentation will be archived under "Events & Presentations" in the Investors section of the Company's website located at www.xencor.com.

About Vibecotamab

[0496] Vibecotamab (XmAb®14045) is a tumor-targeted antibody that contains both a CD 123 binding domain and a cytotoxic T-cell binding domain (CD3) in a Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and other CD 123-expressing hematologic malignancies. An XmAb Bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on vibecotamab. CD 123 is highly expressed on AML cells and leukemic stem cells, and it is associated with poorer prognosis in AML patients. Engagement of CD3 by vibecotamab activates T cells for highly potent and targeted killing of CD 123-expressing tumor cells.

About Xencor, Inc.

[0497] Xencor is a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune diseases. Currently, 18 candidates engineered with Xencor's XmAb® technology are in clinical development internally and with partners. Xencor's XmAb antibody engineering technology enables small changes to the structure of monoclonal antibodies resulting in new mechanisms of therapeutic action. For more information, please visit www.xencor.com.

Forward-Looking Statements

[0498] Statements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of applicable securities laws, including, but not limited to, the quotations from Xencor’s chief medical officer and any statements relating to the timing, expectations and success of clinical trials, product candidates and Xencor's research and development programs. Such statements involve known and unknown risks, uncertainties and other factors that may cause actual results, performance or achievements and the timing of events to be materially different from those implied by such statements, and therefore these statements should not be read as guarantees of future performance or results. Such risks include, without limitation, the risks associated with the process of discovering, developing, manufacturing and commercializing drugs that are safe and effective for use as human therapeutics and other risks described in Xencor's public securities filings. For a discussion of these and other factors, please refer to Xencor's annual report on Form 10-K for the year ended December 31, 2019 as well as Xencor's subsequent filings with the Securities and Exchange Commission. All forward-looking statements are based on Xencor's current information and belief as well as assumptions made by Xencor. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Xencor undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof, except as required by law.

EXAMPLE 2

In Vitro Antitumor Efficacy

[0499] T cell-dependent cytotoxicity of XmAbl4045 against CD 123 -positive (KGla and Kasumi-3) and CD 123 -negative (Ramos) cell lines was examined using purified PBMC or T cell-depleted PBMC as effector cells. In addition, T cell activation was assessed by quantifying CD69 induction (a marker of lymphocyte activation) on both CD4+ and CD8+ T cells. XENP13245, an anti-RSV x anti-CD3 bsAb, was used as a control. XmAbl4045, but not XENP13245, showed robust and potent killing of the CD123⁺ KG-la (EC50 of 0.28 ng/mL; see FIG 8) and Kasumi-3 (EC 50 of 0.01 ng/mL) cell lines when supplied with human PBMC as an effector population along with robust CD69 induction in both CD4⁺ and CD8⁺ T cells. However, when T cells were depleted from PBMC (FIG 8), XmAb 14045 failed to induce killing or induce CD69 expression on T cells. XmAb 14045 did not induce cytotoxicity of the CD 123 Ramos B cell line or induce T cell activation as measured by CD69 expression.

[0500] A series of studies was performed to evaluate the functionality of T-cells derived from AML human subject-derived PBMC. In particular, the ability of XmAb 14045 to mediate RTCC towards various target populations found within, or added to, the AML samples was investigated. The target populations included: 1) a CD123hiCD33hi population that arises in both AML PBMC and healthy PBMC upon incubation in culture for several days; 2) putative AML blast cells identified in the samples by flow cytometry; and 3) added KGla AML cells. CD123- dependent T cell activation was measured by CD25 and Ki-67 upregulation on T cells. CD 123-dependent target cell killing was monitored using annexin-V staining and by monitoring the reduction of counted blast cells.

[0501] Multiple AML human subject PBMC and normal PBMC samples were tested for XmAb 14045- induced target cell killing and T cell activation. Both AML and normal PBMC contained CD123hi_gh and CD33hi_gh (CD123hiCD33hi) cells; therefore, this population likely does not represent leukemic blast cells, but does serve as a useful surrogate target population. After 6 days incubation of PBMCs with XmAb 14045, dose-dependent partial depletion of CD 123hiCD33hi cells was induced in AML human subject-derived PBMC, accompanied by CD4⁺ and CD8⁺ T cell activation and proliferation.

[0502] In a second set of studies, a modified staining process was used to detect leukemic blast cells in PBMC from a human subject with AML. AML PBMCs or PBMCs from a normal control donor were incubated for 24 or 48 hours with XmAbl4045 at concentrations of 9 or 90 ng/mL and the putative blast cell number was obtained by flow cytometry. XmAbl4045 reduced blast number by approximately 80% at 48 hours (FIG 11). As expected, no blasts were seen in the normal donor PBMCs. This result was extended by assessing a total of 6 AML human subjects. XmAb 14045 at concentrations of 9 or 90 ng/mL or XENP13245 (anti-RSV x anti-CD3) as a negative control. XmAbl4045 depleted this putative blast cell population in AML PBMC at 48 hours by approximately 20% to 90%, with no apparent dependence on the number of target cells or T cells in the samples (see FIG 12). The depletion was again associated with activation and proliferation of T cells.

[0503] In a third set of studies, killing of an AML tumor cell line by AML human subject T cells was assessed. PBMC from one AML donor was mixed with the CD 123 -expressing cell line KG-la in the presence of XmAbl4045 for 48 hours (see FIG 13). At 48 hours,

XmAb 14045 with AML human subject-derived PBMC induced robust apoptosis (approximately 50% annexin-V positivity), albeit still slightly lower than that induced with normal PBMC. XmAb 14045 again induced robust proliferation of both AML human subject and healthy donor CD4⁺ and CD8⁺ T cells.

[0504] In summary, XmAb 14045 induced allogeneic CD 123⁺KG-la tumor cell killing by both AML human subject-derived and normal PBMC. More importantly, XmAb 14045 induced autologous leukemic blast cell killing in PBMC from multiple AML human subject samples, suggesting that it could also stimulate depletion of leukemic blast cells in AML human subjects. Additionally, XmAb 14045 in the presence of CD123⁺ target cells induced both CD4⁺ and CD8⁺ T cell activation in AML human subject and normal PBMC, indicating that AML human subject T cells are fully functional and capable of responding to XmAb 14045.

EXAMPLE 3

Antitumor Activity in a Mouse AML Xenograft Model

[0505] The anti-tumor activity of varying doses of XmAb 14045 was examined in NSG mice that were engrafted systemically with KGlaTrS2 cells and normal human PBMCs. KGlaTrS2 cells are derived from the AML cell line KG la, and have been engineered to express luciferase to allow quantification of tumor burden. Mice received lxlO⁶ KGlaTrS2 cells IV on Day 0. Twenty-two days after injection of KGlaTrS2 cells, mice were engrafted intraperitoneally (IP) with lOxlO⁶ PBMC and were treated with 0.03, 0.1, 0.3 or 1.0 mg/kg of XmAb 14045 or vehicle once a week for 3 consecutive weeks. Tumor burden was monitored throughout the study by in vivo imaging (FIG 14). As shown in FIG 14 and FIG 15, mice receiving KGla cells alone or KGla cells plus PBMC displayed steadily increasing AML burden overtime. In contrast, all tested dose levels of XmAb 14045 began reducing tumor burden approximately 3 days after the initial dose, ultimately reducing burden by approximately 3 orders of magnitude relative to the KG la-only control group, and significantly compared to the KGla-plus-huPBMC group. No significant differences in anti tumor activity were observed across the XmAb 14045 dose range, suggesting that even lower doses would likely still exhibit anti-tumor activity.

[0506] Peripheral blood samples were analyzed by flow cytometry. At Day 11, CD4⁺ and CD8⁺ T cell numbers were decreased in the treated mice compared to control, but by Day 20 this difference was no longer apparent, with a trend toward an increase in T cell counts, suggesting T cell activation and expansion mediated by XmAb 14045 (FIG 16). As another sign of T cell activation, PD 1 expression was consistently higher on T cell samples from the XmAb 14045 -treated groups. However, it is unclear from this study whether the increase in PD1 expression interferes with the activity of XmAb 14045.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a CD 123-expressing cancer in a human subject in need of treatment thereof, comprising administering to the human subject a bispecific anti-CD 123 x anti-CD3 antibody in at least a first phase, a second phase, a third phase and a fourth phase, wherein during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered three times a week for one week in a first, second, and third dose amounts, wherein the first dose amount is about 750 ng/kg, the second dose amount is between about 140% and 180% of the first dose amount, and the third dose amount is between about 130% and 160% of the second dose amount, wherein during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, in a dose amount between about 120% and 160% of the first phase third dose amount, wherein during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, in a dose amount between about 120% and 160% of the second phase dose amount, wherein during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week, in a dose amount between about 120% and 160% of the third phase dose amount, thereby treating the CD 123 -expressing cancer.

2. The method of claim 1, wherein during the first and/or second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

3. The method of claims 1 or 2, wherein the fourth phase has a duration of between one and four weeks.

4. The method of claims 1 or 2, wherein the fourth phase is maintained until remission.

5. The method of any one of claims 1 to 4, further comprising administering a maintenance dose.

6. The method of claim 5, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the fourth phase.

7. The method of claim 5 or 6, wherein the maintenance dose is administered once every two weeks for at least one dose.

8. The method of any one of claims 5 to 7, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

9. The method of any one of claims 1 to 8, further comprising a fifth phase wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week, to the human subject, in a dose amount between about 120% and 160% of the fourth phase dose amount.

10. The method of claim 9, wherein during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

11. The method of claims 9 or 10, wherein the fifth phase has a duration of one or two weeks.

12. The method of claims 9 or 10, wherein the fifth phase is maintained until remission.

13. The method of any one of claims 6 to 13, further comprising administering a maintenance dose.

14. The method of claim 13, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the fifth phase.

15. The method of claim 13 or 14, wherein the maintenance dose is administered once every two weeks for at least one dose.

16. The method of any one of claims 13 to 16, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

17. The method of any one of claims 11 to 16, further comprising a sixth phase wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week, to the human subject, in a dose amount between about 120% and 160% of the fifth phase dose amount.

18. The method of claim 17, wherein during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

19. The method of claim 17 or 18, wherein the sixth phase is maintained until remission.

20. The method of any one of claims 14 to 19, further comprising administering a maintenance dose.

21. The method of claim 20, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the sixth phase.

22. The method of claim 20 or 21, wherein the maintenance dose is administered once every two weeks for at least one dose.

23. The method of any one of claims 20 to 22, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

24. The method of any one of claims 18 to 23, further comprising a seventh phase wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week, to the human subject, in a dose amount between about 120% and 160% of the sixth phase dose amount.

25. The method of claim 24, wherein during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

26. The method of claim 24 or 25, wherein the seventh phase is maintained until remission.

27. The method of any one of claims 21 to 26, further comprising administering a maintenance dose.

28. The method of claim 27, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the seventh phase.

29. The method of claim 27 or 28, wherein the maintenance dose is administered once every two weeks for at least one dose.

30. The method of any one of claims 27 to 29, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

31. The method of any one of claims 1 to 8, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the second phase dose amount is about 2,500 ng/kg, wherein the third phase dose amount is about 3,800 ng/kg, and wherein the fourth phase dose amount is about 5,700 ng/kg, until remission.

32. The method of any one of the claims 9-23, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the second phase dose amount is about 2,500 ng/kg, wherein the third phase dose amount is about 3,800 ng/kg, wherein the fourth phase dose amount is about 5,700 ng/kg, and wherein the fifth phase dose amount is about 8,500 ng/kg, until remission.

33. The method of any one of the claims 23-30, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the second phase dose amount is about 2,500 ng/kg, wherein the third phase dose amount is about 3,800 ng/kg, wherein the fourth phase dose amount is about 5,700 ng/kg, wherein the fifth phase dose amount is about 8,500 ng/kg, and wherein the sixth phase dose amount is about 12,800 ng/kg, until remission.

34. The method of any one of the claims 23-30, consisting essentially of a first phase, second phase, third phase, fourth phase, fifth phase, sixth phase, and seventh phase wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the second phase dose amount is about 2,500 ng/kg, wherein the third phase dose amount is about 3,800 ng/kg, wherein the fourth phase dose amount is about 5,700 ng/kg, wherein the fifth phase dose amount is about 8,500 ng/kg, wherein the sixth phase dose amount is about 12,800 ng/kg, wherein the seventh phase dose amount is about 19,200 ng/kg, until remission.

35. The method of any one of the claims 1-8, wherein the first phase second dose amount is about 900 ng/kg, wherein the first phase third dose amount is about 1,200 ng/kg, wherein the second phase dose amount is about 1,500 ng/kg, wherein the third phase dose amount is about 1,800 ng/kg, and wherein the fourth phase dose amount is about 2,300 ng/kg, until remission.

36. The method of any one of the preceding claims, wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered intravenously.

37. The method of any one of the preceding claims, wherein during the third and/or fourth phases, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

38. A method for treating a CD 123 -expressing cancer in a human subject in need of treatment thereof, comprising administering to the human subject a bispecific anti-CD 123 x anti-CD3 antibody in at least a first, second, third, and fourth phase, wherein during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered four times a week for one week in first, second, third, and fourth dose amounts, wherein the first dose amount is about 750 ng/kg, and the second dose amount is between about 120% and 160% of the first dose amount, and the third dose amount is between about 120% and 160% of the second dose amount, and the fourth dose amount is between about 120% and 160% of the third dose amount, wherein during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week in a dose amount between about 120% and 160% of the first phase fourth dose amount, wherein during the third phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week in a dose amount between about 120% and 160% of the second phase dose amount, wherein during the fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week in a dose amount between about 120% and 160% of the third phase dose amount, thereby treating the CD 123 -expressing cancer.

39. The method of claim 38, wherein during the first phase and/or second phase and/or third phase and/or fourth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

40. The method of claims 38 or 39, wherein the fourth phase has a duration of between one and four weeks.

41. The method of claims 38 or 39, wherein the fourth phase is maintained until remission.

42. The method of claim 41, further comprising administering a maintenance dose.

43. The method of claim 42, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the fourth phase.

44. The method of claim 42 or 43, wherein the maintenance dose is administered once every two weeks for at least one dose.

45. The method of any one of claims 42 to 44, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

46. The method of claim 40, further comprising a fifth phase wherein the bispecific anti- CD 123 x anti-CD3 antibody is administered once a week for at least one week in a dose amount of between about 120% and 160% of the fourth phase dose amount.

47. The method of claim 46, wherein during the fifth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

48. The method of claims 46 or 47, wherein the fifth phase has a duration of one or two weeks.

49. The method of claims 46 or 47, wherein the fifth phase is maintained until remission.

50. The method of any one of claims 46 to 49, further comprising administering a maintenance dose.

51. The method of claim 50, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the fifth phase.

52. The method of claim 50 or 51, wherein the maintenance dose is administered once every two weeks for at least one dose.

53. The method of any one of claims 50 to 52, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

54. The method of any one of claims 46 to53, further comprising a sixth phase wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week in a dose amount between about 120% and 160% of the fifth phase dose amount.

55. The method of claim 54, wherein during the sixth phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

56. The method of claim 54 or 55, wherein the sixth phase is maintained until remission.

57. The method of claims 55 or 56, wherein the sixth phase has a duration of one or two weeks.

58. The method of any one of claims 54 to 57, further comprising administering a maintenance dose.

59. The method of claim 58, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the sixth phase.

60. The method of claim 58 or 59, wherein the maintenance dose is administered once every two weeks for at least one dose.

61. The method of any one of claims 58 to 60, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

62. The method of claim 57, further comprising a seventh phase wherein the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for at least one week in a dose amount between about 120% and 160% of the sixth phase dose amount.

63. The method of claim 62, wherein during the seventh phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

64. The method of claim 62 or 63, wherein the seventh phase is maintained until remission.

65. The method of any one of claims 62 to 64, further comprising administering a maintenance dose.

66. The method of claim 65, wherein the maintenance dose comprises the same a mount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the seventh phase.

67. The method of claim 65 or 66, wherein the maintenance dose is administered once every two weeks for at least one dose.

68. The method of any one of claims 65 to 67, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

69. The method of any one of claims 1-68, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the first phase fourth dose amount is about 2,500 ng/kg, wherein the second phase dose amount is about 3,800 ng/kg, wherein the third phase dose amount is about 5,700 ng/kg, wherein the fourth phase dose amount is about 8,500 ng/kg, until remission.

70. The method of any one of claims 14-68, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the first phase fourth dose amount is about 2,500 ng/kg, wherein the second phase dose amount is about 3,800 ng/kg, wherein the third phase dose amount is about 5,700 ng/kg, wherein the fourth phase dose amount is about 8,500 ng/kg, wherein the fifth phase dose amount is about 12,800 ng/kg, until remission.

71. The method of any one of claims 17-68, wherein the first phase second dose amount is about 1,100 ng/kg, wherein the first phase third dose amount is about 1,700 ng/kg, wherein the first phase fourth dose amount is about 2,500 ng/kg, wherein the second phase dose amount is about 3,800 ng/kg, wherein the third phase dose amount is about 5,700 ng/kg, wherein the fourth phase dose amount is about 8,500 ng/kg, wherein the fifth phase dose amount is about 12,800 ng/kg, wherein the sixth phase dose amount is about 19,200 ng/kg, until remission.

72. A method for treating a CD 123 -expressing cancer in a human subject in need of treatment thereof, comprising administering to the human subject a bispecific anti-CD 123 x anti-CD3 antibody in at least a first phase and a second phase, wherein during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered four times a week for one week in a first, second, third, and fourth dose amounts, wherein the first dose amount is about 430 ng/kg, the second dose amount is between about 140% and 180% of the first dose amount, and the third dose amount is between about 130% and 160% of the second dose amount, and the fourth dose amount is between about 130% and 160% of the third dose amount, wherein during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, in a dose amount between about 120% and 160% of the first phase fourth dose amount, thereby treating the CD 123 -expressing cancer.

73. The method of claim 72, wherein during the first and/or second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

74. The method of claims 72 or 73, wherein the second phase has a duration of between one and four weeks.

75. The method of claims 72 or 73, wherein the second phase is maintained until remission.

76. The method of any one of claims 72 to 75, further comprising administering a maintenance dose.

77. The method of claim 76, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the second phase.

78. The method of claim 76 or 77, wherein the maintenance dose is administered once every two weeks for at least one dose.

79. The method of any one of claims 76 to 78, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

80. The method of any one of claims 72 to 79, wherein the first phase second dose amount is about 750 ng/kg, wherein the first phase third dose amount is about 1,100 ng/kg, wherein the first phase fourth dose amount is about 1,700 ng/kg, wherein the second phase dose amount is about 2,500 ng/kg, until remission.

81. The method of any one of the claims 72-79, wherein the first phase second dose amount is about 542 ng/kg, wherein the first phase third dose amount is about 678 ng/kg, wherein the first phase fourth dose amount is about 848 ng/kg, wherein the second phase dose amount is about 1,060 ng/kg, until remission.

82. A method for treating a CD 123 -expressing cancer in a human subject in need of treatment thereof, comprising administering to the human subject a bispecific anti-CD 123 x anti-CD3 antibody in at least a first phase and a second phase, wherein during the first phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered four times a week for one week in a first, second, and third dose amounts, wherein the first dose amount is about 433 ng/kg, the second dose amount is between about 140% and 180% of the first dose amount, and the third dose amount is between about 130% and 160% of the second dose amount, wherein during the second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered once a week for one week, in a dose amount between about 120% and 160% of the first phase third dose amount, thereby treating the CD 123 -expressing cancer.

83. The method of claim 82, wherein during the first and/or second phase, the bispecific anti-CD 123 x anti-CD3 antibody is administered over about two hours.

84. The method of claims 82 or 83, wherein the second phase has a duration of between one and four weeks.

85. The method of claims 82 or 83, wherein the second phase is maintained until remission.

86. The method of any one of claims 82 to 85, further comprising administering a maintenance dose.

87. The method of claim 86, wherein the maintenance dose comprises the same amount of the bispecific anti-CD 123 x anti-CD3 antibody administered in the second phase.

88. The method of claim 86 or 87, wherein the maintenance dose is administered once every two weeks for at least one dose.

89. The method of any one of claims 86 to 88, wherein the maintenance dose is administered once every three or four weeks or once a month for at least one dose.

90. The method of any one of claims 82 to 89, wherein the first phase second dose amount is about 750 ng/kg, wherein the first phase third dose amount is about 1,100 ng/kg, wherein the second phase dose amount is about 1,700 ng/kg, until remission.

91. The method of any one of claims 82 to 89, wherein the first phase second dose amount is about 542 ng/kg, wherein the first phase third dose amount is about 678 ng/kg, wherein the second phase dose amount is about 848 ng/kg, until remission.

92. The method of any one of claims 1 to 91, wherein the CD 123-expressing cancer is a hematologic cancer.

93. The method of any one of claims 1 to 92, wherein the CD 123-expressing cancer is a leukemia.

94. The method of any one of claims 1 to 93, wherein the CD 123-expressing cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and hairy cell leukemia (HCL).

95. The method of any one of claims 1 to 94, wherein the CD 123-expressing cancer is acute myeloid leukemia (AML).

96. The method of claim 95, wherein the acute myeloid leukemia (AML) is blastic plasmacytoid dendritic cell neoplasm (BPDCN).

97. The method of any one of claims 1 to 96, wherein the CD 123-expressing cancer is acute lymphocytic leukemia, and the acute lymphocytic leukemia is B-cell acute lymphocytic leukemia (B-ALL).

98. The method of any one of claims 1 to 97, wherein the remission is a reduction in the number of CD 123-expressing cancer cells or reduction in the rate of growth of CD 123- expressing cancer cells.

99. The method of any one of claims 1 to 98, wherein the remission is an increase in T cell activation or an increase in IFN pathway upregulation.

100. The method of any one of claims 1 to 99, wherein the remission is a partial remission of the CD 123-expressing cancer.

101. The method of any one of claims 1 to 100, wherein the bispecific anti-CD 123 x anti- CD3 antibody comprises a Heavy Chain 1 (HC1) (Fab-Fc) set forth in SEQ ID NO:l, a Heavy Chain 2 (HC2) (scFv-Fc) set forth in SEQ ID NO: 2 and a Light Chain set forth in SEQ ID NO: 3.

102. The method of claim 101, wherein the bispecific anti-CD123 x anti-CD3 antibody consists of a Heavy Chain 1 (HC1) (Fab-Fc) set forth in SEQ ID NO: 1, a Heavy Chain 2 (HC2) (scFv-Fc) set forth in SEQ ID NO: 2 and a Light Chain set forth in SEQ ID NO: 3.

103. The method of any one of claims 1 to 102, further comprising assessing the weight of the human subject prior to the administering of the first phase of the bispecific anti-CD 123 x anti-CD3 antibody.

104. The method of any one of claims 1 to 103, further comprising administering to the human subject one or more therapeutic agents prior to the administering of the first phase of the bispecific anti-CD 123 x anti-CD3 antibody.

105. The method of claim 104, wherein the one or more therapeutic agents ameliorates one or more side effects of the bispecific anti-CD 123 x anti-CD3 antibody administration.

106. The method of claim 105, wherein the one or more therapeutic agents is a steroid, an antihistamine, an anti-allergic agent, an antinausea agent (or anti-emetic), an analgesic agent, an antipyretic agent, a cytoprotective agent, a vasopressor agent, an anticonvulsant agent, an anti-inflammatory agent, or any combination thereof.

107. The method of any one of claims 104 to 106, wherein the one or more therapeutic agents is a combination of a corticosteroid, diphenhydramine, and acetaminophen.

108. The method of any one of claims 1 to 107, further comprising, prior to the first phase administration, determining the percentage of blast cells in the bone marrow in the human subject, and proceeding with the first phase administration if the percentage is 25% or lower.

109. The method of any one of claims 1 to 107, further comprising, prior to the first phase administration, determining the percentage of CD8+ T cells which are PD-1+ in the human subject, and proceeding with the first phase administration if the percentage is 25% or lower.

110. A method of improving therapeutic efficacy for treatment of a CD 123-expressing cancer, comprising: determining the percentage of blast cells in the bone marrow or determining the percentage of CD8+ T cells which are PD-1+ in a human subject having a CD 123-expressing cancer; wherein a percentage 25% or lower indicates the efficacy of a bispecific anti-CD 123 x anti- CD3 antibody.

111. A method of determining susceptibility to treatment of a CD 123 -expressing cancer, comprising: determining the percentage of blast cells in the bone marrow or determining the percentage of CD8+ T cells which are PD-1+ in a human subject having a CD 123-expressing cancer; wherein a percentage 25% or lower indicates the efficacy of a bispecific anti-CD 123 x anti- CD3 antibody.

112. A method of selecting one or more human subjects with increased responsiveness to treatment of a CD 123-expressing cancer, comprising: determining the percentage of blast cells in the bone marrow or determining the percentage of CD8+ T cells which are PD-1+ in a human subject having a CD 123-expressing cancer; wherein a percentage 25% or lower corresponds to an increase in responsiveness in a subject.