TW202146452A - Dosing of a bispecific antibody that binds cd123 and cd3 - Google Patents

Abstract

The methods described here are directed to treating human subjects with bispecific anti-CD123 x anti-CD3 antibodies.

Description

Administration of bispecific antibodies that bind CD123 and CD3

Antibody-based therapies have been successfully used to treat a variety of diseases, including cancer and autoimmune/inflammatory disorders. There is still a need for improvements in this class of antibodies, especially with regard to enhancing their clinical efficacy. One approach being explored is to engineer additional and novel antigen-binding sites into antibodies such that a single immunoglobulin molecule co-engages two different antigens.

CD3 activation of T cells occurs only when the T cell receptor (TCR) associated with CD3 activation of T cells engages antigen-loaded MHCs on antigen-presenting cells at highly active intercellular synapses (Kuhns et al., 2006, Immunity [Immunity] 24:133-139). Indeed, non-specific bivalent cross-linking of CD3 using anti-CD3 antibodies causes interferon storm and toxicity (Perruche et al., 2009, J Immunol 183[2]:953-61; Chatenoud and Bluestone, 2007, Nature Reviews Immunology 7:622-632; expressly incorporated by reference). Therefore, for practical clinical use, a preferred mode of CD3 co-engagement for redirected killing of target cells would result in activated monovalent binding only after engagement with the co-engaged target.

CD123 (also known as interleukin-3 receptor alpha (IL-3Rα)) is expressed on dendritic cells, monocytes, eosinophils, and basophils. CD123 is also constitutively expressed by committed hematopoietic stem/pioneer cells, most myeloid (CD13+, CD14+, CD33+, CD15 _low ) and some CD19+ cells. It is absent in CD3+ cells.

There is a need for improved bispecific anti-CD123 x anti-CD3 antibodies and the use of such antibodies for use in therapy.

In one aspect, the invention provides a method for treating a cancer expressing CD123 in a human subject in need of treatment, the method comprising at least a first stage, and a second stage, and a third stage, and a fourth stage The human subject is administered a bispecific anti-CD123 x anti-CD3 antibody in a phase, wherein in the first phase, the human subject is administered the bispecific in first, second, and third doses Anti-CD123 x anti-CD3 antibody, three times a week for one week, wherein the first dose is about 750 ng/kg, and the second dose is between about 120% and 160% of the first dose and the third dose is between about 120% and 160% of the second dose, wherein in the second phase, the third dose is between about 120% and 160% of the second dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a dose between 120% and 160% once a week for one week, wherein in the third phase, at a dose between the first The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a dose between about 120% and 160% of the dose administered in the second phase, once a week for one week, wherein in the fourth phase In, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the amount administered in the third phase once a week for at least one week to treat the manifestation CD123 in cancer.

i. definition

In order that this application may be more fully understood, several definitions are listed below. Such definitions also include all syntactic equivalents.

The term "about" in relation to a referenced numerical value can include the numerical value itself as well as a range of values within plus or minus 10% of the numerical value. For example, an amount "about 10" includes 10 and any amount from 9 to 11. For example, the term "about" in relation to a reference value can also include a range of plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the numerical value. value. In some cases, a numerical value disclosed throughout may be "about" that numerical value even if the term "about" is not specifically mentioned.

Embodiments herein with the term "comprise" ("comprise", "comprises" or "comprising") may replace this term with "consists of" ("consists of" or "consisting of") or "substantially consists of" ...consists" ("consists essentially of" or "consisting essentially of").

The term "CD3" or "cluster of differentiation 3" refers to both the activation of cytotoxic T cells (eg, CD8+ naive T cells) and T helper cells (eg, CD4+ naive T cells), and consists of four distinct chains T-cell co-receptors: one CD3γ chain (eg, Genbank accession numbers NM_000073 and MP_000064 (human)), one CD3 delta chain (eg, Genbank accession numbers NM_000732, NM_001040651, NP_00732, and NP_001035741 (human)), and two CD3ε chains (eg Genbank accession numbers NM_000733 and NP_00724 (human)). The chain of CD3 is a highly related cell surface protein of the immunoglobulin superfamily containing a single extracellular immunoglobulin domain. The CD3 molecule associates with the T cell receptor (TCR) and the zeta chain to form the T cell receptor (TCR) complex, which acts to generate activation messages in T lymphocytes.

The term "CD123", "cluster of differentiation 123", "CD123 antigen", "interleukin-3 receptor alpha", "IL3RA" or "interleukin-3 receptor subunit alpha" refers to a type I heterodimer Interleukin 3-specific subunits of interleukin receptors (eg, Genbank accession numbers NM_001267713, NM_002183, NP_001254642, and NP_002174 (human)). CD123 interacts with the message transduction beta subunit to form the interleukin-3 receptor, which facilitates interleukin-3 transmission. CD123 is found on pluripotent precursor cells and induces tyrosine phosphorylation intracellularly and promotes proliferation and differentiation in hematopoietic cell lines. CD123 is expressed in acute myeloid leukemia (AML subtype), including leukemia stem cells.

"Bispecific" or "bispecific antibody" as used herein means any non-native or alternative antibody format that engages two different antigens, including those described herein (eg, CD3 x CD123 bispecific antibody).

"Modification" as used herein means amino acid substitutions, insertions and/or deletions in a polypeptide sequence or changes in the portion chemically linked to the protein. For example, the modification can be an altered carbohydrate or PEG structure attached to the protein. "Amino acid modification" herein means amino acid substitutions, insertions and/or deletions in a polypeptide sequence. For clarity, unless otherwise stated, amino acid modifications are always directed to amino acids encoded by DNA, eg, the 20 amino acids that have codons in DNA and RNA.

"Amino acid substitution" or "substitution" herein means replacing an amino acid at a particular position in the parent polypeptide sequence with a different amino acid. Specifically, in some embodiments, the substitution is for a non-naturally occurring amino acid at a particular position that neither occurs naturally in the organism nor in any organism. For example, substitution E272Y refers to a variant polypeptide (in this case an Fc variant) in which the glutamic acid at position 272 is replaced by tyrosine. For clarity, a protein that has been engineered to alter the nucleic acid coding sequence but not the starting amino acid (eg, changing CGG (encoding arginine) to CGA (still encoding arginine) to increase the level of expression in the host organism) Not an "amino acid substitution"; that is, although a new gene encoding the same protein is created, if the protein has the same amino acid at the specific position where it started, it is not an amino acid substitution.

As used herein, "amino acid insertion" or "insertion" means the addition of an amino acid sequence at a specific position in the parent polypeptide sequence. For example, -233E or 233E specifies the insertion of glutamic acid after position 233 and before position 234. Furthermore, -233ADE or A233ADE specifies insertion of AlaAspGlu after position 233 and before position 234.

As used herein, "amino acid deletion" or "deletion" means the removal of an amino acid sequence at a specified position in the parent polypeptide sequence. For example, E233- or E233# specifies a deletion deletion of glutamic acid at position 233. In addition, EDA233- or EDA233# specifies a deletion of the sequence GluAspAla starting at position 233.

As used herein, "variant protein" or "protein variant" or "variant" means a protein that differs from a parent protein by virtue of at least one amino acid modification. A protein variant can refer to the protein itself, a composition comprising the protein, or the sequence of amine motifs encoding the protein. Preferably, the protein variant has at least one amino acid modification compared to the parent protein, eg, from about one to about seventy amino acid modifications compared to the parent protein, and preferably from About one to about five amino acid modifications. As described below, in some embodiments, the parent polypeptide (eg, an Fc parent polypeptide) is a human wild-type sequence, such as the Fc region of IgG1, IgG2, IgG3, or IgG4, although human sequences with variants can also be used as " Parental Polypeptides". The protein variant sequences herein are preferably at least about 80% identical to the parent protein sequence, and most preferably at least about 90% identical, more preferably at least about 95% identical -98%-99% identity. A variant protein can refer to the variant protein itself, a composition comprising the protein variant, or a DNA sequence encoding the protein variant. Thus, as used herein, an "antibody variant" or "variant antibody" means an antibody that differs from a parent antibody by virtue of at least one amino acid modification; as used herein, an "IgG variant" or "variant IgG" means an antibody that differs from a parent IgG (and, in many cases, a human IgG sequence) due to at least one amino acid modification; and as used herein, "variant immunoglobulin" or "variant immunoglobulin" " means an immunoglobulin sequence that differs from a parental immunoglobulin sequence due to at least one amino acid modification. As used herein, "Fc variant" or "variant Fc" means a protein comprising amino acid modifications in the Fc domain. The Fc variants of the present invention are defined in terms of the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant having the substitution serine at position 434 relative to the parent Fc polypeptide, wherein numbering is according to the EU index. Likewise, M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parental Fc polypeptide. The identity of the WT amino acid may be uncertain, in which case the above variant is referred to as 428L/434S. Note that the order in which the substitutions are provided is arbitrary, that is, for example, 428L/434S is the same Fc variant as M428L/N434S, etc. For all positions discussed in the present invention in relation to antibodies, unless otherwise stated, amino acid position numbering is according to the EU index. The EU index or the EU index or EU numbering scheme as in Kabat refers to the numbering of EU antibodies (Edelman et al, 1969, Proc Natl Acad Sci USA [Proceedings of the National Academy of Sciences] 63:78-85, which is hereby incorporated by reference in its entirety incorporated). Modifications can be additions, deletions or substitutions. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include US Patent 6,586,207; WO 98/48032; WO 03/073238; US 2004-0214988 A1; WO 05/35727 A2; WO 05/74524 A2; JW Chin et al, (2002), Journal of the American Chemical Society [ Journal of the American Chemical Society] 124:9026-9027; JW Chin and PG Schultz, (2002), ChemBioChem 11:1135-1137; JW Chin et al, (2002), PICAS United States of America 99:11020-11024; and L. Wang and PG Schultz, (2002), Chem. [Chemistry] 1-10, all incorporated by reference in their entirety.

As used herein, "protein" herein means at least two covalently attached amino acids, including proteins, polypeptides, oligopeptides, and peptides. Peptidyl groups can include naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures (i.e., "analogs" such as peptoids) (see Simon et al., PNAS USA [Proceedings of the National Academy of Sciences] 89( 20):9367 (1992), incorporated by reference in its entirety). Amino acids can be naturally occurring or synthetic (eg, amino acids not encoded by DNA); as will be understood by those skilled in the art. For example, for the purposes of the present invention, homophenylalanine, citrulline, ornithine, and noreleucine are considered to be synthetic amino acids, and D- and L- (R or S) configurations can be utilized for amino acid. Variants of the present invention may include modifications including the incorporation of synthetic amino acids using, for example, techniques developed by Schultz and colleagues including, but not limited to, methods described in: Cropp and Shultz, 2004, Trends Genet. [Trends in Genetics] 20(12):625-30; Anderson et al, 2004, Proc Natl Acad Sci USA [Proceedings of the National Academy of Sciences] 101(2):7566-71; Zhang et al, 2003, 303(5656 ): 371-3; and Chin et al., 2003, Science 301(5635): 964-7, all incorporated by reference in their entirety. Additionally, polypeptides can include synthetic derivatization, glycosylation, pegylation, cyclic permutation, cyclization, linkers to other molecules, fusions to proteins or protein domains, and additions to one or more side chains or ends. Peptide tags or peptide tags.

As used herein, "residue" means the position in a protein and its associated amino acid identity. For example, asparagine 297 (also known as Asn297 or N297) is the residue at position 297 in the human antibody IgG1.

As used herein, an "antigen binding domain" or "ABD" refers to a set of six complementarity determining regions (CDRs) that, when present as part of a polypeptide sequence, specifically bind a target antigen as discussed herein. Thus, a "checkpoint antigen binding domain" binds a target checkpoint antigen as described herein. As known in the art, these CDRs are typically presented as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each set containing three CDRs: for the heavy chain line vhCDR1 , vhCDR2, vhCDR3, and for the light chain lines vlCDRl, vlCDR2, and vlCDR3. Such CDRs are present in the variable heavy and variable light domains, respectively, and together form the Fv region. Thus, in some cases, the six CDRs of an antigen binding domain consist of a variable heavy domain and a variable light domain. In the "Fab" format, the set of 6 CDRs consists of two different polypeptide sequences: a variable heavy domain (vh or VH; comprising vhCDR1, vhCDR2 and vhCDR3) and a variable light domain (vl or VL; comprising vlCDR1, vlCDR2 and vlCDR3), wherein the C-terminus of the vh domain is linked to the N-terminus of the CH1 domain of the heavy chain, and the C-terminus of the vl domain is linked to the N-terminus of the constant light domain (and thus form the light chain). In the scFv format, the vh and vl domains are typically covalently linked into a single polypeptide sequence through the use of a linker as outlined herein ("scFv linker"), which may be (from the N-terminus) vh-linker-vl or vl-linker-vh. Typically, the C-terminus of the scFv domain is linked to the N-terminus of the hinge in the second monomer.

As used herein, "Fab" or "Fab region" refers to a polypeptide comprising VH, CH1, VL, and CL immunoglobulin domains, eg, on two different polypeptide chains (eg, VH-CH1 and CL on one chain). VL-CL on the other strand). Fab can refer to this region in isolation, or in the context of bispecific antibodies, or in the context of full-length antibodies, antibody fragments or Fab fusion proteins. In the context of a Fab, in addition to the CH1 and CL domains, a Fab may also contain an Fv region.

As used herein, "Fv" or "Fv fragment" or "Fv region" means a polypeptide comprising the VL and VH domains of an ABD. Fv regions can be formatted as Fabs (as described above, typically two different polypeptides that also include the constant regions as described above) and scFvs in which the vl and vh domains are combined (usually with the linker discussed herein) ) to form scFv.

"Single-chain Fv" or "scFv" herein refers to a variable heavy domain that is covalently attached to a variable light domain, typically using the scFv linker discussed herein, to form a scFv or scFv domain. The scFv domain can be in either orientation from N-terminal to C-terminal (vh-linker-vl or vl-linker-vh). In the sequences depicted in the Sequence Listing and Figures, the order of the vh and vl domains is indicated in the name, e.g. H.X_L.Y for the N-to-C terminus line vh-linker-vl, while L.Y_H.X line vl-linker-vh.

As used herein, "amino acid" and "amino acid identity" mean one of the 20 naturally occurring amino acids encoded by DNA and RNA.

As used herein, "IgG Fc ligand" means 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, FcγRI, FcγRII, FcγRIII, FcRn, C1q, C3, mannose binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcγR. Fc ligands also include Fc receptor homologues (FcRH), a family of Fc receptors homologous to FcγRs (Davis et al, 2002, Immunological Reviews 190:123-136, by reference in its entirety incorporated). Fc ligands can include undiscovered Fc binding molecules. Specific IgG Fc ligands are FcRn and Fey receptors. As used herein, "Fc ligand" means a molecule (preferably a polypeptide) from any organism that binds to the Fc region of an antibody to form an Fc/Fc ligand complex.

As used herein, "Fcy receptor", "FcyR" or "FcqammaR" means any member of the protein family that binds the Fc region of an IgG antibody and is encoded by the 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-1) and FcγRIIb-2) and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett [Immunology Letters] 82:57-65, incorporated by reference in its entirety), and any undiscovered human FcyR or FcyR isoform or allotype. FcyRs can be from any organism, including but not limited to human, mouse, rat, rabbit and monkey. Mouse FcγRs include, but are not limited to, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγR or FcγR isoform or allotype.

As used herein, "FcRn" or "neonatal Fc receptor" means a protein that binds the Fc region of an IgG antibody and is at least partially encoded by the FcRn gene. FcRn can be from any organism, including but not limited to human, mouse, rat, rabbit and monkey. As known in the art, functional FcRn proteins comprise two polypeptides, commonly referred to as heavy and light chains. The light chain is beta-2-microglobulin, and the heavy chain is encoded by the FcRn gene. Unless otherwise specified herein, FcRn or FcRn protein refers to the complex of the FcRn heavy chain and beta-2-microglobulin. Various FcRn variants can be used to increase binding to the FcRn receptor, and in some cases, to increase serum half-life.

As used herein, "parent polypeptide" means the starting polypeptide, which is subsequently modified to generate a variant. The parent polypeptide can be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. A parent polypeptide can refer to the polypeptide itself, a composition comprising the parent polypeptide, or an amino acid sequence encoding the parent polypeptide. Thus, as used herein, "parent immunoglobulin" means an unmodified immunoglobulin polypeptide that has been modified to produce a variant; and, as used herein, "parent antibody" means modified to produce a variant antibody of unmodified antibodies. It should be noted that "parent antibody" includes known commercially recombinantly produced antibodies, as outlined below.

"Fc" or "Fc region" or "Fc domain" as used herein means a polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, the hinge. In the EU numbering of human IgG1, the CH2-CH3 domain comprises amino acid 231 to amino acid 447, and the hinge is amino acid 216 to amino acid 230. Thus, the definition of "Fc domain" includes 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 the N-terminus and the C-terminus, but still retain dimerization with another Fc domain or Fc fragment The ability of the body, as can be detected using standard methods (usually based on size) (eg, native chromatography, size exclusion chromatography, etc.). Human IgG Fc domains are of particular use in the present invention and can be Fc domains from human IgGl, IgG2 or IgG4.

"Heavy chain constant region" herein refers to the CH1-hinge-CH2-CH3 portion of an antibody (or fragment thereof), excluding the variable heavy domain; in EU numbering for human IgG1, this is amino acid 118- 447. A "heavy chain constant region fragment" as used herein refers to a heavy chain that contains fewer amino acids from the N- or C-terminus, or both, but still retains the ability to dimerize with another heavy chain constant region constant region.

As used herein, "position" means a position in a protein sequence. Positions can be numbered sequentially, or according to established formats such as the EU index for antibody numbering.

As used herein, "target antigen" means a molecule that is specifically bound by an antigen-binding domain comprising the variable region of a given antibody. The two target antigens of the present invention are human CD3 and human CD123.

In the context of the monomers of the heterodimeric antibodies of the invention, "stranded" means like two DNA strands that are "matched", and a heterodimeric variant is incorporated into each monomer to retain the "matched" ability to form heterodimers. For example, if some pi variants are engineered into monomer A (eg, to make the pi higher), the steric variants that are also available as "charge pairs" will not be disturbed by the pi variant, eg, to make the pi Higher charged variants are placed on the same "chain" or "monomer" to retain both functions. Similarly, for "skewed" variants that occur in pairs in a set (as outlined more fully below), the skilled artisan will consider the pi to decide which chain or monomer the incorporated set of pairs will go into, A skewed pI was also used to maximize pI separation.

As used herein, "target cell" means a cell that expresses the target antigen.

A "host cell" in the context of producing a bispecific antibody according to the present invention refers to a cell containing exogenous nucleic acid encoding components of the bispecific antibody and capable of expressing the bispecific antibody under appropriate conditions. Suitable host cells are discussed herein.

"Variable region" or "variable domain" as used herein means a region of an immunoglobulin comprising substantially the Vκ, Vλ, and/or VH genes (which make up the κ, λ, and One or more Ig domains encoded by any of the heavy chain immunoglobulin genetic loci) and contain CDRs that confer antigen specificity. Thus, a "variable heavy domain" is paired with a "variable light domain" to form an antigen binding domain ("ABD"). In addition, each variable domain comprises three hypervariable regions ("complementarity determining regions", "CDRs") (variable heavy domains are vhCDRl, vhCDR2 and vhCDR3 and variable light domains are vlCDRl, vlCDR2 and vlCDR3) and four framework regions (FRs), which are arranged from the amino terminus to the carboxy terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

The sequence identity of two similar sequences (eg, antibody variable domains) can be measured by algorithms such as the following algorithm: Smith, TF and Waterman, MS (1981) "Comparison Of Biosequences. ]," Adv. Appl. Math. [Advances in Applied Mathematics] 2:482 [local homology algorithm]; Needleman, SB and 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 [Homologous Alignment Calculations] homology alignment algorithm], Pearson, WR and Lipman, DJ (1988) “Improved Tools For Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (USA) [National Academy of Sciences] Proceedings] (US) 85:2444 [search for similarity method]; or Altschul, SF et al., (1990) "Basic Local Alignment Search Tool," J. Mol. Biol. [Journal of Molecular Biology] 215:403-10, the “BLAST” algorithm, available at https://blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of the aforementioned algorithms, preset parameters (for window length, gap penalty, etc.) are used. In one embodiment, sequence identities are calculated using the BLAST algorithm, using preset parameters.

"Wild type or WT" as used herein means the amino acid sequence or nucleotide sequence found in nature, including dual genetic variation. WT proteins have amino acid sequences or nucleotide sequences that have not been intentionally modified.

Antibodies of the invention are typically isolated or recombinant. When used to describe the various polypeptides disclosed herein, "isolated" means a polypeptide that has been identified and isolated and/or recovered from the cell or cell culture in which it is expressed. Typically, an isolated polypeptide will be prepared by at least one purification step. An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities. "Recombinant" refers to the use of recombinant nucleic acid techniques to produce antibodies in exogenous host cells and to allow them to be isolated.

"Specifically binds" or "specifically binds to" or "specifically" a particular antigen or epitope means binding that is measurably distinct from nonspecific interactions. Specific binding can be measured, for example, by determining the binding of a molecule compared to that of a control molecule, typically a molecule of similar structure that has no binding activity. For example, specific binding can be determined by competition with a control molecule similar to the target.

Specific binding to a particular antigen or epitope can be demonstrated, for example, by an antibody having a KD for the antigen or epitope: at least about ^10-4 M, at least about ^10-5 M, at least about ^10-6 M, at least about 10 ^-7 M, at least about 10 ^-8 M, at least about 10 ^-9 M, alternatively from about 10 ^-10 M, at least about 10 ^-11 M, at least about 10 ^-12 M or higher, which means a certain KD Dissociation rates of antibody-antigen interactions. Typically, an antibody that specifically binds to an antigen or epitope will have a KD that is 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold or more higher than a control molecule.

Furthermore, specific binding to a particular antigen or epitope can be demonstrated, for example, by an antibody having a KA or Ka for the antigen or epitope that is at least 20-fold, 50-fold higher, relative to a control, for the epitope. fold, 100 fold, 500 fold, 1000 fold, 5,000 fold, 10,000 fold or more, where KA or Ka refers to the association rate of a particular antibody-antigen interaction. Binding affinity is typically measured using Biacore, SPR or BLI assays.

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 specific biomarkers associated with CD123 disorder pathology.

In the context of cancer, "refractory" is intended to mean that a particular cancer is resistant or unresponsive to therapy with a particular therapeutic agent. During a first treatment period with a therapeutic agent or during a subsequent treatment period with a therapeutic agent, either from treatment with a particular therapeutic agent (ie, unresponsive to initial exposure to the therapeutic agent) or due to Cancers may be refractory to treatment with specific therapeutic agents.

As used herein, IC ₅₀ refers to an assay that measures such response in the amount of 50% inhibition of the maximum response to a particular test compound (e.g., inhibit the biological activity of the CD123), concentration or dosage.

As used herein, EC ₅₀ refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximal performance of a particular response induced, elicited or enhanced by a particular test compound.

The term "remission" in relation to cancer refers to the reduction or disappearance of cancer signs (eg, tumor size, biomarkers) and/or symptoms. In some cases, remission can be partial or complete. For example, remission can result in a reduction, amelioration or elimination of progression, severity, and/or impact associated with a CD123-expressing cancer (eg, blood cancer) and/or improvement in one or more symptoms associated with a CD123-expressing cancer. In certain instances, alleviation can be associated with an increase in the immune system response in a human subject, or an improvement in one or more symptoms of a cancer expressing CD123 as a result of administration of an antibody described herein. In certain instances, remission can result in an improvement in at least one measurable physical parameter of the cancer, such as tumor size, tumor growth rate, tumor cell number, tumor aggressiveness, presence or extent of metastasis. In other embodiments, amelioration can result in inhibition of the progression of a cancer expressing CD123 physically, eg, by stabilizing discernible symptoms, or physiologically, eg, by stabilizing physical parameters, or both. In some cases, remission may be associated with one or more of the following: (1) a ^{decrease in the number of CD123+} cancer-associated cells, including CD123 ⁺ peripheral blood blasts and/or bone marrow blasts, such as a decrease below the MRD ( minimal residual disease) levels of detection limit of detection (i.e. flow cytometry assays, RT-qPCR assays, or next-generation sequence-based MRD assays) (or, for example, increased T cell activation or increased IFN pathway upregulation); ( 2) ^{increased cell death associated with CD123+} expressing cancers; (3) ^{inhibition of cell survival associated with CD123+} expressing cancers; (5) inhibition of proliferation associated with CD123+ expressing cancers (ie, to some extent (6) increased survival in human subjects; (6) increased survival in human subjects; (7) Improvement in peripheral cytopenias associated with cancers expressing CD123; and (8) Reduction (subjective and/or objective) of any degree of reduction (subjective and/or objective) of one or more symptoms of cancers expressing CD123.

Response can be determined by standardized response criteria for the cancer expressing CD123. Examples of such response criteria include the European Leukemia Network Response Assessment Category for clinical trials. An example for AML can be found in Döhner et al. Blood, 2017; 129(4): 424. Examples for ALL, including extramedullary 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 [Revised Recommendations of the International Working Group on Standardization of Diagnosis, Response Criteria, Treatment Outcomes, and Reporting Standards for Treatment Trials for Acute Myeloid Leukemia]. J Clin Oncol. 2003;21(24):4642 -9 found. An example 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. Workshop Report] 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 [Hematology]. 2013;98(2):239-46. An example of chronic myeloid leukemia for the blast stage can be found in Cortes et al. Blood. 2007;109(8):3207-13.

Improvement in one or more symptoms associated with cancer expressing CD123 including: feeling less tired, feeling less weak, feeling less dizzy or light-headed, decreased shortness of breath, decreased fever, decreased infection, faster recovery from infection, Less prone to bruising, less bleeding episodes, weight gain, less night sweats, increased appetite, less swollen belly, less swollen lymph nodes, less bone or joint pain, and less swollen thymus.

Improvement in CD123-expressing cancers can be characterized as "complete remission" or "complete response." The terms "complete remission" or "complete response" in relation to cancer may refer to the disappearance of all signs and/or symptoms of cancer, although in some cases cancer patients may still have cancer cells in their body. Complete remission results in the absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF). In one setting, complete response was defined as <5% bone marrow blasts, no circulating blasts or Auer rod blasts, no extramedullary disease, normalization of blood counts (absolute neutrophil count ≥ 1000/µL, and platelet count ≥ 100,000/µL). In some cases, for blood cancers such as AML and ALL, complete remission can result in normal blood counts returning to the normal range in addition to the absence of morphological evidence of leukemia.

Alternatively, improvement in CD123-expressing cancers can be characterized as a "partial remission" or "partial response." The terms "partial remission" or "partial response" in relation to cancer may refer to the disappearance of some, but not all, signs and/or symptoms of cancer. For example, in some cases a partial response may refer to at least one measurable tumor burden (ie, the number of malignant cells present in the subject or the measured quality or abnormality of the tumor mass) in the absence of new lesions The amount of monoselectin) is reduced by at least about 5%, which can last for 4 to 8 weeks or 6 to 8 weeks. In some instances, a partial response can result in at least about a 10% reduction in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 15% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 20% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 25% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 30% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 35% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 40% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 45% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 50% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 60% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 70% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 80% in at least one measurable tumor burden. In some instances, a partial response refers to a reduction of at least about 90% in at least one measurable tumor burden.

The terms "patient" and "human subject" are used interchangeably herein. II. Overview

Disclosed herein are methods of treating cancers comprising cells expressing CD123 ("CD123 expressing cancers") (eg, blood cancers such as leukemia) by administering certain bispecific anti-CD123 x anti-CD3 antibodies at specific doses. The term "CD123-expressing cancer" can refer to a CD123-expressing cancer or a CD123-overexpressing cancer. The invention also provides methods of combination therapy, eg, by administering certain bispecific anti-CD123xanti-CD3 antibodies in combination with one or more therapeutic agents that ameliorate one or more side effects of the anti-CD123xanti-CD3 bispecific antibodies (eg, XmAb14045) for the treatment of cancers comprising cells expressing CD123 ("CD123 expressing cancers") (eg, blood cancers such as leukemia). III. Antibodies

The present invention relates to the administration of bispecific antibodies (eg, anti-CD123 x anti-CD3 antibodies) for the treatment of cancers expressing CD123, such as certain leukemias. For example, some embodiments of bispecific formats of antibodies having profiles and polynucleotide/polypeptide sequences are disclosed in US Patent Application Publication No. 2016/0229924.

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibodies having a "corkscrew" form as generally depicted in FIG. In this embodiment, the anti-CD3 antigen binding domain is a scFv-Fc domain monomer, and the anti-CD123 antigen binding domain is a Fab monomer (see US Patent Application Publication Nos. 2014/0288275; 2014/0294823; and 2016/0355608).

An alternative format of the bispecific heterodimeric anti-CD123 x anti-CD3 antibody is shown in Figure 7 , which typically also relies on the use of different formats of the Fab and scFv domains.

In addition, other heterodimeric and non-heterodimeric anti-CD123 x anti-CD3 bispecific antibodies can be administered at the same dosage levels and in the same manner as described herein.

The anti-CD3 scFv antigen binding domain can have the sequence depicted in Figure 2 , or can be selected from the group consisting of: 1) the anti-CD3 antigen depicted in Figures 2 and 6 from US Patent Application Publication No. 2014/0288275 A set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) of any one of the binding domain sequences; 2) the anti-CD3 depicted in Figures 2 and 6 from U.S. Patent Application Publication No. 2014/0288275 Variable heavy and variable light chains of any of the antigen binding domain sequences; 3) scFv domains from any of the anti-CD3 scFV sequences depicted in Figure 2 of US Patent Application Publication No. 2014/0288275 4) other known anti-CD3 variable heavy and variable light chains that can be combined to form a scFv (or Fab, when the form is reversed or an alternative form is used); and 5) Any of the anti-CD3 antigen binding domains of Figures 2, 3, 4, 5, 6 and 7 of US Patent Application Publication No. 2016/0229924.

The anti-CD123 Fab binding domain can have the sequence depicted in Figure 2 or 5 , or can be selected from the group consisting of: 1) from the anti-CD123 antigen binding domain sequence depicted in US Patent Application Publication No. 2016/0229924 A set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) of any of (including those depicted in Figures 2, 3 and 12); 2) from US Patent Application Publication No. 2016/0229924 variable heavy chain and variable light chain of any of the depicted anti-CD123 antigen binding domain sequences (including those depicted in Figures 2, 3 and 12); and 3) other also known anti-CD123 variable heavy chains chain and variable light chain, which can be combined to form a Fab (or scFv, when the format is reversed or an alternative format is used).

As shown in FIG. A bispecific anti XmAb14045 system may be used in the dosage regimen of 2 throughout. The XmAb14045 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 heavy chain 1 (HCl) (Fab-Fc) as set forth in SEQ ID NO: 1, heavy chain 2 as set forth in SEQ ID NO: 2 ( HC2) (scFv-Fc) and the light chain shown in SEQ ID NO: 3. In an exemplary embodiment, the bispecific anti-CD123 x anti-CD3 antibody is composed of heavy chain 1 (HCl) (Fab-Fc) shown in SEQ ID NO: 1, heavy chain 2 (heavy chain 2) shown in SEQ ID NO: 2 ( HC2) (scFv-Fc) and the light chain composition shown in SEQ ID NO: 3.

Bispecific anti-CD123 x anti-CD3 antibodies used throughout can be prepared by known methods. The present disclosure further provides polynucleotide compositions encoding bispecific anti-CD123 x anti-CD3 antibodies. Furthermore, the polynucleotide composition will depend on the format and scaffold of the bispecific anti-CD123 x anti-CD3 antibody. Thus, for example, when the format requires three amino acid sequences, such as for the triple F format (eg, the first amino acid monomer comprising the Fc domain and the scFv, the second amino acid monomer comprising the heavy chain) and light chain), the three polynucleotide sequences can be incorporated into one or more vectors for expression. Similarly, some form (e.g., as in FIG. 7 discloses a double scFv format) requires only two polynucleotides; may be one or both of them into expression vectors.

Polynucleotides encoding bispecific antibody components can be incorporated into expression vectors and, depending on the host cell, can be used to generate bispecific anti-CD123 x anti-CD3 antibodies. Typically, the polynucleotide is operably linked to any number of regulatory elements (promoters, origins of replication, selectable markers, ribosome binding sites, inducers, etc.). The expression vector can be an extrachromosomal or integrating vector.

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, and mammalian cells (e.g., CHO cells).

In some embodiments, the polynucleotides encoding each monomer and the polynucleotides (depending on format) encoding the light chain are each contained in a single expression vector under the control of the use of different or the same promoter . In some embodiments, each of the two or three polynucleotides is contained on a different expression vector.

Heterodimeric bispecific anti-CD123 x anti-CD3 antibodies are prepared by culturing host cells comprising the one or more expression vectors. After production, conventional antibody purification steps, such as ion exchange chromatography steps, are performed. As discussed in US Patent No. 9,650,446 and International Publication No. WO 2014/145806, having the pi of the two monomers differ by at least 0.5 may allow the use of ion exchange chromatography or isoelectric focusing or other methods sensitive to the isoelectric point. method separation. That is, the inclusion of pI substitutions that alter the isoelectric point (pI) of each monomer so that each monomer has a different pI and the heterodimer also has a different pI, thereby contributing to the "triple F" heterodimer Isoelectric purification of aggregates (eg, anion exchange columns, cation exchange columns). These substitutions also aid in the identification and monitoring of any contaminating dual scFv-Fc and mAb homodimers after purification (eg, IEF gels, cIEF and analytical IEX columns).

Once prepared, the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects at the doses outlined herein. IV. Pharmaceutical Compositions and Drug Administration

According to the dosage regimen described herein, XmAb14045 can be incorporated into a pharmaceutical composition suitable for administration to human subjects. As used herein, a "dosage regimen" refers to a systemic drug administration plan with respect to formulation, route of administration, drug dosage, dosing interval, and duration of treatment. Typically, the pharmaceutical composition comprises XmAb14045 and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic agents and absorption delaying agents that are physiologically compatible and suitable for administering to a subject the methods described herein agent, etc. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and any combination thereof. In certain instances, isotonic agents such as sugars, polyols (eg, mannitol, sorbitol), or sodium chloride may be included in the composition. The pharmaceutically acceptable carrier may also contain minor amounts of auxiliary substances that enhance the shelf-life or effectiveness of XmAb14045, such as surfactants (eg, nonionic surfactants), wetting or emulsifying agents (eg, polysorbates), preservatives or buffers (such as organic acids as citrate or acetate). Examples of pharmaceutically acceptable carriers include polysorbate (polysorbate-80).

In one embodiment, the pharmaceutical composition comprises XmAb14045 and a preservative or buffer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and histidine. In one embodiment, the pharmaceutical composition comprises XmAb14045 and acetate. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium acetate. In one embodiment, the pharmaceutical composition comprises XmAb14045 and citrate. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and an isotonicity agent. In one embodiment, the pharmaceutical composition comprises XmAb14045 and a polyol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and mannitol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAb14045 and potassium chloride.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and a wetting or emulsifying agent. In one embodiment, the pharmaceutical composition comprises XmAb14045 and polysorbate. In one embodiment, the pharmaceutical composition comprises XmAb14045 and polysorbate-80.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and an intravenous solution stabilizer. In one embodiment, the intravenous solution stabilizer comprises polysorbate and citrate. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate and polysorbate-80.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and a buffer and an isotonicity agent. In one embodiment, the pharmaceutical composition comprises XmAb14045 and a buffer and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and an acetate salt and an isotonicity agent. In one embodiment, the pharmaceutical composition comprises XmAb14045 and histidine and an isotonicity agent. In one embodiment, the pharmaceutical composition comprises XmAb14045 and acetate and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium acetate and sorbitol. In one embodiment, the pharmaceutical composition comprises XmAb14045 and histidine and sorbitol.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and buffering and isotonicity agents and intravenous solution stabilizers. In one embodiment, the pharmaceutical composition comprises XmAb14045 and a buffer and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and an acetate salt and an isotonicity agent and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and histidine and an isotonicity agent and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and acetate and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium acetate and sorbitol and an intravenous solution stabilizer. In one embodiment, the pharmaceutical composition comprises XmAb14045 and histidine and sorbitol and an intravenous solution stabilizer.

In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium chloride and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate and sodium chloride. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate, sodium chloride and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate, sodium chloride, sodium acetate, sorbitol, and polysorbate-80. In one embodiment, the pharmaceutical composition comprises XmAb14045 and sodium citrate, sodium chloride, histidine, sorbitol, and polysorbate-80.

Such pharmaceutical compositions can take various forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (eg, 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 to passively immunize 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.

Pharmaceutical compositions must generally 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 filtered 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.

XmAb14045 can be administered by known methods. In one embodiment, the route/mode of administration is intravenous injection. The route and/or mode of administration can vary depending on the desired result. V. Treatment options for cancers expressing CD123

In one embodiment, the antibodies of the invention treat cancers expressing CD123. In one embodiment, the cancer expressing CD123 is a hematological cancer. In one embodiment, the cancer expressing CD123 is a leukemia.

CD123 is frequently expressed in hematological malignancies, such as 96%-98% of acute myeloid leukemia cases; >50% of myelodysplastic syndrome cases; 82%-100% of B-cell acute lymphoblastic leukemia cases; 83% -100% of blastocytic plasmacytoid dendritic cell tumor cases; 75%-100% of chronic myeloid leukemia cases; and 95%-100% of hairy cell leukemia cases.

Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells (white blood cells). The leukemia lineage is a broad term covering a wide variety of diseases. The first division is between its acute and chronic forms: (i) Acute leukemia is characterized by a rapid increase in immature blood cells. This crowding prevents the bone marrow from producing healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of malignant cells that then spill into the blood and spread to other organs of the body. The acute form of leukemia is the most common form of leukemia in children; (ii) chronic leukemia differs by the excessive accumulation of relatively mature but still abnormal white blood cells. Usually taking months or years to progress, this cell is produced at a higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia occurs mainly in the elderly, but can theoretically occur in any age group. In addition, the disease is subdivided according to the type of blood cells involved. This segmentation divides leukemia into lymphoblastic or lymphocytic leukemia and myeloid or myeloid leukemia: (i) lymphoblastic leukemia or lymphocytic leukemia, where cancer develops in myeloid cell types that normally go on to form lymphocytes , the lymphocytes are cells of the immune system that fight infection; (ii) myeloid or myeloid leukemia, which develops cancer in the bone marrow cell type that normally goes on to form red blood cells, some other types of white blood cells, and platelets.

In one embodiment, the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), and blast cells Sexual plasmacytoid dendritic cell tumor (BPDCN). In one embodiment, the leukemia is acute lymphoblastic leukemia (ALL). In one embodiment, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and hairy cell leukemia (HCL). In one embodiment, the leukemia is acute lymphoblastic leukemia (ALL). In one embodiment, the leukemia is acute lymphoblastic leukemia, and the acute lymphoblastic leukemia is B-cell acute lymphoblastic 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 blastocytic plasmacytoid dendritic cell tumor (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-stage 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), wherein the AML is primary acute myeloid leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML), wherein 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), wherein the AML does not include acute promyelocytic leukemia. In one embodiment, the leukemia is acute myeloid leukemia (AML), wherein the AML is a blastocytic plasmacytoid dendritic cell tumor. In one embodiment, the leukemia is B-cell acute lymphoblastic leukemia (B-ALL). In one embodiment, the leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

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

In some embodiments, the cancer is treated according to the methods described herein. In one embodiment, the cancer is treated by distributing XmAb14045 to a human subject in one or more stages. Each phase includes one or more doses of XmAb14045 provided on a weekly or monthly basis (the "Dosage Regimen"). Each stage 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.

In one embodiment, the method of treatment comprises dispensing the antibody in one to four stages. In one embodiment, a phase has the same dosing regimen that occurs between one (1) to twenty (20) times, or until remission). In one embodiment, the dosage regimen has an amount administered (amount of antibody) and a time of administration (length of time over which the administered amount is administered).

In one embodiment, the method includes a first stage. In one embodiment, the method includes a first stage. In one embodiment, the method includes a first stage and a second stage. In one embodiment, the method includes a first stage and a second stage, wherein each stage is different. In one embodiment, the method includes a first stage and a second stage, wherein each stage is different. In one embodiment, the method includes a first stage and a second stage and a third stage. In one embodiment, the method includes a first stage and a second stage and a third stage. In one embodiment, the method includes a first stage and a second stage and a third stage, wherein each stage is different. In one embodiment, the method includes first and second and third and fourth stages. In one embodiment, the method includes first and second and third and fourth stages. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage, wherein each stage is different. In one embodiment, the method includes a first and second stage and a third and fourth stage and a fifth stage. In one embodiment, the method includes a first and second stage and a third and fourth stage and a fifth stage. In one embodiment, the method includes a first and second stage and a third and fourth stage and a fifth stage, wherein each stage is different. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage. In one embodiment, the method includes first and second and third and fourth and fifth and sixth stages, wherein each stage is different. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage. In one embodiment, the method includes a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein each stage is different. In one embodiment, the dosage regimen is continued until the cancer (eg, blood cancer) is in remission (eg, full or partial). V. a). Dosage

A dose has a specified amount of antibody administered to a human subject over a specified period of time. The amount of antibody administered to a human subject is also referred to as the dose administered. The time during which a dose is administered to a human subject is also referred to as the time of administration. V. a) i). Dosage

The amount administered can be determined or adjusted by measuring the amount of bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) in the blood after administration, for example, by removing a biological sample and using a targeted bispecific anti-CD123 x anti-CD3 antibody ( For example, anti-idiotypic antibodies to the antigen-binding region of XmAb14045). The amount administered can be determined based on the body weight of the human subject, such as by multiplying the body weight of the human subject (in kg, for example) by the amount administered (such as those described herein). The human subject's body weight can be assessed prior to administration of the first-phase bispecific anti-CD123 x anti-CD3 antibody, such as the day before the first-phase administration. For human subjects weighing more than 100 kg, the dosing amount may be calculated based on the body weight of 100 kg rather than the actual body weight of the human subject.

Subsequent doses may be modified if the human subject's body weight changes by a certain amount after the first dose administered in the first phase (eg, more than about 5%, more than about 10% from the weight assessment prior to the first phase assessment) . At this point, the weight for the day used for the infusion can be recalculated using the current body weight.

Paragraph A includes the following administration amounts: In one embodiment, the administration amounts are between about 350 ng/kg and about 21,000 ng/kg.

Paragraph B includes any of the following administration amounts: In one embodiment, the administration amount is between about 350 ng/kg and about 650 ng/kg. In one embodiment, the amount administered is between about 400 ng/kg and about 600 ng/kg. In one embodiment, the amount administered is between about 400 ng/kg and about 500 ng/kg. In one embodiment, the amount administered is between about 425 ng/kg and about 475 ng/kg. In one embodiment, the amount administered is between about 450 ng/kg and about 470 ng/kg. In one embodiment, the amount administered is about 460 ng/kg. In one embodiment, the amount administered is 460 ng/kg. In one embodiment, the amount administered is between about 525 ng/kg and about 600 ng/kg. In one embodiment, the amount administered is between about 550 ng/kg and about 600 ng/kg. In one embodiment, the amount administered is between about 560 ng/kg and about 580 ng/kg. In one embodiment, the amount administered is about 570 ng/kg. In one embodiment, the dose is 570 ng/kg. In one embodiment, the amount administered is about 575 ng/kg. In one embodiment, the amount administered is 575 ng/kg. In one embodiment, the amount administered is between about 450 ng/kg and about 550 ng/kg. In one embodiment, the amount administered is between about 475 ng/kg and about 525 ng/kg. In one embodiment, the amount administered is about 500 ng/kg. In one embodiment, the amount administered is 500 ng/kg.

Paragraph C includes any of the following doses: In one embodiment, the dose is between about 600 ng/kg and about 900 ng/kg. In one embodiment, the amount administered is between about 100 ng/kg and about 750 ng/kg. In one embodiment, the amount administered is between about 500 ng/kg and about 750 ng/kg. In one embodiment, the amount administered is between about 600 ng/kg and about 750 ng/kg. In one embodiment, the amount administered is between about 700 ng/kg and about 750 ng/kg. In one embodiment, the amount administered is between about 600 ng/kg and about 700 ng/kg. In one embodiment, the amount administered is between about 625 ng/kg and about 675 ng/kg. In one embodiment, the amount administered is between about 640 ng/kg and about 660 ng/kg. In one embodiment, the amount administered is about 650 ng/kg. In one embodiment, the amount administered is 650 ng/kg. In one embodiment, the amount administered is between about 650 ng/kg and about 700 ng/kg. In one embodiment, the amount administered is between about 660 ng/kg and about 680 ng/kg. In one embodiment, the amount administered is about 667 ng/kg. In one embodiment, the amount administered is 667 ng/kg. In one embodiment, the amount administered is between about 725 ng/kg and about 775 ng/kg. In one embodiment, the amount administered is between about 740 ng/kg and about 780 ng/kg. In one embodiment, the amount administered is between about 760 ng/kg and about 780 ng/kg. In one embodiment, the amount administered is between about 750 ng/kg and about 780 ng/kg. In one embodiment, the amount administered is about 767 ng/kg. In one embodiment, the amount administered is 767 ng/kg. In one embodiment, the amount administered is about 770 ng/kg. In one embodiment, the amount administered is 770 ng/kg. In one embodiment, the amount administered is between about 700 ng/kg and about 900 ng/kg. In one embodiment, the amount administered is between about 750 ng/kg and about 850 ng/kg. In one embodiment, the amount administered is between about 775 ng/kg and about 825 ng/kg. In one embodiment, the amount administered is about 800 ng/kg. In one embodiment, the amount administered is 800 ng/kg. In one embodiment, the amount administered is between about 650 ng/kg and about 850 ng/kg. In one embodiment, the amount administered is between about 700 ng/kg and about 800 ng/kg. In one embodiment, the amount administered is between about 725 ng/kg and about 775 ng/kg. In one embodiment, the amount administered is between about 740 ng/kg and about 760 ng/kg. In one embodiment, the amount administered is about 750 ng/kg. In one embodiment, the amount administered is 750 ng/kg.

Paragraph D includes any of the following doses: In one embodiment, the dose is between about 700 ng/kg and about 1,900 ng/kg. In one embodiment, the amount administered is between about 1,500 ng/kg and about 1,900 ng/kg. In one embodiment, the amount administered is between about 1,300 ng/kg and about 1,500 ng/kg. In one embodiment, the amount administered is between about 1,350 ng/kg and about 1,450 ng/kg. In one embodiment, the amount administered is about 1,400 ng/kg. In one embodiment, the amount administered is 1,400 ng/kg. In one embodiment, the amount administered is between about 300 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 700 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 900 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 950 ng/kg and about 1,050 ng/kg. In one embodiment, the amount administered is about 1,000 ng/kg. In one embodiment, the amount administered is 1,000 ng/kg. In one embodiment, the amount administered is between about 1,100 ng/kg and about 1,200 ng/kg. In one embodiment, the amount administered is between about 1,125 ng/kg and about 1,175 ng/kg. In one embodiment, the amount administered is about 1,125 ng/kg. In one embodiment, the amount administered is 1,125 ng/kg. In one embodiment, the amount administered is about 1,150 ng/kg. In one embodiment, the amount administered is 1,150 ng/kg. In one embodiment, the amount administered is between about 1,150 ng/kg and about 1,180 ng/kg. In one embodiment, the amount administered is between about 1,160 ng/kg and about 1,175 ng/kg. In one embodiment, the amount administered is about 1,167 ng/kg. In one embodiment, the amount administered is 1,167 ng/kg. In one embodiment, the amount administered is between about 700 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 800 ng/kg and about 1,000 ng/kg. In one embodiment, the amount administered is between about 850 ng/kg and about 950 ng/kg. In one embodiment, the amount administered is between about 875 ng/kg and about 925 ng/kg. In one embodiment, the amount administered is between about 890 ng/kg and about 910 ng/kg. In one embodiment, the amount administered is about 900 ng/kg. In one embodiment, the amount administered is 900 ng/kg. In one embodiment, the amount administered is between about 1,000 ng/kg and about 1,500 ng/kg. In one embodiment, the amount administered is between about 1,000 ng/kg and about 1,250 ng/kg. In one embodiment, the amount administered is between about 1,050 ng/kg and about 1,200 ng/kg. In one embodiment, the amount administered is between about 1,050 ng/kg and about 1,150 ng/kg. In one embodiment, the amount administered is between about 1,075 ng/kg and about 1,125 ng/kg. In one embodiment, the amount administered is between about 1,090 ng/kg and about 1,110 ng/kg. In one embodiment, the amount administered is about 1,100 ng/kg. In one embodiment, the amount administered is 1,100 ng/kg. In one embodiment, the amount administered is between about 1,100 ng/kg and about 1,400 ng/kg. In one embodiment, the amount administered is between about 1,100 ng/kg and about 1,300 ng/kg. In one embodiment, the amount administered is between about 1,150 ng/kg and about 1,250 ng/kg. In one embodiment, the amount administered is between about 1,175 ng/kg and about 1,225 ng/kg. In one embodiment, the amount administered is between about 1,190 ng/kg and about 1,210 ng/kg. In one embodiment, the amount administered is about 1,200 ng/kg. In one embodiment, the amount administered is 1,200 ng/kg. In one embodiment, the amount administered is between about 800 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 900 ng/kg and about 1,050 ng/kg. In one embodiment, the amount administered is between about 950 ng/kg and about 1,100 ng/kg. In one embodiment, the amount administered is between about 850 ng/kg and about 1,750 ng/kg. In one embodiment, the amount administered is between about 1,000 ng/kg and about 1,600 ng/kg. In one embodiment, the amount administered is between about 1,000 ng/kg and about 1,400 ng/kg. In one embodiment, the amount administered is between about 1,150 ng/kg and about 1,450 ng/kg. In one embodiment, the amount administered is between about 1,300 ng/kg and about 1,350 ng/kg. In one embodiment, the amount administered is about 1,333 ng/kg. In one embodiment, the amount administered is 1,333 ng/kg. In one embodiment, the amount administered is about 1,300 ng/kg. In one embodiment, the amount administered is 1,300 ng/kg.

Paragraph E includes any of the following amounts to be administered: 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 amount administered is about 1,750 ng/kg. In one embodiment, the amount administered 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 amount administered is about 1,714 ng/kg. In one embodiment, the amount administered is 1,714 ng/kg. In one embodiment, the amount administered is between about 1,300 ng/kg and about 1,700 ng/kg. In one embodiment, the amount administered is between about 1,350 ng/kg and about 1,650 ng/kg. In one embodiment, the amount administered is between about 1,400 ng/kg and about 1,600 ng/kg. In one embodiment, the amount administered is between about 1,450 ng/kg and about 1,550 ng/kg. In one embodiment, the amount administered is between about 1,475 ng/kg and about 1,525 ng/kg. In one embodiment, the amount administered is between about 1,490 ng/kg and about 1,510 ng/kg. In one embodiment, the amount administered is about 1,500 ng/kg. In one embodiment, the amount administered is 1,500 ng/kg. In one embodiment, the amount administered is between about 1,600 ng/kg and about 1,800 ng/kg. In one embodiment, the amount administered is between about 1,650 ng/kg and about 1,750 ng/kg. In one embodiment, the amount administered is between about 1,675 ng/kg and about 1,725 ng/kg. In one embodiment, the amount administered is between about 1,690 ng/kg and about 1,710 ng/kg. In one embodiment, the amount administered is about 1,700 ng/kg. In one embodiment, the amount administered is 1,700 ng/kg. In one embodiment, the amount administered is between about 1,600 ng/kg and about 2,000 ng/kg. In one embodiment, the amount administered is between about 1,650 ng/kg and about 1,950 ng/kg. In one embodiment, the amount administered is between about 1,700 ng/kg and about 1,900 ng/kg. In one embodiment, the amount administered is between about 1,750 ng/kg and about 1,850 ng/kg. In one embodiment, the amount administered is between about 1,775 ng/kg and about 1,825 ng/kg. In one embodiment, the amount administered is between about 1,790 ng/kg and about 1,810 ng/kg. In one embodiment, the amount administered is about 1,800 ng/kg. In one embodiment, the amount administered 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 amount administered is between about 1,800 ng/kg and about 2,200 ng/kg. In one embodiment, the amount administered is between about 1,900 ng/kg and about 2,100 ng/kg. In one embodiment, the amount administered is about 2,000 ng/kg. In one embodiment, the amount administered is 2,000 ng/kg. In one embodiment, the amount administered is between about 1,800 ng/kg and about 2,800 ng/kg. In one embodiment, the amount administered is between about 2,000 ng/kg and about 2,600 ng/kg. In one embodiment, the amount administered is between about 2,250 ng/kg and about 2,500 ng/kg. In one embodiment, the amount administered is between about 2,300 ng/kg and about 2,350 ng/kg. In one embodiment, the amount administered is about 2,333 ng/kg. In one embodiment, the amount administered is 2,333 ng/kg. In one embodiment, the amount administered is about 2,400 ng/kg. In one embodiment, the amount administered is 2,400 ng/kg. In one embodiment, the amount administered is between about 2,200 ng/kg and about 2,400 ng/kg. In one embodiment, the amount administered is about 2,300 ng/kg. In one embodiment, the amount administered is 2,300 ng/kg.

Paragraph F includes any of the following doses: In one embodiment, the dose is between about 2,000 ng/kg and about 5,000 ng/kg. In one embodiment, the amount administered is between about 2,000 ng/kg and about 4,000 ng/kg. In one embodiment, the amount administered is between about 3,000 ng/kg and about 4,000 ng/kg. In one embodiment, the amount administered is between about 3,250 ng/kg and about 3,750 ng/kg. In one embodiment, the amount administered is between about 3,400 ng/kg and about 3,600 ng/kg. In one embodiment, the amount administered is about 3,500 ng/kg. In one embodiment, the amount administered is 3,500 ng/kg. In one embodiment, the amount administered is between about 3,500 ng/kg and about 3,700 ng/kg. In one embodiment, the amount administered is about 3,600 ng/kg. In one embodiment, the amount administered is 3,600 ng/kg. In one embodiment, the amount administered is between about 3,000 ng/kg and about 5,000 ng/kg. In one embodiment, the amount administered is between about 3,400 ng/kg and about 3,600 ng/kg. In one embodiment, the amount administered is about 3,500 ng/kg. In one embodiment, the amount administered is 3,500 ng/kg. In one embodiment, the amount administered is between about 2,500 ng/kg and about 3,500 ng/kg. In one embodiment, the amount administered is between about 2,750 ng/kg and about 3,250 ng/kg. In one embodiment, the amount administered is about 3,000 ng/kg. In one embodiment, the amount administered is 3,000 ng/kg. In one embodiment, the amount administered is between about 2,750 ng/kg and about 3,000 ng/kg. In one embodiment, the amount administered is between about 2,800 ng/kg and about 2,900 ng/kg. In one embodiment, the amount administered is between about 2,830 ng/kg and about 2,880 ng/kg. In one embodiment, the amount administered is about 2,857 ng/kg. In one embodiment, the amount administered is 2,857 ng/kg. In one embodiment, the amount administered is between about 2,000 ng/kg and about 3,000 ng/kg. In one embodiment, the amount administered is between about 2,100 ng/kg and about 2,900 ng/kg. In one embodiment, the amount administered is between about 2,200 ng/kg and about 2,800 ng/kg. In one embodiment, the amount administered is between about 2,300 ng/kg and about 2,700 ng/kg. In one embodiment, the amount administered is between about 2,350 ng/kg and about 2,650 ng/kg. In one embodiment, the amount administered is between about 2,400 ng/kg and about 2,600 ng/kg. In one embodiment, the amount administered is between about 2,425 ng/kg and about 2,575 ng/kg. In one embodiment, the amount administered is between about 2,450 ng/kg and about 2,550 ng/kg. In one embodiment, the amount administered is between about 2,475 ng/kg and about 2,525 ng/kg. In one embodiment, the amount administered is between about 2,490 ng/kg and about 2,510 ng/kg. In one embodiment, the amount administered is about 2,500 ng/kg. In one embodiment, the amount administered is 2,500 ng/kg. In one embodiment, the amount administered is between about 2,500 ng/kg and about 3,500 ng/kg. In one embodiment, the amount administered is between about 2,600 ng/kg and about 3,300 ng/kg. In one embodiment, the amount administered is between about 2,700 ng/kg and about 3,200 ng/kg. In one embodiment, the amount administered is between about 2,800 ng/kg and about 3,100 ng/kg. In one embodiment, the amount administered is between about 2,850 ng/kg and about 3,000 ng/kg. In one embodiment, the amount administered is between about 2,850 ng/kg and about 2,950 ng/kg. In one embodiment, the amount administered is between about 2,875 ng/kg and about 2,925 ng/kg. In one embodiment, the amount administered is between about 2,890 ng/kg and about 2,910 ng/kg. In one embodiment, the amount administered is about 2,900 ng/kg. In one embodiment, the amount administered is 2,900 ng/kg. In one embodiment, the amount administered is between about 3,500 ng/kg and about 4,000 ng/kg. In one embodiment, the amount administered is between about 3,600 ng/kg and about 3,900 ng/kg. In one embodiment, the amount administered is between about 3,700 ng/kg and about 3,900 ng/kg. In one embodiment, the amount administered is between about 3,750 ng/kg and about 3,850 ng/kg. In one embodiment, the amount administered is between about 3,775 ng/kg and about 3,825 ng/kg. In one embodiment, the amount administered is between about 3,790 ng/kg and about 3,810 ng/kg. In one embodiment, the amount administered is about 3,800 ng/kg. In one embodiment, the amount administered is 3,800 ng/kg. In one embodiment, the amount administered is between about 3,200 ng/kg and about 3,400 ng/kg. In one embodiment, the amount administered is between about 3,300 ng/kg and about 3,350 ng/kg. In one embodiment, the amount administered is about 3,333 ng/kg. In one embodiment, the amount administered is 3,333 ng/kg. In one embodiment, the amount administered is between about 4,000 ng/kg and about 5,000 ng/kg. In one embodiment, the amount administered is between about 4,100 ng/kg and about 4,900 ng/kg. In one embodiment, the amount administered is between about 4,200 ng/kg and about 4,800 ng/kg. In one embodiment, the amount administered is between about 4,300 ng/kg and about 4,700 ng/kg. In one embodiment, the amount administered is between about 4,400 ng/kg and about 4,600 ng/kg. In one embodiment, the amount administered is about 4,500 ng/kg. In one embodiment, the amount administered is 4,500 ng/kg. In one embodiment, the amount administered is between about 2,500 ng/kg and about 5,000 ng/kg. In one embodiment, the amount administered is between about 3,000 ng/kg and about 5,000 ng/kg. In one embodiment, the amount administered is between about 3,500 ng/kg and about 4,500 ng/kg. In one embodiment, the amount administered is between about 3,750 ng/kg and about 4,250 ng/kg. In one embodiment, the amount administered is about 4,000 ng/kg. In one embodiment, the amount administered is 4,000 ng/kg.

Paragraph G includes any of the following dosages: In one embodiment, the dosage is between about 3,000 ng/kg and about 11,000 ng/kg. In one embodiment, the amount administered is between about 4,000 ng/kg and about 10,000 ng/kg. In one embodiment, the amount administered is between about 6,000 ng/kg and about 7,000 ng/kg. In one embodiment, the amount administered is between about 6,500 ng/kg and about 6,750 ng/kg. In one embodiment, the amount administered is about 6,667 ng/kg. In one embodiment, the amount administered is 6,667 ng/kg. In one embodiment, the amount administered is about 6,700 ng/kg. In one embodiment, the amount administered is 6,700 ng/kg. In one embodiment, the amount administered is between about 4,000 ng/kg and about 6,000 ng/kg. In one embodiment, the amount administered is between about 4,500 ng/kg and about 5,500 ng/kg. In one embodiment, the amount administered is between about 4,750 ng/kg and about 5,250 ng/kg. In one embodiment, the amount administered is between about 4,900 ng/kg and about 5,100 ng/kg. In one embodiment, the amount administered is about 5,000 ng/kg. In one embodiment, the amount administered is 5,000 ng/kg. In one embodiment, the amount administered is between about 4,000 ng/kg and about 8,000 ng/kg. In one embodiment, the amount administered is between about 5,000 ng/kg and about 7,000 ng/kg. In one embodiment, the amount administered is between about 5,500 ng/kg and about 6,000 ng/kg. In one embodiment, the amount administered is between about 5,500 ng/kg and about 5,700 ng/kg. In one embodiment, the amount administered is about 5,600 ng/kg. In one embodiment, the amount administered is 5,600 ng/kg. In one embodiment, the amount administered is between about 5,750 ng/kg and about 5,900 ng/kg. In one embodiment, the amount administered is about 5,833 ng/kg. In one embodiment, the amount administered is 5,833 ng/kg. In one embodiment, the amount administered is between about 5,600 ng/kg and about 5,900 ng/kg. In one embodiment, the amount administered is between about 5,600 ng/kg and about 5,800 ng/kg. In one embodiment, the amount administered is between about 5,650 ng/kg and about 5,750 ng/kg. In one embodiment, the amount administered is between about 5,675 ng/kg and about 5,725 ng/kg. In one embodiment, the amount administered is between about 5,690 ng/kg and about 5,710 ng/kg. In one embodiment, the amount administered is about 5,700 ng/kg. In one embodiment, the amount administered is 5,700 ng/kg. In one embodiment, the amount administered is between about 6,000 ng/kg and about 11,000 ng/kg. In one embodiment, the amount administered is between about 6,500 ng/kg and about 10,500 ng/kg. In one embodiment, the amount administered is between about 7,000 ng/kg and about 10,000 ng/kg. In one embodiment, the amount administered is between about 7,500 ng/kg and about 9,500 ng/kg. In one embodiment, the amount administered is between about 8,000 ng/kg and about 9,000 ng/kg. In one embodiment, the amount administered is between about 8,100 ng/kg and about 8,900 ng/kg. In one embodiment, the amount administered is between about 8,200 ng/kg and about 8,800 ng/kg. In one embodiment, the amount administered is between about 8,300 ng/kg and about 8,700 ng/kg. In one embodiment, the amount administered is between about 8,350 ng/kg and about 8,650 ng/kg. In one embodiment, the amount administered is between about 8,400 ng/kg and about 8,600 ng/kg. In one embodiment, the amount administered is between about 8,425 ng/kg and about 8,575 ng/kg. In one embodiment, the amount administered is between about 8,450 ng/kg and about 8,550 ng/kg. In one embodiment, the amount administered is between about 8,475 ng/kg and about 8,525 ng/kg. In one embodiment, the amount administered is between about 8,490 ng/kg and about 8,510 ng/kg. In one embodiment, the amount administered is about 8,500 ng/kg. In one embodiment, the amount administered is 8,500 ng/kg. In one embodiment, the amount administered is between about 5,500 ng/kg and about 6,500 ng/kg. In one embodiment, the amount administered is between about 5,900 ng/kg and about 6,100 ng/kg. In one embodiment, the amount administered is about 6,000 ng/kg. In one embodiment, the amount administered is 6,000 ng/kg. In one embodiment, the amount administered is between about 5,000 ng/kg and about 9,000 ng/kg. In one embodiment, the amount administered is between about 6,000 ng/kg and about 8,000 ng/kg. In one embodiment, the amount administered is between about 6,500 ng/kg and about 7,500 ng/kg. In one embodiment, the amount administered is about 7,000 ng/kg. In one embodiment, the amount administered is 7,000 ng/kg.

Paragraph H includes any of the following dosages: In one embodiment, the dosage is between about 7,000 ng/kg and about 17,000 ng/kg. In one embodiment, the amount administered is between about 8,000 ng/kg and about 16,000 ng/kg. In one embodiment, the amount administered is between about 8,000 ng/kg and about 14,000 ng/kg. In one embodiment, the amount administered is between about 8,000 ng/kg and about 12,000 ng/kg. In one embodiment, the amount administered is between about 9,000 ng/kg and about 11,000 ng/kg. In one embodiment, the amount administered is between about 9,500 ng/kg and about 10,500 ng/kg. In one embodiment, the amount administered is about 10,000 ng/kg. In one embodiment, the amount administered is 10,000 ng/kg. In one embodiment, the amount administered is between about 8,000 ng/kg and about 9,500 ng/kg. In one embodiment, the amount administered is between about 8,250 ng/kg and about 9,250 ng/kg. In one embodiment, the amount administered is between about 8,500 ng/kg and about 9,000 ng/kg. In one embodiment, the amount administered is about 8,750 ng/kg. In one embodiment, the amount administered is 8,750 ng/kg. In one embodiment, the amount administered is between about 9,000 ng/kg and about 15,000 ng/kg. In one embodiment, the amount administered is between about 10,000 ng/kg and about 14,000 ng/kg. In one embodiment, the amount administered is between about 11,250 ng/kg and about 12,500 ng/kg. In one embodiment, the amount administered is between about 11,250 ng/kg and about 12,000 ng/kg. In one embodiment, the amount administered is between about 11,500 ng/kg and about 11,750 ng/kg. In one embodiment, the amount administered is about 11,667 ng/kg. In one embodiment, the amount administered is 11,667 ng/kg. In one embodiment, the amount administered is about 11,700 ng/kg. In one embodiment, the amount administered is 11,700 ng/kg. In one embodiment, the amount administered is between about 11,000 ng/kg and about 13,000 ng/kg. In one embodiment, the amount administered is about 12,000 ng/kg. In one embodiment, the amount administered is 12,000 ng/kg. In one embodiment, the amount administered is between about 10,500 ng/kg and about 13,500 ng/kg. In one embodiment, the amount administered is between about 11,000 ng/kg and about 13,000 ng/kg. In one embodiment, the amount administered is between about 12,500 ng/kg and about 13,000 ng/kg. In one embodiment, the amount administered is between about 12,600 ng/kg and about 12,950 ng/kg. In one embodiment, the amount administered is between about 12,650 ng/kg and about 12,950 ng/kg. In one embodiment, the amount administered is between about 12,700 ng/kg and about 12,950 ng/kg. In one embodiment, the amount administered is between about 12,700 ng/kg and about 12,900 ng/kg. In one embodiment, the amount administered is between about 12,750 ng/kg and about 12,850 ng/kg. In one embodiment, the amount administered is between about 12,775 ng/kg and about 12,825 ng/kg. In one embodiment, the amount administered is between about 12,790 ng/kg and about 12,810 ng/kg. In one embodiment, the amount administered is about 12,800 ng/kg. In one embodiment, the amount administered is 12,800 ng/kg.

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

Paragraph J includes any of the following doses: In one embodiment, the dose is between about 20,000 ng/kg and about 50,000 ng/kg. In one embodiment, the amount administered is between about 25,000 ng/kg and about 45,000 ng/kg. In one embodiment, the amount administered is between about 28,000 ng/kg and about 30,000 ng/kg. In one embodiment, the amount administered is between about 28,500 ng/kg and about 29,500 ng/kg. In one embodiment, the amount administered is about 28,800 ng/kg. In one embodiment, the amount administered is 28,800 ng/kg. In one embodiment, the amount administered is between about 30,000 ng/kg and about 40,000 ng/kg. In one embodiment, the amount administered is between about 31,000 ng/kg and about 38,000 ng/kg. In one embodiment, the amount administered is between about 34,000 ng/kg and about 36,000 ng/kg. In one embodiment, the amount administered is about 35,000 ng/kg. In one embodiment, the amount administered is 35,000 ng/kg. V. a) ii). Investment time

In one embodiment, the dose to a human subject is administered between about 5 minutes and about 10 hours. In one embodiment, the dose to a human subject is administered between about 5 minutes and about 5 hours. In one embodiment, the dose to a human subject is administered between about 5 minutes and about 60 minutes. In one embodiment, the dose to a human subject is administered between about 5 minutes and about 30 minutes. In one embodiment, the dose to a human subject is administered between about 30 minutes and about 60 minutes. In one embodiment, the dose to a human subject is administered between about 60 minutes and about 90 minutes. In one embodiment, the dose to a human subject is administered between about 90 minutes and about 2 hours. In one embodiment, the dose to a human subject is administered between about one hour and about three hours. In one embodiment, the dose to a human subject is administered between about two hours and about four hours. In one embodiment, the dose to a human subject is administered between about three hours and about five hours. In one embodiment, the dose to a human subject is administered between about four hours and about six hours. In one embodiment, the dose to a human subject is administered between about five hours and about seven hours. In one embodiment, the dose to a human subject is administered between about six hours and about eight hours. In one embodiment, the dose to a human subject is administered between about seven hours and about nine hours. In one embodiment, the dose to a human subject is administered between about eight hours and about ten hours. In one embodiment, the dose to a human subject is administered over a period of 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 vote. In one embodiment, the dose to a human subject is administered between about 90 minutes and about 150 minutes. In one embodiment, the dose to a human subject is administered between about 105 minutes and about 135 minutes. In one embodiment, the dose to a human subject is administered over about two hours. In one embodiment, the dose to a human subject is administered over two hours. V. b). Dosage schedule

In one embodiment, each dosage regimen comprises at least one dose of a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) provided to the human subject (weekly or monthly/set day or days or one or more weeks). Dosage regimens are adjusted to provide the best desired response (eg, therapeutic response). Effective dosages and dosage regimens of bispecific anti-CD123 x anti-CD3 antibodies used in the present invention depend on the disease or condition to be treated. daily dosage regimen

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or paragraph H, or paragraph I, or paragraph J, or any combination thereof, are provided once daily. The time of administration can be any described throughout the specification. every other day dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or paragraph H, or paragraph I, or paragraph J, or any combination thereof, are provided every other day. The time of administration can be any described throughout the specification. Dosing schedule six times a week

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided six times per week. The time of administration can be any described throughout the specification. Five times a week dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided five times per week. The time of administration can be any described throughout the specification. Four times a week dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided four times per week. The time of administration can be any described throughout the specification. Dosing regimen three times a week

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided three times per week. The time of administration can be any described throughout the specification. twice-weekly dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided twice weekly. The time of administration can be any described throughout the specification. weekly dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided once a week. The time of administration can be any described throughout the specification.

In an exemplary embodiment, the dose is administered once every about 5 days to about 10 days. In an exemplary embodiment, the dose is administered every 5-10 days. In an exemplary embodiment, the dose is administered once every about 5 days to about 9 days. In an exemplary embodiment, the dose is administered every 5-9 days. In an exemplary embodiment, the dose is administered once every about 6 days to about 8 days. In an exemplary embodiment, the dose is administered every 6-8 days. In an exemplary embodiment, the dose is administered once every about 6 days to about 10 days. In an exemplary embodiment, the dose is administered every 6-10 days. In an exemplary embodiment, the dose is administered once every about 7 days to about 9 days. In an exemplary embodiment, the dose is administered every 7-9 days. In an exemplary embodiment, an intravenous dose of XmAb14045 is administered about every 7 days. In an exemplary embodiment, the dose is administered every 7 days. In an exemplary embodiment, the dose is administered once a week. In an exemplary embodiment, an intravenous dose of XmAb14045 is administered once a week. biweekly dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided every two weeks. The time of administration can be any described throughout the specification. Dosing schedule every three weeks

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any one of G, or paragraph H, or paragraph I, or paragraph J, or any combination thereof, are provided every three weeks. The time of administration can be any described throughout the specification. Every four weeks dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided every four weeks. The time of administration can be any described throughout the specification. twice-monthly dosing schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) dose is selected from segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or The dosing amount of segment G, or segment H, or segment I, or segment J, or any combination thereof, is provided twice per month. The time of administration can be any described throughout the specification. three-monthly dosing regimen

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided three times per month. The time of administration can be any described throughout the specification. Monthly Dosing Schedule

In one embodiment, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is dosed at a dose in segment A, or segment B, or segment C, or segment D, or segment E, or segment F, or segment The dosing amounts disclosed in any of G, or Paragraph H, or Paragraph I, or Paragraph J, or any combination thereof, are provided once a month. The time of administration can be any described throughout the specification.

In an exemplary embodiment, the dose is administered once every about 12 days to about 17 days. In an exemplary embodiment, the dose is administered once every about 13 days to about 15 days. In an exemplary embodiment, the dose is administered every 13-15 days. In an exemplary embodiment, the dose is administered once every about 12 days to about 16 days. In an exemplary embodiment, the dose is administered every 12-16 days. In an exemplary embodiment, the dose is administered every 14-16 days. In an exemplary embodiment, the dose is administered about every 14 days. In an exemplary embodiment, the dose is administered every 14 days. In an exemplary embodiment, the dose is administered about every two weeks. In an exemplary embodiment, the dose is administered every two weeks. In an exemplary embodiment, the dose is administered once every about 13 days to about 17 days. In an exemplary embodiment, the dose is administered every 13-17 days. In an exemplary embodiment, the dose is administered about every 15 days. In an exemplary embodiment, the dose is administered every 15 days. V. c). Stage

In one embodiment, a phase includes the occurrence of a certain number of dosage regimens. In one embodiment, the dosage regimen occurs once in a phase. In one embodiment, the dosage regimen occurs twice in a phase. In one embodiment, the dosage regimen occurs three times in a phase. In one embodiment, the dosage regimen occurs four times in a phase. In one embodiment, the dosage regimen occurs five times in a phase. In one embodiment, the dosage regimen occurs six times in a phase. In one embodiment, the dosage regimen occurs seven times in a phase. In one embodiment, the dosage regimen occurs eight times in a phase. In one embodiment, the dosage regimen occurs nine times in a phase. In one embodiment, the dosage regimen occurs ten times in a phase. In one embodiment, the dosage regimen occurs eleven times in a phase. In one embodiment, the dosage regimen occurs twelve times in a phase. In one embodiment, the dosage regimen occurs thirteen times in a phase. In one embodiment, the dosage regimen occurs fourteen times in a phase. In one embodiment, the dosage regimen occurs fifteen times in a phase. In one embodiment, the dosage regimen occurs sixteen times in a phase. In one embodiment, the dosage regimen occurs seventeen times in a phase. In one embodiment, the dosage regimen occurs eighteen times in a phase. In one embodiment, the dosage regimen occurs nineteen times in a phase. In one embodiment, the dosage regimen occurs twenty times in a phase. In one embodiment, the dosage regimen is continued until the cancer (eg, blood cancer) is in remission (eg, full or partial).

In one embodiment, this phase is a weekly dosing regimen as described herein, and is one week in duration. In one embodiment, this phase is a weekly dosing regimen as described herein and is two weeks in duration. In one embodiment, this phase is the once-weekly dosing regimen described herein and is three weeks in duration. In one embodiment, this phase is a weekly dosing regimen as described herein, and is four weeks in duration.

In one embodiment, this phase is a twice-weekly dosing regimen as described herein, and is one week in duration. In one embodiment, this phase is a twice-weekly dosing regimen as described herein, and is two weeks in duration. In one embodiment, this phase is the twice-weekly dosing regimen described herein and is three weeks in duration. In one embodiment, this phase is a twice-weekly dosing regimen as described herein, and is four weeks in duration.

In one embodiment, this phase is a three-weekly dosing regimen as described herein, and is one week in duration. In one embodiment, this phase is a three-weekly dosing regimen as described herein, and is two weeks in duration. In one embodiment, this phase is a three-weekly dosing regimen as described herein, and is three weeks in duration. In one embodiment, this phase is a three-weekly dosing regimen as described herein, and is four weeks in duration.

In one embodiment, this phase is a four times weekly dosing regimen as described herein, and is one week in duration. In one embodiment, this phase is a four-weekly dosing regimen as described herein, and is two weeks in duration. In one embodiment, this phase is the four times weekly dosing regimen described herein and is three weeks in duration. In one embodiment, this phase is a four-weekly dosing regimen as described herein, and is four weeks in duration.

In one embodiment, this phase is a five-times-a-week dosing regimen as described herein, and is one week in duration. In one embodiment, this phase is a five-weekly dosing regimen as described herein, and is two weeks in duration. In one embodiment, this phase is a five-weekly dosing regimen as described herein, and is three weeks in duration. In one embodiment, this phase is a five-weekly dosing regimen as described herein, and is four weeks in duration. V. d). To maintain

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) treats refractory leukemia or lymphoma. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is maintenance therapy. In one embodiment, for any of the methods described herein, when the cancer exhibits CD123 remission, such as partial remission and/or complete remission, the method further comprises according to the dosage regimen described herein, for remission (e.g., partial remission) and/or complete remission) of the same dose as a maintenance dose, or at about 10% (plus or minus) of this dose, or at about 20% (plus or minus) of this dose, or at this dose Within about 30% (plus or minus) of the dose administered, for at least one dose, the bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAb14045) is provided until no efficacy is determined, an unacceptable level of toxicity is observed, or an Human subjects terminated. In one embodiment, for any of the methods described herein, when the cancer exhibits CD123 remission, such as partial remission and/or complete remission, the method further comprises according to the weekly dosing regimen described herein or as described herein The once every three weeks dosing regimen or the once every four weeks dosing regimen described herein or the twice monthly dosing regimen described herein or the thrice monthly dosing regimen described herein or the monthly dosing regimen described herein Dosage regimen for remission (eg, partial remission and/or complete remission) at a maintenance dose of the same dose administered, or at about 10% (plus or minus) of this dose, or at (plus or minus) the dose or minus) about 20%, or within about 30% (plus or minus) of the dose administered, for at least one dose, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is provided until no efficacy is determined, Unsatisfactory toxicity levels were observed, or discontinued by human subjects. In one embodiment, for any of the methods described herein, when the cancer exhibits CD123 remission, such as partial remission and/or complete remission, the method further comprises a biweekly dosing regimen as described herein, for remission (eg partial remission and/or complete remission) maintenance dose of the same amount administered, or at about 10% (plus or minus) of this dose, or at about 20% (plus or minus) of this dose , or within about 30% (plus or minus) of the dose administered, for at least one dose, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is provided until no efficacy is determined, and substandard toxicity is observed levels, or terminated by human subjects. VI. Four Stages of Implementation

The methods of treatment disclosed herein can include first and second and third and fourth stages. In the first phase, the antibody may be provided according to a first dosage regimen, in a first administered amount. In the second phase, the antibody may be provided according to a second dosage regimen, with a second administered amount. In the third phase, the antibody may be provided according to a third dosage regimen, with a third administration amount. In the fourth phase, the antibody may be provided according to a fourth dosage regimen, with a fourth dosing amount. The time of administration can independently be any described throughout the specification. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Four-phase, no-dose regimen

The methods of treatment disclosed herein can include first and second and third and fourth stages. In the first phase, the antibody may be provided according to the daily or every other day or six times a week or five times a week or four times a week or three times a week or twice a week as described herein for up to four weeks (eg, one, two, three, or four weeks), wherein the one or more doses are described in paragraph B or paragraph C or paragraph D or paragraph E or paragraph F. In the second phase, the antibody may be provided in a second dosing amount described in paragraph E or paragraph F or paragraph G according to a second dosage regimen described herein for up to four weeks (eg, one, two, three, or four weeks). In the third phase, the antibody may be provided in a third dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fourth phase, the antibody may be provided in a fourth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In one embodiment, the fourth stage continues until the cancer (eg, a cancer expressing CD123) is in remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Two phases, of which the first phase is administered three times a week

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided three times per week in three different dosing amounts for one week, and wherein in the second stage the antibody is given in the third Two doses are provided once a week. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein the antibody is provided three times a week for one week in the first stage, wherein the first dose is as described in paragraph B in the first stage, and two subsequent each dose is greater than the first dose and is each independently selected from segment C or segment D or segment E, and wherein in the second phase the antibody is provided weekly in the second dose, and the second phase This dose is greater than any dose administered in the first phase. The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided three times per week for one week, wherein the first dose in the first stage is about 400 ng/kg and about 500 ng/kg ng/kg, and two subsequent doses greater than the first dose and each independently selected from paragraph C or paragraph D, and wherein the antibody is provided weekly in the second dose in a second dose Once, the second dose is selected from paragraph E, and the dose in the second phase is greater than any dose in the first phase. The methods of treatment disclosed herein may include a first stage and a second stage, wherein the antibody is provided three times a week for one week in the first stage, wherein the first dose is about 430 ng/kg in the first stage, and then two doses greater than the first dose and each independently selected from paragraph C or paragraph D, and wherein the antibody is provided weekly in a second dose, the second dose, in the second phase is selected from paragraph E, and the dose administered in the second phase is greater than any dose administered in the first phase. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose administered in the 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 administered in the first phase is the first phase Between about 100% and about 180% of the first dose, such as between about 140% and about 180%, such as between about 170% and about 180%, and the third dose in the first stage is Between about 100% and about 160% of the second dose administered in the first phase, such as between about 130% and about 160%, wherein in the second phase, at about 100% to about 160% of the third dose administered in the first phase A second dose of between 100% and about 160% (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase is about 430 ng/kg, the second dose in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose in the first phase is Between about 1,000 ng/kg and about 1,250 ng/kg, wherein in the second stage, between about 100% and about 160% of the third dose administered in the first stage (eg, about 130% to about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between ) once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase is about 430 ng/kg, the second dose in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose in the first phase is Between about 1,000 ng/kg and about 1,250 ng/kg, wherein in the second phase, the dual dose is administered to the human subject at a second dose of between about 1,500 ng/kg and about 1,900 ng/kg. Specific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase is about 430 ng/kg, the second dose in the first phase is about 750 ng/kg, and the third dose in the first phase is about 1,100 ng/kg, wherein the In the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of about 1,700 ng/kg once a week until remission (eg, complete or partial), or continued up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Decrease Increment Groups:

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided three times per week for one week, wherein the first dose in the first stage is from about 400 ng/kg to about 500 ng/kg ng/kg, and two subsequent doses greater than the first dose and each independently selected from paragraph C, and wherein the antibody is provided weekly in the second dose in the second phase, the The second dose administered is selected from paragraph D, and the dose administered in the second phase is greater than any dose administered in the first phase. The methods of treatment disclosed herein may include a first stage and a second stage, wherein the antibody is provided three times a week for one week in the first stage, wherein the first dose is about 430 ng/kg in the first stage, and then Two doses greater than the first dose and each independently selected from paragraph C, and wherein the antibody is provided weekly in a second dose selected from paragraph C in the second phase D, and the dose administered in the second phase is greater than any dose administered in the first phase. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose administered in the 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 administered in the first phase is the first phase between about 100% and about 130%, such as between about 120% and about 130% of the first dose in the first phase, and the third dose in the first phase is about the second dose in the first phase. Between 100% and about 130%, such as between about 120% and about 130%, and wherein in the second stage, between about 100% and about 130% of the third dose administered in the first stage (such as The bispecific anti-CD123 x anti-CD3 antibody is administered weekly to the human subject at a second dose of between about 120% and about 130%. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase is between about 430 ng/kg, the second dose in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose in the first phase is Between about 624 ng/kg and about 732 ng/kg, wherein in the second stage, between about 100% and about 130% (such as about 120% to about 130%) of the third dose administered in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between ) once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase is between about 430 ng/kg, the second dose in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose in the first phase is Between about 624 ng/kg and about 732 ng/kg, wherein in the second phase, the dual dose is administered to the human subject at a second dose of between about 900 ng/kg and about 1,238 ng/kg. Specific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first The first dose in the first phase was about 430 ng/kg, the second dose in the first phase was about 542 ng/kg, and the third dose in the first phase was about 678 ng/kg, wherein the In the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of about 848 ng/kg once a week until remission (eg, complete or partial), or continued up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Four phases, of which the first phase is administered three times a week

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided in a first dosing amount three times a week for one week, and wherein in the first stage In the second phase, the antibody is provided in a second dose once a week, and in a third phase, the antibody is provided in a third dose once a week, and in a fourth phase, the antibody is provided in a A fourth dose provides the antibody once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fourth phase is between one week and four weeks. In one embodiment, the fourth stage continues until the cancer (eg, a cancer expressing CD123) is in remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for one week, wherein in the first stage a first dose is administered Described in paragraph B, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage, the second dose is the antibody is provided in a dose once a week, and wherein in the third phase, the antibody is provided in a third dose once a week, and wherein in the fourth phase, the antibody is provided in a fourth dose, Once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount. In some embodiments, the duration of the fourth phase is between one week and four weeks. In one embodiment, the fourth stage continues until the cancer (eg, a cancer expressing CD123) is in remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for a week, wherein in the first stage a first dose is administered Described in paragraph C, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage, the second dose is the antibody is provided in a dose once a week, and wherein in the third phase, the antibody is provided in a third dose once a week, and wherein in the fourth phase, the antibody is provided in a fourth dose, Once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for a week, wherein in the first stage a first dose is administered is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, with A second dose selected from paragraph E or paragraph F provides the antibody once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph F once a week, and wherein In a fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the third dosing amount Two doses. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for a week, wherein in the first stage a first dose is administered is about 750 ng/kg, and the two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, to be selected from paragraph E or paragraph F The antibody is provided in a second dosing amount once a week, and wherein in a third stage, the antibody is provided in a third dosing amount selected from paragraph F, once a week, and wherein in a fourth stage, the antibody is provided in a selected The antibody is provided from a fourth dose of segment G, once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fourth phase is between one week and four weeks. In one embodiment, the fourth stage continues until the cancer (eg, a cancer expressing CD123) is in remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subject is tested in the first, second, and third doses The bispecific anti-CD123 x anti-CD3 antibody is administered three times per week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about 900 ng/kg between, such as about 750 ng/kg, and the second dose in the first stage is between about 100% to about 160%, such as about 130% to about 160% of the first dose in the first stage and the third dose in the first stage is between about 100% and about 160% of the second dose in the first stage, such as between about 130% and about 160%, wherein in the second stage administering the bispecific to a human subject at a second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose in the first phase anti-CD123 x anti-CD3 antibody, once a week for one week, wherein in the third phase, at between about 100% and about 160% (eg, between about 130% and about 160%) of the second dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose once a week for one week, and wherein in the fourth phase, from about 100% to about 100% of the third dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between 160% (eg, between about 130% and about 160%) once a week. In some embodiments, the duration of the fourth phase is between one week and four weeks. In one embodiment, the fourth stage continues until the cancer (eg, a cancer expressing CD123) is in remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses were administered the bispecific anti-CD123 x anti-CD3 antibody three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase was about 750 ng/kg Between 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first stage is between about 1,600 ng/kg and about 1,800 ng/kg, wherein in the second stage, at the first stage A second dose of between about 100% and about 160% of the third dose (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject , once a week for one week, wherein in the third phase, the third dose is between about 100% and about 160% of the second dose (eg, between about 130% and about 160%) to The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, between about 100% and about 160% of the third dose administered (e.g. administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between about 130% and about 160%) once a week until remission (eg, complete or partial), or continued up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses were administered the bispecific anti-CD123 x anti-CD3 antibody three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase was about 750 ng/kg Between 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first stage is between about 1,600 ng/kg and about 1,800 ng/kg, and in the second stage, at about 2,400 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between kg and about 2,600 ng/kg once a week for one week, and wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at about The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between 3,600 ng/kg and about 3,900 ng/kg once a week for one week, and wherein in the fourth phase , administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between about 5,600 ng/kg and about 5,900 ng/kg weekly until remission (eg, complete or part), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses were administered the bispecific anti-CD123 x anti-CD3 antibody three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase was about 750 ng/kg 1,100 ng/kg, and a third dose of about 1,700 ng/kg in the first phase, wherein the dual dose is administered to a human subject at a second dose of about 2,500 ng/kg in the second phase. A specific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x is administered to a human subject in a third dose at a third dose of about 3,800 ng/kg The anti-CD3 antibody, once a week, for one week, and wherein in the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of about 5,700 ng/kg, each Once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for one week, wherein in the first stage a first dose is administered is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, with The antibody is provided in a second dose selected from paragraph E once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth In phase, the antibody is provided in a fourth dose selected from paragraph E, once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose quantity. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided three times a week for one week, wherein in the first stage a first dose is administered is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, with a second dose selected from paragraph E The antibody is provided in a dose once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph E, once a week, and wherein in the fourth phase, the antibody is provided in a dose selected from paragraph E A fourth dose of the antibody is provided once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses The bispecific anti-CD123 x anti-CD3 antibody is administered three times per week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about 900 ng/kg between, such as about 750 ng/kg, and the second dose in the first stage is between about 100% to about 130%, such as about 120% to about 130% of the first dose in the first stage and the third dose in the first stage is between about 100% and about 130% of the second dose in the first stage, such as between about 120% and about 130%, wherein in the second stage administering the bispecific to a human subject at a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose in the first phase anti-CD123 x anti-CD3 antibody, once a week for one week, wherein in the third phase, at between about 100% and about 130% (eg, between about 120% and about 130%) of the second dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose once a week for one week, and wherein in the fourth phase, from about 100% to about 100% of the third dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between 130% (eg, between about 120% and about 130%) once a week until remission (eg, complete remission) or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses were administered the bispecific anti-CD123 x anti-CD3 antibody three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase was about 750 ng/kg Between 800 ng/kg and about 1,000 ng/kg, and the third dose in the first stage is between about 1,100 ng/kg and about 1,300 ng/kg, wherein in the second stage, the amount of the first stage is A second dose of between about 100% and about 130% of the third dose (eg, between about 120% and about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject , once a week for one week, wherein in the third phase, the third dose is between about 100% and about 130% of the second dose (eg, between about 120% and about 130%) to The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, between about 100% and about 130% of the third dose administered (eg, administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between about 120% and about 130%, once a week until remission (eg, complete or partial), or continued up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the human subjects are tested in the first, second, and third doses were administered the bispecific anti-CD123 x anti-CD3 antibody three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase was about 750 ng/kg Between 800 ng/kg and about 1,000 ng/kg, and the third dose in the first stage is between about 1,100 ng/kg and about 1,300 ng/kg, wherein in the second stage, at about 1,400 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose between kg and about 1,600 ng/kg once a week for one week, and wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at about The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between 1,700 ng/kg and about 1,900 ng/kg once a week for one week, and wherein in the fourth phase , administer the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between about 2,200 ng/kg and about 2,400 ng/kg once weekly until remission (eg, complete or part), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is about 900 ng/kg, and the third dose is about 1,200 ng/kg in the first phase, wherein in the second phase, the human subject is administered a second dose of about 1,500 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific is administered to a human subject at a third dose of about 1,800 ng/kg in a third phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a fourth dose of about 2,300 ng/kg in a fourth phase CD3 antibody, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. five stages

The methods of treatment disclosed herein can include the first and second stages and the third and fourth stages and the fifth stage. In the first phase, the antibody may be provided according to a first dosage regimen, in a first administered amount. In the second phase, the antibody may be provided according to a second dosage regimen, with a second administered amount. In the third phase, the antibody may be provided according to a third dosage regimen, with a third administration amount. In the fourth phase, the antibody may be provided according to a fourth dosage regimen, with a fourth dosing amount. In the fifth stage, the antibody may be provided according to a fifth dosage regimen, with a fifth dosing amount. The time of administration can independently be any described throughout the specification. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Five-phase, no-dose regimen

The methods of treatment disclosed herein can include the first and second stages and the third and fourth stages and the fifth stage. In the first phase, the antibody may be provided according to the daily or every other day or six times a week or five times a week or four times a week or three times a week or twice a week as described herein for up to four weeks (eg, one, two, three, or four weeks), wherein the one or more doses are described in paragraph B or paragraph C or paragraph D or paragraph E or paragraph F. In the second phase, the antibody may be provided in a second dosing amount described in paragraph E or paragraph F or paragraph G according to a second dosage regimen described herein for up to four weeks (eg, one, two, three, or four weeks). In the third phase, the antibody may be provided in a third dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fourth phase, the antibody may be provided in a fourth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fifth stage, the antibody may be provided in a fifth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H or paragraph I according to the fifth dosage regimen described herein. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Five phases, of which the first phase is administered three times a week

The methods of treatment disclosed herein can include the first and second and third and fourth and fifth stages, wherein in the first stage, the antibody is provided in a first dosing amount three times per week for one week , and wherein in the second period, the antibody is provided in a second dose once a week, and wherein in a third period, the antibody is provided in a third dose once a week, and wherein in the fourth period In phase, the antibody is provided in a fourth dose once a week, and wherein in a fifth phase, the antibody is provided in a fifth dose once a week, and the fifth dose is greater than the fourth dose and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is described in Paragraph B, and two subsequent doses are greater than the first dose and are each independently selected from Paragraph C or Paragraph D or Paragraph E or Paragraph F, and wherein in the second stage, The antibody is provided in a second dosing amount once a week, and wherein in the third period, the antibody is provided in a third dosing amount once a week, and wherein in the fourth period, the antibody is provided in a fourth dosing amount The antibody is provided once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose once a week, and the fifth dose is greater than the fourth dose, and the fourth dose is provided The dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is described in paragraph C, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage, The antibody is provided in a second dosing amount once a week, and wherein in the third period, the antibody is provided in a third dosing amount once a week, and wherein in the fourth period, the antibody is provided in a fourth dosing amount The antibody is provided weekly, and wherein in the fifth phase, the antibody is provided weekly in a fifth dosing amount. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second In phase, the antibody is provided in a second dose selected from paragraph E or paragraph F, once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph F, weekly once, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and wherein in the fifth stage, with a fifth dosing selected from paragraph G or paragraph H providing the antibody in an amount once a week, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount Dosage. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is between about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from Paragraph D or Paragraph E, and wherein in the second phase, as in Paragraph E or the second dose described in paragraph F provides the antibody once a week, and wherein in the third phase, the antibody is provided in a third dose as described in paragraph F once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount as described in paragraph G, once a week, and wherein in the fifth stage, in a fifth dose as described in paragraph G or paragraph H Dosing amounts provide the antibody once a week, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the Second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about Between 900 ng/kg, such as about 750 ng/kg, and the second dose in the first stage is between about 100% and about 160% of the first dose in the first stage, such as about 130% to Between about 160%, and the third dose in the first stage is between about 100% and about 160% of the second dose in the first stage, such as between about 130% and about 160%, wherein In the second stage, a second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose in the first stage is administered to the human subject The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, wherein in the third phase, between about 100% and about 160% of the second dose (eg, about 130% to about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose between the administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose between 100% and about 160% (eg, between about 130% and about 160%) once a week for one week and wherein in the fifth stage, the human subject is administered a fifth dose of between about 100% and about 160% (such as between about 130% and about 160%) of the fourth dose The bispecific anti-CD123 x anti-CD3 antibody once a week. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, wherein in the second phase, the The bispecific anti-CD123 is administered to the human subject at a second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose of the first phase x anti-CD3 antibody, once a week for one week, wherein the dual dose is administered to a human subject in a third dose between about 130% and about 160% of the second dose in a third phase Specific anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fourth phase, between about 100% and about 160% of the third dose (such as between about 130% and about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose during the % to about 160% (eg, between about 130% and about 160%) of the fifth dose of the bispecific anti-CD123 x anti-CD3 antibody is administered weekly until remission (eg, complete or partial) ), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase The dose is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, wherein in the second phase, the The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 2,400 ng/kg and about 2,600 ng/kg once a week for one week, and wherein in a third phase The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 3,600 ng/kg and about 3,900 ng/kg once a week for one week, and wherein the In the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dosing amount between about 5,600 ng/kg and about 5,900 ng/kg once a week for one week, and wherein in the fifth stage, the bispecific anti-CD123 x anti-CD3 antibody is administered at a fifth dose of between about 8,300 ng/kg and about 8,700 ng/kg once a week until remission (eg, fully or partially), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is about 1,100 ng/kg, and the third dose is about 1,700 ng/kg in the first phase, wherein in the second phase, the human subject is administered a second dose of about 2,500 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein the bispecific is administered to a human subject at a third dose of about 3,800 ng/kg in a third phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a fourth dose of about 5,700 ng/kg in a fourth phase CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered at a fifth dose of about 8,500 ng/kg in a fifth phase once a week until remission ( For example, fully or partially), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second In phase, the antibody is provided in a second dose selected from paragraph E once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dosing amount selected from paragraph F, every Once a week, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein in the first stage the antibody is provided three times a week for one week One dose is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, to be selected from paragraph E The antibody is provided weekly in a second dose of A fourth dose selected from paragraph E provides the antibody once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose selected from paragraph F once a week, and the fifth dose The dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject three times a week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about Between 900 ng/kg, such as about 750 ng/kg, and the second dose in the first stage is between about 100% and about 130% of the first dose in the first stage, such as about 120% to Between about 130%, and the third dose in the first stage is between about 100% and about 130% of the second dose in the first stage, such as between about 120% and about 130%, wherein In the second stage, a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose in the first stage is administered to the human subject The bispecific anti-CD123 x anti-CD3 antibody, once a week, for one week, wherein in the third phase, between about 100% and about 130% of the second dose (eg, about 120% to about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose between the administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between 100% and about 130% (eg, between about 120% and about 130%) once a week for one week and wherein in the fifth stage, the human subject is administered a fifth dose of between about 100% and about 130% (such as between about 120% and about 130%) of the fourth dose The bispecific anti-CD123 x anti-CD3 antibody once a week. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is between about 800 ng/kg and about 1,000 ng/kg, and the third dose is between about 1,100 ng/kg and about 1,300 ng/kg in the first phase, wherein in the second phase, the The bispecific anti-CD123 is administered to the human subject at a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose of the first phase x anti-CD3 antibody, once a week for one week, wherein in the third phase, the third dose is between about 100% and about 130% (eg, between about 120% and about 130%) of the second dose Dosing amounts of the bispecific anti-CD123 x anti-CD3 antibody are administered to a human subject once a week for one week, and wherein in the fourth phase, at about 100% to about 130% of the third dosing amount The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between (eg, between about 120% and about 130%) once a week for one week, and wherein at the fifth In the stage, the bispecific anti-CD123 x anti-CD3 antibody is administered in a fifth dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose, Once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is between about 800 ng/kg and about 1,000 ng/kg, and the third dose is between about 1,100 ng/kg and about 1,300 ng/kg in the first phase, wherein in the second phase, the The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 1,400 ng/kg and about 1,600 ng/kg once a week for one week, and wherein in a third phase The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 1,700 ng/kg and about 1,900 ng/kg once a week for one week, and wherein the In the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dosing amount between about 2,200 ng/kg and about 2,400 ng/kg once a week for one week, and wherein in the fifth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at a fifth dose of between about 2,800 ng/kg and about 3,000 ng/kg once a week until remission (eg, fully or partially), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the first, second, and third doses are administered The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects three times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase The dose is about 900 ng/kg, and the third dose is about 1,200 ng/kg in the first phase, wherein in the second phase, the human subject is administered a second dose of about 1,500 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific is administered to a human subject at a third dose of about 1,800 ng/kg in a third phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a fourth dose of about 2,300 ng/kg in a fourth phase CD3 antibody once a week for one week and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered in a fifth dose of approximately 2,900 ng/kg weekly until remission ( For example, fully or partially), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. six stages

The methods of treatment disclosed herein can include the first and second and third and fourth and fifth and sixth stages. In the first phase, the antibody may be provided according to a first dosage regimen, in a first administered amount. In the second phase, the antibody may be provided according to a second dosage regimen, with a second administered amount. In the third phase, the antibody may be provided according to a third dosage regimen, with a third administration amount. In the fourth phase, the antibody may be provided according to a fourth dosage regimen, with a fourth dosing amount. In the fifth stage, the antibody may be provided according to a fifth dosage regimen, with a fifth dosing amount. In the sixth phase, the antibody may be provided according to a sixth dosage regimen, with a sixth dosing amount. The time of administration can independently be any described throughout the specification. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Six-phase, no-dose regimen

The methods of treatment disclosed herein can include the first and second and third and fourth and fifth and sixth stages. In the first phase, the antibody may be provided according to the daily or every other day or six times a week or five times a week or four times a week or three times a week or twice a week as described herein for up to four weeks (eg, one, two, three, or four weeks), wherein the one or more doses are described in paragraph B or paragraph C or paragraph D or paragraph E or paragraph F. In the second phase, the antibody may be provided in a second dosing amount described in paragraph E or paragraph F or paragraph G according to a second dosage regimen described herein for up to four weeks (eg, one, two, three, or four weeks). In the third phase, the antibody may be provided in a third dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fourth phase, the antibody may be provided in a fourth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fifth stage, the antibody may be provided in a fifth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H or paragraph I according to the fifth dosage regimen described herein. In the sixth stage, the antibody may be provided in a sixth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H or paragraph I or paragraph J according to the sixth dosage regimen described herein. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Six phases, of which the first phase is administered three times a week

The methods of treatment disclosed herein can include first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the antibody is provided in a first dosing amount, weekly three times for one week, and wherein in the second phase, the antibody is provided in a second dose once a week, and wherein in a third phase, the antibody is provided in a third dose once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount once a week, and wherein in a fifth stage, the antibody is provided in a fifth dosing amount once a week, and wherein in the sixth stage , the antibody is provided in a sixth dosing amount, once a week, and the sixth dosing amount is greater than the fifth dosing amount, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing amount The dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times per week for one week, wherein the first A first dose administered in a phase is described in paragraph B, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in paragraph In the second phase, the antibody is provided in the second dose once a week, and in the third phase, the antibody is provided in the third dose once a week, and in the fourth phase, the antibody is provided in the Four doses provide the antibody once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose, once a week, and wherein in the sixth phase, the antibody is provided in a sixth dose Antibody, once a week, and the sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose , and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first A first dose administered in a phase is described in paragraph C, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in paragraph In the second phase, the antibody is provided in a second dose once a week, and in a third phase, the antibody is provided in a third dose once a week, and in a fourth phase, the antibody is provided in the Four doses provide the antibody once a week, and wherein in a fifth phase, the antibody is provided in a fifth dose, once a week, and wherein in a sixth phase, the antibody is provided in a sixth dose Antibodies, once a week. The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first The first dose administered in one phase is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from segment D or segment E, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph E or paragraph F, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph F Antibody, once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in the fifth stage, with a fourth dose selected from paragraph G or paragraph H The antibody is provided in a fifth dosing amount once a week, and wherein in the sixth phase, the antibody is provided in a sixth dosing amount selected from paragraph G or paragraph H or paragraph I, once a week, and the sixth dosing amount is provided The dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the Second dose. The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first The first dose administered in one phase is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second phase, with The antibody is provided in a second dosing amount as described in paragraph E or paragraph F, once a week, and wherein in a third phase, the antibody is provided in a third dosing amount as described in paragraph F, weekly once, and wherein in the fourth phase, the antibody is provided in a fourth dosing amount as described in paragraph G, once a week, and wherein in the fifth phase, as described in paragraph G or paragraph H A fifth dosing amount provides the antibody once a week, and wherein in the sixth phase, the antibody is provided in a sixth dosing amount as described in paragraph G or paragraph H or paragraph I, once a week, and the The sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first Three doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects three times per week for one week, wherein the first dose in Phase 1 is found in paragraph C, such as about 600 ng /kg to about 900 ng/kg, such as about 750 ng/kg, and the second dose in the first stage is between about 100% and about 160% of the first dose in the first stage, such as Between about 130% and about 160%, and the third dose in the first phase is between about 100% and about 160% of the second dose in the first phase, such as between about 130% and about 160% wherein, in the second stage, the second dose administered to the human subject is between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose dosed in the first stage. The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, wherein in the third phase, between about 100% and about 160% (such as about 130%) of the second dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 160%) once a week for one week, and wherein in the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in a third dose A fourth dose of between about 100% and about 160% of the dose (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject weekly once for one week, and wherein in the fifth phase, the human subject is administered a fifth dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose. The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the sixth phase, between about 100% and about 160% of the fifth dose (eg, about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a sixth dose of between % and about 160%, once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first The bispecific anti-CD123 x anti-CD3 antibody was administered to human subjects in three doses three times a week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose is between about 1,600 ng/kg and about 1,800 ng/kg in the first period, wherein in the second In the phase, the dual dose is administered to the human subject in a second dose that is between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose in the first phase. A specific anti-CD123 x anti-CD3 antibody once a week for one week, wherein in a third phase, a third dose between about 130% and about 160% of the second dose is administered to the human subject The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein in the fourth phase, between about 100% to about 160% (such as about 130% to about 160% of the third dose) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between about 160%) once a week for one week, and wherein in the fifth phase, the fourth dose is administered A fifth dose of between about 100% and about 160% of the amount (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week , for one week, and wherein in the sixth phase, the human subject is administered a sixth dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fifth dose. The bispecific anti-CD123 x anti-CD3 antibody is administered weekly until remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first Three doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose is between about 1,600 ng/kg and about 1,800 ng/kg in the first period, wherein in the second During the phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 2,400 ng/kg and about 2,600 ng/kg once a week for one week, and wherein In a third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dosing amount between about 3,600 ng/kg and about 3,900 ng/kg once a week for one week , and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between about 5,600 ng/kg and about 5,900 ng/kg once a week in a fourth phase , for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a fifth dosing amount between about 8,300 ng/kg and about 8,700 ng/kg in a fifth period, Once a week for one week, and wherein the bispecific anti-CD123 x antibody is administered to the human subject in a sixth dose between about 12,500 ng/kg and about 13,000 ng/kg in a sixth dose CD3 antibody, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first Three doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is about 1,100 ng/kg in the first phase, and the third dose is about 1,700 ng/kg in the first phase, wherein in the second phase, the second dose is about 2,500 ng/kg. The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the third phase, the human subject is administered a third dose of about 3,800 ng/kg. with the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific is administered to human subjects at a fourth dose of about 5,700 ng/kg in a fourth phase an anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 is administered to a human subject in a fifth dose at a fifth dose of about 8,500 ng/kg The antibody, once a week, for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week at a sixth dose of about 12,800 ng/kg in a sixth phase , until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first The first dose administered in one phase is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from segment D or segment E, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph E, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph E, each once a week, and wherein in the fourth phase, the antibody is provided in a fourth dose selected from paragraph E, once a week, and wherein in the fifth phase, provided in a fifth dose selected from paragraph F the antibody, once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph F, once a week, and the sixth dosing amount is greater than the fifth dosing amount, and The fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first The first dose administered in one phase is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second phase, with A second dose selected from paragraph E provides the antibody once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth In stage, the antibody is provided in a fourth dosing amount selected from paragraph E, once a week, and wherein in a fifth stage, the antibody is provided in a fifth dosing amount selected from paragraph F, once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph F, once a week, and the sixth dosing amount is greater than the fifth dosing amount, and the fifth dosing amount is greater than the a fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first Three doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects three times per week for one week, wherein the first dose in Phase I is found in paragraph C, such as about 600 ng /kg to about 900 ng/kg, such as about 750 ng/kg, and the second dose in the first stage is between about 100% and about 130% of the first dose in the first stage, such as Between about 120% and about 130%, and the third dose in the first phase is between about 100% and about 130% of the second dose in the first phase, such as between about 120% and about 130%. wherein in the second phase, the second dose administered to the human subject is between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose dosed in the first phase The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, wherein in the third phase, between about 100% and about 130% (such as about 120%) of the second dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 130%) once a week for one week, and wherein in the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in a third dose A fourth dose of between about 100% and about 130% of the dose (eg, between about 120% and about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject weekly once for one week, and wherein in the fifth phase, the human subject is administered a fifth dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose. The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the sixth phase, between about 100% and about 130% of the fifth dose (eg, about 120%) % to about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first The bispecific anti-CD123 x anti-CD3 antibody was administered to human subjects in three doses three times a week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is between about 800 ng/kg and about 1,000 ng/kg, and the third dose is between about 1,100 ng/kg and about 1,300 ng/kg in the first period, wherein in the second In the phase, the dual dose is administered to the human subject in a second dose that is between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose in the first phase. Specific anti-CD123 x anti-CD3 antibodies, once a week for one week, wherein in the third phase, between about 100% and about 130% of the second dose (such as between about 120% and about 130%) ) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the fourth phase, at about 100% of the third dose administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fourth dose of between about 130%, such as between about 120% and about 130%, once a week for one week, and wherein in the fifth stage, the dual dose is administered to the human subject in a fifth dosing amount between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dosing amount. Specific anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the sixth stage, between about 100% and about 130% (such as between about 120% and about 130% of the fifth dose) A sixth dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first The bispecific anti-CD123 x anti-CD3 antibody was administered to human subjects in three doses three times a week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is between about 800 ng/kg and about 1,000 ng/kg, and the third dose is between about 1,100 ng/kg and about 1,300 ng/kg in the first period, wherein in the second During the phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 1,400 ng/kg and about 1,600 ng/kg once a week for one week, and wherein In a third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dosing amount between about 1,700 ng/kg and about 1,900 ng/kg once a week for one week , and wherein in the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between about 2,200 ng/kg and about 2,400 ng/kg once a week , for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a fifth dosing amount between about 2,800 ng/kg and about 3,000 ng/kg in a fifth period, Once a week for one week, and wherein the bispecific anti-CD123 x antibody is administered to the human subject in a sixth dose at a sixth dose of between about 3,500 ng/kg to about 3,700 ng/kg CD3 antibody once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises the first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the first, second, and first Three doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose was about 750 ng/kg in the first phase, and the first phase The second dose is about 900 ng/kg in the first stage, and the third dose is about 1,200 ng/kg in the first stage, wherein in the second stage, the second dose is about 1,500 ng/kg. The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in a third phase, the human subject is administered a third dose of about 1,800 ng/kg. with the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific is administered to human subjects at a fourth dose of about 2,300 ng/kg in a fourth phase an anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 is administered to a human subject at a fifth dose of about 2,900 ng/kg in a fifth phase The antibody, once a week, for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week at a sixth dose of about 3,600 ng/kg in a sixth phase , until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. seven stages

The methods of treatment disclosed herein may include the first and second and third and fourth and fifth and sixth and seventh stages. In the first phase, the antibody may be provided according to a first dosage regimen, in a first administered amount. In the second phase, the antibody may be provided according to a second dosage regimen, with a second administered amount. In the third phase, the antibody may be provided according to a third dosage regimen, with a third administration amount. In the fourth phase, the antibody may be provided according to a fourth dosage regimen, with a fourth dosing amount. In the fifth stage, the antibody may be provided according to a fifth dosage regimen, with a fifth dosing amount. In the sixth phase, the antibody may be provided according to a sixth dosage regimen, with a sixth dosing amount. In the seventh phase, the antibody may be provided according to a seventh dosage regimen, with a seventh dosing amount. The time of administration can independently be any described throughout the specification. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Seven-phase, no-dose regimen

The methods of treatment disclosed herein may include the first and second and third and fourth and fifth and sixth and seventh stages. In the first phase, the antibody may be provided according to the daily or every other day or six times a week or five times a week or four times a week or three times a week or twice a week as described herein for up to four weeks (eg, one, two, three, or four weeks), wherein the one or more doses are described in paragraph B or paragraph C or paragraph D or paragraph E or paragraph F. In the second phase, the antibody can be provided in a second dosing amount described in paragraph E or paragraph F or paragraph G for up to four weeks (eg, one, two, three, or four weeks). In the third phase, the antibody may be provided in a third dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fourth phase, the antibody may be provided in the fourth dosing amount described in Paragraph E or Paragraph F or Paragraph G or Paragraph H for up to four weeks (eg, one, two , three, or four weeks). In the fifth stage, the antibody may be provided in a fifth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H or paragraph I according to the fifth dosage regimen described herein. In the sixth stage, the antibody may be provided in a sixth dosing amount described in paragraph E or paragraph F or paragraph G or paragraph H or paragraph I or paragraph J according to the sixth dosage regimen described herein. In the seventh stage, the antibody may be provided in a seventh dosing amount described in paragraph F or paragraph G or paragraph H or paragraph I or paragraph J according to the seventh dosage regimen described herein. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Seven phases, of which the first phase is administered three times a week

The methods of treatment disclosed herein can include first and second and third and fourth and fifth and sixth and seventh stages, wherein in the first stage, the The antibody, three times a week for one week, and wherein in the second phase, the antibody is provided in a second dose, once a week, and wherein in the third phase, the antibody is provided in a third dose, each once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose once a week, and wherein in a fifth stage, the antibody is provided in a fifth dose once a week, and wherein in In the sixth stage, the antibody is provided in a sixth dosing amount once a week, and wherein in a seventh stage, the antibody is provided in a seventh dosing amount once a week, and the seventh dosing amount is greater than the The sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose , and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include the first and second and third and fourth and fifth and sixth and seventh stages, wherein in the first stage the antibody is provided three times per week for one week, wherein the first dose in the first period is described in paragraph B, and two subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second phase, the antibody is provided in a second dose once a week, and wherein in a third phase, the antibody is provided in a third dose once a week, and wherein in the fourth phase , the antibody is provided in a fourth dosing amount once a week, and wherein in a fifth stage, the antibody is provided in a fifth dosing amount once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount The antibody is provided in a dose once a week, and wherein in the seventh phase, the antibody is provided in a seventh dose once a week, and the seventh dose is greater than the sixth dose, and the seventh dose is provided Sixth, the dosage is greater than the fifth dosage, and the fifth dosage is greater than the fourth dosage, and the fourth dosage is greater than the third dosage, and the third dosage is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first and a second and a third and a fourth and a fifth and a sixth and a seventh stage, wherein in the first stage the antibody is provided three times a week for One week, wherein the first dose in the first period is described in segment C, and two subsequent doses are greater than the first dose and are each independently selected from segment C or segment D or segment E or segment F, and wherein in the second phase, the antibody is provided in a second dose once a week, and wherein in a third phase, the antibody is provided in a third dose once a week, and wherein in the fourth phase , the antibody is provided in a fourth dosing amount once a week, and wherein in a fifth stage, the antibody is provided in a fifth dosing amount once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount The antibody is provided in a dose once a week, and wherein in the seventh phase, the antibody is provided in a seventh dose once a week. The methods of treatment disclosed herein can include a first and a second and a third and a fourth and a fifth and a sixth and a seventh stage, wherein in the first stage the antibody is provided three times a week for One week, wherein the first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or Paragraph E, and wherein in the second stage, the antibody is provided in a second dose selected from paragraph E or paragraph F, once a week, and wherein in the third stage, with a third dose selected from paragraph F. The antibody is provided in a dose once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in the fifth stage, the antibody is provided in a fourth dose selected from paragraph G or a fifth dosing amount of paragraph H provides the antibody once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph G or paragraph H or paragraph I once a week, and wherein in the seventh stage, the antibody is provided in a seventh dose selected from segment G or segment H or segment I or segment H, once a week, and the seventh dose is greater than the sixth dose , and the sixth dosage is greater than the fifth dosage, and the fifth dosage is greater than the fourth dosage, and the fourth dosage is greater than the third dosage, and the third dosage The dose is greater than the second dose. The methods of treatment disclosed herein may include first and second and third and fourth and fifth and sixth stages, wherein in the first stage the antibody is provided three times a week for one week, wherein the first The first dose administered in one phase is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second phase, with The antibody is provided in a second dosing amount as described in paragraph E or paragraph F, once a week, and wherein in a third phase, the antibody is provided in a third dosing amount as described in paragraph F, weekly once, and wherein in the fourth phase, the antibody is provided in a fourth dosing amount as described in paragraph G, once a week, and wherein in the fifth phase, as described in paragraph G or paragraph H A fifth dosing amount provides the antibody once a week, and wherein in the sixth phase, the antibody is provided in a sixth dosing amount as described in paragraph G or paragraph H or paragraph I, once a week, and wherein In the seventh stage, the antibody is provided in a seventh dosing amount as described in paragraph G or paragraph H or paragraph I or paragraph J, once a week, and the seventh dosing amount is greater than the sixth dosing amount , and the sixth dosage is greater than the fifth dosage, and the fifth dosage is greater than the fourth dosage, and the fourth dosage is greater than the third dosage, and the third dosage The dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects three times per week for one week, wherein the first dose in Phase 1 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 in the first stage is about 100% to about 160% of the first dose in the first stage between, such as between about 130% and about 160%, and the third dose in the first stage is between about 100% and about 160% of the second dose in the first stage, such as between about 130% and Between about 160%, wherein in the second stage, the second dose is between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in an amount once a week for one week, wherein in the third phase, between about 100% and about 160% of the second administered amount ( The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose, such as between about 130% and about 160%, once a week for one week, and wherein in the fourth phase, administering the bispecific anti-CD123 x anti-CD3 to the human subject in a fourth dose that is between about 100% and about 160% of the third dose (eg, between about 130% and about 160%) The antibody, once a week, for one week, and wherein in the fifth phase, the fifth dose is between about 100% and about 160% of the fourth dose (eg, between about 130% and about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in an amount once a week for one week, and wherein in the sixth phase, between about 130% and about 160% of the fifth dose administered A sixth dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the seventh phase, at about 100% of the sixth dose to A seventh dosing amount of between about 160% (eg, between about 130% and about 160%) administers the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, wherein in the second stage, the human subject is administered a second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose dosed in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, wherein in the third phase, between about 100% to about 160% (such as about 130% to about 160% of the second dose) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between 160% and 160%, once a week for one week, and wherein in the fourth phase, the third dose is administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between about 100% and about 160% (such as between about 130% and about 160%) once a week, for one week, and wherein in the fifth stage, the human subject is administered a fifth dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein in the sixth phase, between about 100% to about 160% (such as about 130% to about 160% of the fifth dose) Administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a sixth dose of between about 160%) once a week for one week and at about 100% to about 100% of the sixth dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a seventh dose of between 160% (eg, between about 130% and about 160%) once a week until remission (eg, complete remission) or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first phase is between about 1,600 ng/kg and about 1,800 ng/kg, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dosing amount between about 2,400 ng/kg and about 2,600 ng/kg once a week for a duration of One week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 3,600 ng/kg and about 3,900 ng/kg in a third period, weekly once for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a fourth dose between about 5,600 ng/kg and about 5,900 ng/kg in a fourth period , once a week for one week, and wherein the bispecific anti-CD123 x is administered to the human subject in a fifth dosing amount between about 8,300 ng/kg and about 8,700 ng/kg An anti-CD3 antibody, once a week for one week, and wherein the bispecific is administered to a human subject in a sixth dose between about 12,500 ng/kg and about 13,000 ng/kg in a sixth phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the human subject is administered the anti-CD123 x anti-CD3 antibody in a seventh dose between about 19,000 ng/kg to about 19,500 ng/kg in a seventh phase Bispecific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, And the second dose is about 1,100 ng/kg in the first stage, and the third dose is about 1,700 ng/kg in the first stage, wherein in the second stage, the second dose is about 2,500 ng/kg. Dosing Amount The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week for one week, and wherein in a third phase, a third dosing amount of about 3,800 ng/kg is administered to the human The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, the human subject is administered a fourth dose of about 5,700 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific antibody is administered to human subjects in a fifth dose of about 8,500 ng/kg in a fifth phase CD123 x anti-CD3 antibody once a week for one week and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a sixth dose at a sixth dose of about 12,800 ng/kg , weekly for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered weekly to human subjects at a seventh dose of about 19,200 ng/kg in a seventh phase, Until remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first and a second and a third and a fourth and a fifth and a sixth and a seventh stage, wherein in the first stage the antibody is provided three times a week for One week, wherein the first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or Paragraph E, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph E, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph E The antibody, once a week, and wherein in the fourth phase, the antibody is provided in a fourth dosing amount selected from paragraph E, once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose selected from paragraph F The antibody is provided in a dose once a week, and wherein in the sixth stage, the antibody is provided in a sixth dose selected from paragraph F, once a week, and wherein in the seventh stage, the antibody is provided in a sixth dose selected from paragraph A seventh dosing amount of F or paragraph G provides the antibody once a week, and the seventh dosing amount is greater than the sixth dosing amount, and the sixth dosing amount is greater than the fifth dosing amount, and the The fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein can include a first and a second and a third and a fourth and a fifth and a sixth and a seventh stage, wherein in the first stage the antibody is provided three times a week for One week, wherein the first dose in the first period is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second In phase, the antibody is provided in a second dose selected from paragraph E once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dosing amount selected from paragraph F, every Once a week, and wherein in the sixth stage, the antibody is provided in a sixth dose selected from paragraph F, once a week, and wherein in the seventh stage, with a seventh dose selected from paragraph F or paragraph G The antibody is provided in doses once a week, and the seventh dose is greater than the sixth dose, and the sixth dose is greater than the fifth dose, and the fifth dose is greater than the sixth dose Four doses, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects three times per week for one week, wherein the first dose in Phase 1 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 in the first stage is about 100% to about 130% of the first dose in the first stage between, such as between about 120% and about 130%, and the third dose in the first stage is between about 100% and about 130% of the second dose in the first stage, such as between about 120% and Between about 130%, wherein in the second stage, the second dose is between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in an amount once a week for one week, wherein in the third phase, between about 100% and about 130% of the second administered amount ( The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose, such as between about 120% and about 130%, once a week for one week, and wherein in the fourth phase, administering the bispecific anti-CD123 x anti-CD3 to the human subject in a fourth dose that is between about 100% and about 130% of the third dose (eg, between about 120% and about 130%) The antibody, once a week, for one week, and wherein in the fifth phase, the fifth dose is between about 100% and about 130% of the fourth dose (eg, between about 120% and about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in an amount once a week for one week, and wherein in the sixth phase, between about 100% and about 130% of the fifth dose administered administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a sixth dosing amount (eg, between about 120% and about 130%) once a week for one week, and wherein in the seventh phase , administering the bispecific anti-CD123 x antibody to the human subject at a seventh dosing amount between about 100% and about 130% of the sixth dosing amount (such as between about 120% and about 130%) CD3 antibody, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first stage is between about 800 ng/kg and about 1,000 ng/kg, and the third dose in the first stage is between about 1,100 ng/kg and about 1,300 ng/kg, wherein in the second stage, the human subject is administered a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose dosed in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, wherein in the third phase, between about 100% to about 130% (such as about 120% to about 120%) of the second dose administered 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the fourth phase, the third dose is administered between about 100% and about 130% (eg, between about 120% and about 130%) of a fourth dose of the bispecific anti-CD123 x anti-CD3 antibody administered to the human subject once a week, for one week, and wherein in the fifth stage, the human subject is administered a fifth dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein in the sixth phase, between about 100% to about 130% (such as about 120% to about 130%) of the fifth dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a sixth dose of between about 130%) once a week for one week, and wherein in the seventh phase, the sixth dose is administered A seventh dose of between about 100% and about 130% of the amount (eg, between about 120% and about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week , until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, and the second dose in the first stage is between about 800 ng/kg and about 1,000 ng/kg, and the third dose in the first stage is between about 1,100 ng/kg and about 1,300 ng/kg, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 1,400 ng/kg and about 1,600 ng/kg once a week for a duration One week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 1,700 ng/kg and about 1,900 ng/kg in a third period, weekly once for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a fourth dose between about 2,200 ng/kg and about 2,400 ng/kg in a fourth period , once a week for one week, and wherein the bispecific anti-CD123 x is administered to the human subject in a fifth dosing amount between about 2,800 ng/kg and about 3,000 ng/kg anti-CD3 antibody, once a week for one week, and wherein the bispecific is administered to a human subject in a sixth dose between about 3,500 ng/kg and about 3,700 ng/kg in a sixth phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the seventh phase, the human subject is administered the Bispecific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the Second, and third doses of the bispecific anti-CD123 x anti-CD3 antibody were administered to human subjects three times per week for one week, wherein the first dose in the first phase was about 750 ng/kg, And the second dose is about 900 ng/kg in the first stage, and the third dose is about 1,200 ng/kg in the first stage, wherein in the second stage, the second dose is about 1,500 ng/kg. Dosing Amount The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week for one week, and wherein in a third phase, a third dosing amount of about 1,800 ng/kg is administered to the human The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in a fourth phase, the human subject is administered a fourth dose of about 2,300 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific antibody is administered to human subjects in a fifth dose of about 2,900 ng/kg in a fifth phase CD123 x anti-CD3 antibody weekly for one week and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a sixth dose at a sixth dose of about 3,600 ng/kg , once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week at a seventh dose of about 4,500 ng/kg in a seventh phase, Until remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Two phases, of which the first phase is administered four times a week

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided four times a week in four different doses for one week, and wherein in the second stage the antibody The second dose is provided once a week. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include a first stage and a second stage, wherein the antibody is provided four times a week for one week in the first stage, wherein the first dose is as described in paragraph B in the first stage, and then three dosing amounts greater than the first dosing amount and each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein the antibody is provided weekly in the second dosing amount in the second phase, And the dose administered in the second phase is greater than any dose administered in the first phase. The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided four times a week for one week, wherein the first dose in the first stage is about 400 ng/kg and about Between 500 ng/kg, and the subsequent three doses are greater than the first dose and are each independently selected from segment C or segment D or segment E, and wherein the antibody is administered in a second dose in the second phase The dose is provided once a week, the second dose is selected from paragraph F, and the dose in the second phase is greater than any dose in the first phase. The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided four times a week for one week, wherein the first dose in the first stage is about 433 ng/kg, and Three subsequent doses are greater than the first dose and are each independently selected from segment C or segment D or segment E, and wherein in the second phase the antibody is provided weekly in a second dose, the first dose The second dose is selected from paragraph F, and the dose in the second phase is greater than any dose in the first phase. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose administered 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 administered in the first phase is the first dose 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 administered in the phase, and a third dose in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose in the first phase, and the fourth dose in the first phase is the third dose in the first phase. Between about 100% and about 160% of the dose, such as between about 140% and about 160%, wherein in the second stage, between about 100% and about 160% of the fourth dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose between about 130% and about 160% once a week. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in one phase is about 433 ng/kg, the second dose in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the fourth dose in the first phase is between about 1,500 ng/kg and about 1,900 ng/kg, wherein in the second phase, the first A second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose in the phase is administered to the human subject to administer the bispecific anti-CD123 x antibody. CD3 antibody, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in one phase is about 433 ng/kg, the second dose in the first phase is between about 700 ng/kg and about 800 ng/kg, and the third dose in the first phase is between about 1,000 ng/kg and about 1,250 ng/kg, and the fourth dose in the first stage is between about 1,500 ng/kg and about 1,900 ng/kg, wherein in the second stage, the dose is about 2,000 ng/kg administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a second dose of between ng/kg and about 3,000 ng/kg once a week until remission (eg, complete or partial), or Continues up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in the first phase is about 433 ng/kg, the second dose in the first phase is about 750 ng/kg, and the third dose in the first phase is about 1,100 ng/kg, and The fourth dose in the first phase is about 1,700 ng/kg, wherein in the second phase, the bispecific anti-CD123 x antibody is administered to the human subject at a second dose of about 2,500 ng/kg. CD3 antibody once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Decrease Increment Groups:

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided four times a week for one week, wherein the first dose in the first stage is about 400 ng/kg and about Between 500 ng/kg, and the subsequent three doses are greater than the first dose and are each independently selected from segment C or segment D or segment E, and wherein the antibody is administered in a second dose in the second phase The dose is provided once a week, the second dose is selected from paragraph F, and the dose in the second phase is greater than any dose in the first phase. The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage the antibody is provided four times a week for one week, wherein the first dose in the first stage is about 433 ng/kg, and Three subsequent doses are greater than the first dose and are each independently selected from segment C or segment D or segment E, and wherein in the second phase the antibody is provided weekly in a second dose, the first dose The second dose is selected from paragraph F, and the dose in the second phase is greater than any dose in the first phase. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose administered in one 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 administered in the first phase is the first dose Between about 100% and about 130% of the first dose administered in the phase, such as between about 120% and about 130%, and the third dose in the first phase is between about 100% and about 130% of the second dose in the first phase. Between about 100% and about 130%, such as between about 120% and about 130%, and the fourth dose in the first stage is between about 100% and about 130% of the third dose in the first stage. time, such as between about 120% and about 130%, and wherein in the second stage, between about 100% and about 130% of the fourth dose administered in the first stage (such as about 120% to about 130%) A second dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week. In some embodiments, the duration of the second phase is between one week and four weeks. In some embodiments, the second stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in one phase is about 433 ng/kg, the second dose in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose in the first phase is between about 624 ng/kg and about 732 ng/kg, and the fourth dose in the first stage is between about 750 ng/kg and about 952 ng/kg, wherein in the second stage, the first dose is A second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose in the phase is administered to the human subject to administer the bispecific anti-CD123x antibody CD3 antibody once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in one phase is about 433 ng/kg, the second dose in the first phase is between about 520 ng/kg and about 563 ng/kg, and the third dose in the first phase is between about 624 ng/kg and about 732 ng/kg, and the fourth dose in the first stage is between about 750 ng/kg and about 952 ng/kg, wherein in the second stage, the dose is about 900 ng/kg. administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a second dose between ng/kg and about 1,238 ng/kg once a week until remission (eg, complete or partial), or Continues up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject four times a week for one week, wherein the first The first dose in the first phase is about 433 ng/kg, the second dose in the first phase is about 542 ng/kg, and the third dose in the first phase is about 678 ng/kg, and The fourth dose in the first phase is about 848 ng/kg, wherein in the second phase, the bispecific anti-CD123 x antibody is administered to the human subject at a second dose of about 1,060 ng/kg. CD3 antibody once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Four phases, of which the first phase is administered four times a week

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided in a first dosing amount four times a week for one week, and wherein In the second stage, the antibody is provided in a second dose once a week, and wherein in a third stage, the antibody is provided in a third dose once a week, and wherein in the fourth stage, The antibody is provided in a fourth dose once a week. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amounts are described in paragraph B, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage, the The antibody is provided in a dosing amount once a week, and wherein in the third stage, the antibody is provided in a third dosing amount once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount , once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amounts are described in paragraph C, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second phase, the The antibody is provided in a dosing amount once a week, and wherein in the third stage, the antibody is provided in a third dosing amount once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount , once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amount is between about 600 ng/kg and about 900 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, providing the antibody in a second dose selected from paragraph E or paragraph F once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph F once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the Second dose. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amount is about 750 ng/kg, and two subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, to be selected from paragraph E or paragraph F The antibody is provided weekly in a second dose of A fourth dosing amount selected from paragraph G provides the antibody once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose 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 first dose is The second dose in one phase is between about 100% and about 160% of the first dose in the first phase, such as between about 130% and about 160%, and the third dose in the first phase is between about 100% and about 160%, such as between about 130% and about 160%, of the second dose in the first phase, and the fourth dose in the first phase is the third dose in the first phase. Between about 100% and about 160% of the dose, such as between about 130% and about 160%, wherein in the second stage, between about 100% and about 160% of the fourth dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose between about 130% and about 160%, once a week for one week, wherein in the third phase administering the bispecific anti-CD123 x antibody to the human subject at a third dose of between about 100% and about 160% (such as between about 130% and about 160%) of the second dose CD3 antibody, once a week, for one week, and wherein in the fourth phase, the fourth dose is between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose Dosage The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects once a week. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first period is about 750 ng/kg and the second dose in the first period is between about 1,000 ng/kg and about 1,250 ng/kg , and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is between about 2,400 ng/kg and about 2,600 ng/kg , wherein, in the second phase, a second dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose in the first phase is administered to the human subject are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, wherein in the third phase, between about 100% and about 160% of the second dose (eg, about 130% to about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 160%) once a week for one week, and wherein in the fourth phase, the third dose is administered A fourth dose of between about 100% and about 160% of the amount (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week , until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first period is about 750 ng/kg and the second dose in the first period is between about 1,000 ng/kg and about 1,250 ng/kg , and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is between about 2,400 ng/kg and about 2,600 ng/kg , wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 3,600 ng/kg and about 3,900 ng/kg once a week, for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a third dose of between about 5,600 ng/kg and about 5,900 ng/kg, each once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 is administered to the human subject in a fourth dose between about 8,400 ng/kg and about 8,600 ng/kg in a fourth dose Antibodies, once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first period is about 750 ng/kg, and the second dose in the first period is about 1,100 ng/kg, and the third dose in the first period is about 1,100 ng/kg The dose is about 1,700 ng/kg, and the fourth dose in the first phase is about 2,500 ng/kg, wherein in the second phase, the human subject is tested at a second dose of about 3,800 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of about 5,700 ng/kg in a third phase A specific anti-CD123x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123x is administered to a human subject at a fourth dose of about 8,500 ng/kg in a fourth phase Anti-CD3 antibodies, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amount is between about 600 ng/kg and about 900 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, The antibody is provided in a second dosing amount selected from paragraph E, once a week, and wherein in the third stage, the antibody is provided in a third dosing amount selected from paragraph E, once a week, and wherein in the third stage In the fourth stage, the antibody is provided in a fourth dose selected from paragraph E or paragraph F, once a week, and the fourth dose is greater than the third dose, and the third dose is greater than the Second dose. The methods of treatment disclosed herein can include a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the antibody is provided four times a week for one week, wherein in the first stage the first administration The amount is about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, with the second selected from paragraph E. The antibody is provided in a dose once a week, and wherein, in the third phase, the antibody is provided in a third dose selected from paragraph E, once a week, and wherein in the fourth phase, the antibody is provided in a dose selected from paragraph E A fourth dosing amount of E or paragraph F provides the antibody once a week, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose 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 first dose is The second dose in the first phase is between about 100% and about 130% of the first dose in the first phase, such as between about 120% and about 130%, and the third dose in the first phase is between about 100% and about 130%, such as between about 120% and about 130%, of the second dose in the first phase, and the fourth dose in the first phase is the third dose in the first phase. Between about 100% and about 130% of the dose, such as between about 120% and about 130%, and wherein in the second stage, at about 100% to about 130% of the fourth dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between (eg, between about 120% and about 130%) once a week for one week, wherein in a third phase The bispecific anti-CD123 x The anti-CD3 antibody, once a week, for one week, and wherein in the fourth phase, at between about 100% and about 130% (such as between about 120% and about 130%) of the fourth dose of the third dose Dosing Amounts The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects once a week. In some embodiments, the duration of the fourth phase is between one week and four weeks. In some embodiments, the fourth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first period is about 750 ng/kg and the second dose in the first period is between about 800 ng/kg and about 1,000 ng/kg , and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is between about 1,400 ng/kg and about 1,600 ng/kg , wherein, in the second phase, a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose of the first phase is administered to the human subject are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, wherein in the third phase, between about 100% and about 130% of the second dose (eg, about 120% to about 120%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 130%) once a week for one week, and wherein in the fourth phase, the third dose is administered A fourth dose of between about 100% and about 130% of the amount (eg, between about 120% and about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week , until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first period is about 750 ng/kg and the second dose in the first period is between about 800 ng/kg and about 1,000 ng/kg , and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is between about 1,400 ng/kg and about 1,600 ng/kg , wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 1,700 ng/kg and about 1,900 ng/kg once a week, for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a third dose of between about 2,200 ng/kg and about 2,400 ng/kg, each once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 is administered to the human subject in a fourth dose between about 2,800 ng/kg and about 3,000 ng/kg in a fourth dose Antibodies, once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage, wherein in the first stage, the bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject , four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 900 ng/kg, and the third dose in the first phase is about 900 ng/kg The dose is about 1,200 ng/kg, and the fourth dose is about 1,500 ng/kg in the first phase, wherein in the second phase, the human subject is tested at a second dose of about 1,800 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of about 2,300 ng/kg in a third phase A specific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x is administered to a human subject at a fourth dose of about 2,900 ng/kg in a fourth phase Anti-CD3 antibodies, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Five phases, of which the first phase is administered four times a week

The methods of treatment disclosed herein can include a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the antibody is provided in a first dosing amount, four times a week, for a duration One week, and wherein in the second period, the antibody is provided in a second dose once a week, and wherein in a third period, the antibody is provided in a third dose once a week, and wherein in the third period In the fourth phase, the antibody is provided in a fourth dose once a week, and in a fifth phase, the antibody is provided in a fifth dose once a week, and the fifth dose is greater than the first dose Four doses, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage A first dosing amount is described in paragraph B, and three subsequent dosing amounts are greater than this first dosing amount and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage , the antibody is provided in a second dosing amount once a week, and wherein in a third period, the antibody is provided in a third dosing amount once a week, and wherein in a fourth period, the antibody is provided in a fourth dosing amount The antibody is provided in an amount once a week, and wherein in the fifth phase, the antibody is provided in a fifth dosing amount once a week, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing amount is The administered amount is greater than the third administered amount, and the third administered amount is greater than the second administered amount. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage A first dosing amount is described in paragraph C, and two subsequent dosing amounts are greater than the first dosing amount and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein in the second stage , the antibody is provided in a second dosing amount once a week, and wherein in a third period, the antibody is provided in a third dosing amount once a week, and wherein in a fourth period, the antibody is provided in a fourth dosing amount The antibody is provided in an amount once a week, and wherein in the fifth phase, the antibody is provided in a fifth dosing amount once a week. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage The first dose is between about 600 ng/kg and about 900 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph F, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph G, each Once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in the fifth stage, with a fifth dose selected from paragraph G or paragraph H The antibody is provided in doses once a week, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the third dose Two doses. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage The first dose is between about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from Paragraph D or Paragraph E or Paragraph F, and wherein in the second stage , the antibody is provided in a second dosing amount as described in paragraph F, once a week, and wherein in a third phase, the antibody is provided in a third dosing amount as described in paragraph G, once a week , and wherein in the fourth phase, the antibody is provided in a fourth dosing amount as described in paragraph G, once a week, and wherein in the fifth phase, the antibody is provided in a fourth dose as described in paragraph G or paragraph H Five doses provide the antibody once a week, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x anti-CD3 antibody, four times per week for one week, wherein the first dose 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 kg, and the second dose in the first stage is between about 100% and about 160% of the first dose in the first stage, such as between about 130% and about 160%, and the first dose in the first stage The third dose is between about 100% and about 160% of the second dose in the first stage, such as between about 130% and about 160%, and the fourth dose in the first stage is the first stage Between about 100% and about 160%, such as between about 130% and about 160% of the third dose in the second stage, wherein in the second stage, between about 100% and about 160% of the fourth dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 160% (eg, between about 130% and about 160%) once a week for one week, wherein in In the third stage, the bispecific is administered to the human subject in a third dose that is between about 100% and about 160% of the second dose (eg, between about 130% and about 160%) anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fourth phase, between about 100% and about 160% (eg, between about 130% and about 160%) of the third dose administered A fourth dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the fifth phase, at about 100% of the fourth dose to A fifth dose of between about 160% (eg, between about 130% and about 160%) is administered to the human subject once a week of the bispecific anti-CD123 x anti-CD3 antibody. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x Anti-CD3 antibody, four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase is about 1,000 ng/kg to about 1,250 ng between about 1,600 ng/kg and about 1,800 ng/kg in the first phase, and between about 2,400 ng/kg and about 2,600 ng in the fourth dose in the first phase between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose in the first stage in the second stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, wherein in the third phase, between about 100% and about 160% of the second dose administered (e.g. The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dosing amount of between about 130% and about 160%, once a week for one week, and wherein in the fourth phase, with A fourth dosing amount between about 100% and about 160% of the third dosing amount (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject , once a week for one week, and wherein in the fifth phase, the fifth dose is between about 100% and about 160% of the fourth dose (eg, between about 130% and about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered once a week until remission (eg, complete or partial), or up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x Anti-CD3 antibody, four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase is about 1,000 ng/kg to about 1,250 ng between about 1,600 ng/kg and about 1,800 ng/kg in the first phase, and between about 2,400 ng/kg and about 2,600 ng in the first phase between about 3,600 ng/kg and about 3,900 ng/kg, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a second dose of between about 3,600 ng/kg and about 3,900 ng/kg, Once a week for one week, and wherein the bispecific anti-CD123x antibody is administered to the human subject in a third dose between about 5,600 ng/kg and about 5,900 ng/kg in a third dose CD3 antibody once a week for one week and wherein the bispecific antibody is administered to the human subject in a fourth dose between about 8,300 ng/kg and about 8,700 ng/kg in a fourth phase CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x is administered in a fifth dose between about 12,500 ng/kg and about 13,000 ng/kg in a fifth phase Anti-CD3 antibodies, once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x anti-CD3 antibody, four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 1,100 ng/kg, and the first dose The third dose is between about 1,700 ng/kg in the phase and the fourth dose is about 2,500 ng/kg in the first phase, wherein in the second phase the second dose is about 3,800 ng/kg Dosage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the third phase, the human subject is administered a third dose of about 5,700 ng/kg. The bispecific anti-CD123 x anti-CD3 antibody is administered to the subject once a week for one week, and wherein the human subject is administered the bispecific anti-CD123 x anti-CD3 antibody in a fourth dose at a fourth dose of about 8,500 ng/kg. a bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered in a fifth dose of about 12,800 ng/kg in a fifth phase, Once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage The first dosing amount is between about 600 ng/kg and about 900 ng/kg, and three subsequent dosing amounts are greater than the first dosing amount and are each independently selected from paragraph D or paragraph E, and wherein the In the second phase, the antibody is provided in a second dose selected from paragraph E once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dose selected from paragraph F, Once a week, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing amount is greater than the third dosing amount, and the third dosing amount is greater than the second dosing amount. The methods of treatment disclosed herein may include first and second and third and fourth and fifth stages, wherein in the first stage the antibody is provided four times a week for one week, wherein in the first stage The first dose is about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, to be selected from paragraph A second dosing amount of E provides the antibody once a week, and wherein in the third stage, the antibody is provided in a third dosing amount selected from paragraph E, once a week, and wherein in the fourth stage, The antibody is provided in a fourth dosing amount selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dosing amount selected from paragraph F, once a week, and the fifth dosing amount is provided once a week The dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x anti-CD3 antibody, four times per week for one week, wherein the first dose 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 kg, and the second dose in the first stage is between about 100% and about 130% of the first dose in the first stage, such as between about 120% and about 130%, and the first dose in the first stage The third dose is between about 100% and about 130% of the second dose in the first stage, such as between about 120% and about 130%, and the fourth dose in the first stage is the first stage Between about 100% and about 130%, such as between about 120% and about 130%, of the third dose in the second stage, wherein in the second stage, between about 100% and about 130% of the fourth dose in the first stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 130% (eg, between about 120% and about 130%) once a week for one week, wherein in In the third stage, the bispecific is administered to the human subject in a third dose that is between about 100% and about 130% of the second dose (eg, between about 120% and about 130%) anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fourth phase, between about 100% and about 130% of the third dose (eg, between about 120% and about 130%) A fourth dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, and wherein in the fifth phase, at about 100% of the fourth dose to A fifth dose of between about 130% (eg, between about 120% and about 130%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week. In some embodiments, the duration of the fifth phase is one or two weeks. In some embodiments, the duration of the fifth phase is between one week and four weeks. In some embodiments, the fifth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x Anti-CD3 antibody, four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase is about 800 ng/kg to about 1,000 ng between about 1,100 ng/kg and about 1,300 ng/kg in the first phase, and between about 1,100 ng/kg and about 1,300 ng/kg in the first phase, with a fourth dose in the second phase and about 1,400 in the first phase ng/kg to about 1,600 ng/kg, wherein in the second stage, between about 100% and about 130% (such as between about 120% and about 130% of the fourth dose administered in the first stage) ) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, wherein in the third phase, at about 100% of the second dose to The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between about 130% (eg, between about 120% and about 130%) once a week for one week, and wherein In the fourth stage, the bispecific is administered to the human subject in a fourth dose that is between about 100% and about 130% of the third dose (eg, between about 120% and about 130%) anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fifth stage, between about 100% and about 130% of the fourth dose (such as between about 120% and about 130%) ) in a fifth dosing amount of the bispecific anti-CD123 x anti-CD3 antibody once a week until remission (eg, complete or partial), or for up to until cancer remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x Anti-CD3 antibody, four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase is about 800 ng/kg to about 1,000 ng between about 1,100 ng/kg and about 1,300 ng/kg in the first phase, and about 1,400 ng in the first phase in the second phase Between about 1,600 ng/kg and about 1,600 ng/kg, wherein the bispecific antibody is administered to the human subject in a second dose of between about 1,700 ng/kg and about 1,900 ng/kg in the second phase CD123 x anti-CD3 antibody once a week for one week and wherein the dual dose is administered to a human subject in a third dose between about 2,200 ng/kg and about 2,400 ng/kg in a third phase The specific anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fourth phase, is administered to the human subject at a fourth dosing amount between about 2,800 ng/kg to about 3,000 ng/kg with the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, the fifth dose is administered between about 3,500 ng/kg to about 3,700 ng/kg Bispecific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first and second stage and a third and fourth stage and a fifth stage, wherein in the first stage, the bispecific anti-CD123 is administered to a human subject x anti-CD3 antibody, four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 900 ng/kg, and the first dose is about 900 ng/kg The third dose in the phase is between about 1,200 ng/kg, wherein in the second phase, the fourth dose is about 1,500 ng/kg in the first phase, wherein in the second phase, the dose is about 1,800 ng The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects at a second dose/kg once a week for one week, and wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at a third dose of about 2,300 ng/kg in the third phase. Dosing Amount The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week for one week, and wherein in a fourth phase, the human subject is administered a fourth dosing amount of about 2,900 ng/kg The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, the bispecific antibody is administered at a fifth dose of about 3,600 ng/kg CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Six phases, of which the first phase is administered four times a week

The methods of treatment disclosed herein can include first and second and third and fourth and fifth and sixth stages, wherein in the first stage, the antibody is provided in a first dosing amount, weekly Four times for one week, and wherein in the second period, the antibody is provided in the second dose once a week, and wherein in the third period, the antibody is provided in a third dose once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount once a week, and wherein in a fifth stage, the antibody is provided in a fifth dosing amount once a week, and wherein in the sixth stage , the antibody is provided in a sixth dosing amount once a week, and the sixth dosing amount is greater than the fifth dosing amount, and the fifth dosing amount is greater than the fourth dosing amount, and the fourth dosing The administered amount is greater than the third administered amount, and the third administered amount is greater than the second administered amount. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first phase is described in paragraph B, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein In the second phase, the antibody is provided in a second dose once a week, and in a third phase, the antibody is provided in a third dose once a week, and in a fourth phase, with The antibody is provided in a fourth dose once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose once a week, and wherein in the sixth phase, the antibody is provided in a sixth dose The antibody, once a week, and the sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first phase is described in paragraph C, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F, and wherein In the second phase, the antibody is provided in a second dose once a week, and in a third phase, the antibody is provided in a third dose once a week, and in a fourth phase, with The antibody is provided in a fourth dose once a week, and wherein in the fifth phase, the antibody is provided in a fifth dose once a week, and wherein in the sixth phase, the antibody is provided in a sixth dose The antibody, once a week. The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E or Paragraph F, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph F, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph G The antibody, once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dose selected from paragraph H The antibody is provided in a dosing amount once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph H or paragraph I, once a week, and the sixth dosing amount is greater than the A fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose . The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first period is between about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E or paragraph F, and wherein in In the second phase, the antibody is provided in a second dose selected from paragraph F once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph G once a week , and wherein in a fourth stage, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in a fifth stage, the antibody is provided in a fifth dose selected from paragraph H , once a week, and wherein in the sixth stage, the antibody is provided in a sixth dose selected from paragraph H or paragraph I, once a week, and the sixth dose is greater than the fifth dose, And the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, wherein the first dose 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 in the first stage is between about 100% and about 160% of the first dose in the first stage, such as between about 130% and about 160%, and The third dose in the first phase is between about 100% and about 160% of the second dose in the first phase, such as between about 130% and about 160%, and the fourth dose in the first phase is between about 100% and about 160% of the third dose administered in the first stage, such as between about 130% and about 160%, wherein in the second stage, the amount of the fourth dose administered in the first stage is between about 100% and about 160%. The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 100% and about 160% (eg, between about 130% and about 160%), once a week, for a duration One week, wherein in the third period, the human subject is administered a third dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the second dose The bispecific anti-CD123 x anti-CD3 antibody is weekly for one week, and wherein in the fourth phase, between about 100% and about 160% of the third dose (eg, about 130% to about 160%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose between administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a fifth dose of between about 100% and about 160% (eg, between about 130% and about 160%) once a week for One week, and wherein in the sixth phase, the human subject is administered a sixth dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fifth dose. with this bispecific anti-CD123 x anti-CD3 antibody once a week. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, with a first dose of about 750 ng/kg in the first phase and a second dose of about 1,000 ng/kg in the first phase to between about 1,250 ng/kg, and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is about 2,400 ng/kg To between about 2,600 ng/kg, wherein in the second phase, the first dose is between about 100% and about 160% (eg, between about 130% and about 160%) of the fourth dose administered in the first phase. Two doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects once a week for one week, wherein in the third phase, from about 100% to about 160% of the second dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose of between (eg, between about 130% and about 160%) once a week for one week, and wherein in the fourth During the phase, the bispecific anti-CD123 is administered to the human subject in a fourth dose that is between about 100% and about 160% of the third dose (eg, between about 130% and about 160%) x anti-CD3 antibody, once a week for one week, and wherein in the fifth phase, at between about 100% and about 160% (such as between about 130% and about 160%) of the fourth dose Five doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to the human subject once a week for one week, and wherein in the sixth phase, from about 100% to about 160% of the fifth dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a sixth dose of between % (eg, between about 130% and about 160%) once a week until remission (eg, complete or part), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, with a first dose of about 750 ng/kg in the first phase and a second dose of about 1,000 ng/kg in the first phase to between about 1,250 ng/kg, and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is about 2,400 ng/kg to between about 2,600 ng/kg, wherein the bispecific anti-CD123x is administered to the human subject in a second dose of between about 3,600 ng/kg to about 3,900 ng/kg in the second phase An anti-CD3 antibody, once a week for one week, and wherein the bispecific is administered to a human subject at a third dose of between about 5,600 ng/kg to about 5,900 ng/kg in a third phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the human subject is administered the anti-CD123 x anti-CD3 antibody in a fourth dose of between about 8,300 ng/kg to about 8,700 ng/kg in a fourth phase A bispecific anti-CD123 x anti-CD3 antibody once a week for one week and wherein a fifth dose of between about 12,500 ng/kg and about 13,000 ng/kg is administered to the human subject in the fifth stage The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein in the sixth phase, the human is administered a sixth dose of between about 19,000 ng/kg to about 19,500 ng/kg The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, with a first dose of about 750 ng/kg in the first phase and a second dose of about 1,100 ng/kg in the first phase , and the third dose in the first stage is about 1,700 ng/kg, and the fourth dose in the first stage is about 2,500 ng/kg, wherein in the second stage, the dose is about 3,800 ng/kg. Two doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects once a week for one week, and wherein in a third phase, a third dose of about 5,700 ng/kg is administered to the human subject. The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, the human subject is administered a fourth dose of about 8,500 ng/kg. with the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific is administered to human subjects at a fifth dose of about 12,800 ng/kg in a fifth phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in a sixth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week until remission (eg, complete or part of it), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E or Paragraph F, and wherein in the second phase, the antibody is provided in a second dose selected from paragraph F, once a week, and wherein in the third phase, the antibody is provided in a third dose selected from paragraph G The antibody, once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dose selected from paragraph H The antibody is provided in a dosing amount once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph H or paragraph I, once a week, and the sixth dosing amount is greater than the A fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose . The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose in the first period is between about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E or paragraph F, and wherein in In the second phase, the antibody is provided in a second dose selected from paragraph F once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph G once a week , and wherein in a fourth stage, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in a fifth stage, the antibody is provided in a fifth dose selected from paragraph H , once a week, and wherein in the sixth stage, the antibody is provided in a sixth dose selected from paragraph H or paragraph I, once a week, and the sixth dose is greater than the fifth dose, And the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, wherein the first dose 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 in the first phase is between about 100% and about 130% of the first dose in the first phase, such as between about 120% and about 130%, and The third dose in the first phase is between about 100% and about 130% of the second dose in the first phase, such as between about 120% and about 130%, and the fourth dose in the first phase is between about 100% and about 130% of the third dose administered in the first stage, such as between about 120% and about 130%, wherein in the second stage, the amount of the third dose administered in the first stage is between about 100% and about 130%. The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) once a week for a duration One week, wherein in the third period, the human subject is administered a third dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the second dose The bispecific anti-CD123 x anti-CD3 antibody is weekly for one week, and wherein in the fourth phase, between about 100% and about 130% of the third dose (eg, about 120% to about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose between The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fifth dose of between about 100% and about 130% (eg, between about 120% and about 130%) once a week for a duration One week, and wherein in the sixth phase, the human subject is administered a sixth dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fifth dose. with this bispecific anti-CD123 x anti-CD3 antibody once a week. In some embodiments, the sixth phase is one week or two weeks in duration. In some embodiments, the duration of the sixth phase is between one week and four weeks. In some embodiments, the sixth stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibody, four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg and the second dose in the first phase is about 800 ng/kg to between about 1,000 ng/kg, and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is about 1,400 ng/kg To between about 1,600 ng/kg, wherein in the second phase, the first dose is between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose administered in the first phase. The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in two doses once a week for one week, wherein in the third phase, at about 120% to about 130% of the second dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a third dose between once a week for one week, and wherein in the fourth phase, about 100% of the third dose is administered. % to about 130% (eg, between about 120% to about 130%) of the fourth dosing amount to administer the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week for one week, and wherein in the fifth stage, the human subject is administered the human subject in a fifth dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose. The bispecific anti-CD123 x anti-CD3 antibody, once a week, for one week, and wherein in the sixth phase, between about 100% and about 130% of the fifth dose (eg, about 120% to about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a sixth dose of between ) once a week until remission (eg, complete or partial), or for up to until cancer remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, with a first dose of about 750 ng/kg in the first phase and a second dose of about 800 ng/kg in the first phase to between about 1,000 ng/kg, and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is about 1,400 ng/kg to between about 1,600 ng/kg, wherein the bispecific anti-CD123x is administered to the human subject in a second dose of between about 1,700 ng/kg to about 1,900 ng/kg in the second phase An anti-CD3 antibody, once a week for one week, and wherein the bispecific is administered to a human subject in a third dose between about 2,200 ng/kg and about 2,400 ng/kg in a third phase anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, the human subject is administered the A bispecific anti-CD123 x anti-CD3 antibody once a week for one week and wherein in the fifth phase, the human subject is administered a fifth dose of between about 3,500 ng/kg to about 3,700 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered once a week for one week, and wherein in a sixth phase, the human is administered a sixth dose of between about 4,400 ng/kg to about 4,600 ng/kg The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises first and second and third and fourth and fifth and fifth and sixth stages, wherein in the first stage, the dual is administered to a human subject Specific anti-CD123 x anti-CD3 antibodies, four times a week for one week, with a first dose of about 750 ng/kg in the first phase and a second dose of about 900 ng/kg in the first phase , and the third dose in the first stage is about 1,200 ng/kg, and the fourth dose in the first stage is about 1,500 ng/kg, wherein in the second stage, the dose is about 1,800 ng/kg. Two doses of the bispecific anti-CD123 x anti-CD3 antibody are administered to human subjects once a week for one week, and wherein in a third phase, a third dose of about 2,300 ng/kg is administered to the human subject. The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, the human subject is administered a fourth dose of about 2,900 ng/kg. with the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific is administered to human subjects in a fifth dose of about 3,600 ng/kg in a fifth phase an anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the bispecific anti-CD123 x anti-CD3 is administered to a human subject in a sixth dose at a sixth dose of about 4,500 ng/kg Antibodies, once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification. Seven phases, of which the first phase is administered four times a week

The methods of treatment disclosed herein can include first and second and third and fourth and fifth and sixth and seventh stages, wherein in the first stage, the the antibody, four times a week for one week, and wherein in the second phase, the antibody is provided in a second dose, once a week, and wherein in the third phase, the antibody is provided in a third dose, once a week, and wherein in the fourth phase, the antibody is provided in a fourth dose, once a week, and wherein in a fifth phase, the antibody is provided in a fifth dose, once a week, and wherein In the sixth stage, the antibody is provided in a sixth dosing amount once a week, and wherein in a seventh stage, the antibody is provided in a seventh dosing amount once a week, and the seventh dosing amount is greater than The sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI and Phase Seven, wherein in Phase I the antibody is provided four times per week, for one week, wherein the first dose in the first period is described in paragraph B, and three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F , and wherein in the second period, the antibody is provided in a second dose once a week, and wherein in a third period, the antibody is provided in a third dose once a week, and wherein in the fourth period During the period, the antibody is provided in a fourth dose once a week, and wherein in a fifth period, the antibody is provided in a fifth dose once a week, and wherein in the sixth period, the antibody is provided in a sixth dose. The antibody is provided in a dose once a week, and wherein in the seventh phase, the antibody is provided in a seventh dose once a week, and the seventh dose is greater than the sixth dose, and the The sixth dose is greater than the fifth dose, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI and Phase Seven, wherein in Phase I, the antibody is provided four times per week, for one week, wherein the first dose in the first period is described in paragraph C, and three subsequent doses are greater than the first dose and are each independently selected from paragraph C or paragraph D or paragraph E or paragraph F , and wherein in the second phase, the antibody is provided in a second dose once a week, and wherein in a third phase, the antibody is provided in a third dose once a week, and in a fourth dose In phase, the antibody is provided in a fourth dose once a week, and in a fifth phase, the antibody is provided in a fifth dose once a week, and in a sixth phase, the antibody is provided in a sixth dose The dosing amount provides the antibody once a week, and wherein in the seventh phase, the antibody is provided in a seventh dosing amount once a week. The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI and Phase Seven, wherein in Phase I, the antibody is provided four times per week, for one week, wherein the first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from paragraph D Either paragraph E or paragraph F, and wherein in the second stage, the antibody is provided in a second dosing amount selected from paragraph F, once a week, and wherein in the third stage, with a third dose selected from paragraph G The antibody is provided at a dose once a week, and wherein in the fourth phase, the antibody is provided in a fourth dose selected from paragraph G, once a week, and wherein in the fifth phase, the antibody is provided at a dose selected from paragraph G A fifth dosing amount of H provides the antibody once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph H or paragraph I, once a week, and wherein in the seventh During the phase, the antibody is provided in a seventh dosing amount selected from paragraph I or paragraph J, once a week, and the seventh dosing amount is greater than the sixth dosing amount, and the sixth dosing amount is greater than the sixth dosing amount. Five doses, and the fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI, wherein in Phase I, the antibody is provided four times a week for one week, wherein The first dose administered in the first phase is about 750 ng/kg, and the three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E or paragraph F, and wherein in the second In phase, the antibody is provided in a second dose selected from paragraph F once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph G once a week, and wherein in the fourth stage, the antibody is provided in a fourth dosing amount selected from paragraph G, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dosing amount selected from paragraph H, every Once a week, and wherein in the sixth stage, the antibody is provided in a sixth dosing amount selected from paragraph H or paragraph I, once a week, and wherein in the seventh stage, with as in paragraph I or paragraph J. Said seventh dose provides the antibody once a week, and the seventh dose is greater than the sixth dose, and the sixth dose is greater than the fifth dose, and the fifth dose is The dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises stage one and stage two and stage three and stage four and stage five and stage six and stage seven, wherein in the first stage, the human subject is administered administering the bispecific anti-CD123 x anti-CD3 antibody four times per week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about 900 ng/kg between, such as about 750 ng/kg, and the second dose in the first stage is between about 100% to about 160%, such as about 130% to about 160% of the first dose in the first stage and the third dose in the first stage is between about 100% and about 160% of the second dose in the first stage, such as between about 130% and about 160%, and the third dose in the first stage is between about 100% and about 160% of the second dose in the first stage The fourth dose is between about 100% and about 160% of the third dose in the first stage, such as between about 130% and about 160%, wherein in the second stage, with the third dose in the first stage A second dose of between about 100% and about 160% of the dose administered (eg, between about 130% and about 160%) of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject, each Once a week for one week, wherein, in the third phase, a third dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the second dose is administered to the human subject. The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fourth phase, between about 100% and about 160% of the third dose (eg, about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose between A fifth dosing amount between about 100% and about 160% of the dosing amount (eg, between about 130% and about 160%) is administered to the human subject of the bispecific anti-CD123 x anti-CD3 antibody, each once a week for one week, and wherein in the sixth stage, the human is administered a sixth dose of between about 100% and about 160% (eg, between about 130% and about 160%) of the fifth dose The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the seventh phase, between about 100% and about 160% of the sixth dose (eg, about 100%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a seventh dose of between 130% and about 160%) once a week until remission (e.g., complete or partial), or prolonged until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg Between 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is about Between 2,400 ng/kg and about 2,600 ng/kg, wherein in the second stage, between about 100% and about 160% (such as between about 130% and about 160% of the fourth dose administered in the first stage) A second dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, wherein in the third phase, about 100% of the second dose is administered administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a third dose of between about 160%, such as between about 130% and about 160%, once a week for one week, and wherein in the fourth stage, the dual dose is administered to the human subject in a fourth dose that is between about 100% and about 160% of the third dose (eg, between about 130% and about 160%) Specific anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fifth stage, between about 100% and about 160% (such as between about 130% and about 160% of the fourth dose) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fifth dosing amount during the administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a sixth dose of between % and about 160% (eg, between about 130% and about 160%) once a week for one week, administering the bispecific anti-CD123 x anti-CD3 to the human subject in a seventh dosing amount between about 100% and about 160% (eg, between about 130% and about 160%) of the sixth dosing amount Antibodies, once a week until remission (eg, complete or partial), or as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg Between 1,000 ng/kg and about 1,250 ng/kg, and the third dose in the first period is between about 1,600 ng/kg and about 1,800 ng/kg, and the fourth dose in the first period is about Between 2,400 ng/kg and about 2,600 ng/kg, wherein the bispecific is administered to the human subject in a second dose of between about 3,600 ng/kg and about 3,900 ng/kg in the second phase Anti-CD123 x anti-CD3 antibody, once weekly for one week, and wherein in a third phase, a third dose of between about 5,600 ng/kg to about 5,900 ng/kg is administered to the human subject The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week and wherein, in the fourth phase, a fourth dose of between about 8,300 ng/kg and about 8,700 ng/kg is administered to human subjects are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, the fifth dose is between about 12,500 ng/kg and about 13,000 ng/kg to the The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the sixth dose is between about 19,000 ng/kg to about 19,500 ng/kg in the sixth stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a dose once a week for one week, and wherein in the seventh phase, at a dose of between about 28,000 ng/kg to about 30,000 ng/kg The seventh dosing amount administers the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg 1,100 ng/kg, and the third dose in the first stage is about 1,700 ng/kg, and the fourth dose in the first stage is about 2,500 ng/kg, wherein in the second stage, the dose is about 3,800 ng The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects at a second dose/kg once a week for one week, and wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at a third dose of about 5,700 ng/kg in the third phase. Dosing Amount The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week for one week, and wherein in a fourth phase, the human subject is administered a fourth dosing amount of about 8,500 ng/kg to the human The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, the human subject is administered a fifth dose of about 12,800 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific antibody is administered to human subjects in a sixth dose at a sixth dose of about 19,200 ng/kg CD123 x anti-CD3 antibody once a week for one week and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects at a seventh dose of about 28,800 ng/kg in a seventh phase , once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI and Phase Seven, wherein in Phase I, the antibody is provided four times per week, for one week, wherein the first dose in the first period is between about 600 ng/kg and about 900 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the second stage, the antibody is provided in a second dose selected from paragraph E, once a week, and wherein in the third stage, with a third dose selected from paragraph E The antibody is provided once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fourth dose selected from paragraph F Five doses of the antibody are provided once a week, and wherein in the sixth phase, the antibody is provided in a sixth dose selected from paragraph F, once a week, and wherein in the seventh phase, the antibody is provided in a A seventh dosing amount of paragraph F or paragraph G provides the antibody once a week, and the seventh dosing amount is greater than the sixth dosing amount, and the sixth dosing amount is greater than the fifth dosing amount, and The fifth dose is greater than the fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. The methods of treatment disclosed herein may include Phase I and Phase II and Phase III and Phase IV and Phase V and Phase VI and Phase Seven, wherein in Phase I, the antibody is provided four times per week, For one week, wherein the first dose in the first period is about 750 ng/kg, and three subsequent doses are greater than the first dose and are each independently selected from paragraph D or paragraph E, and wherein in the first In the second phase, the antibody is provided in a second dose selected from paragraph E once a week, and wherein in a third phase, the antibody is provided in a third dose selected from paragraph E once a week, and wherein in the fourth stage, the antibody is provided in a fourth dose selected from paragraph E, once a week, and wherein in the fifth stage, the antibody is provided in a fifth dose selected from paragraph F, once a week, and wherein in the sixth stage, the antibody is provided in a sixth dose selected from paragraph F, once a week, and wherein in the seventh stage, with a seventh selected from paragraph F or paragraph G Dosing amounts provide the antibody once a week, and the seventh dosing amount is greater than the sixth dosing amount, and the sixth dosing amount is greater than the fifth dosing amount, and the fifth dosing amount is greater than the a fourth dose, and the fourth dose is greater than the third dose, and the third dose is greater than the second dose. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises stage one and stage two and stage three and stage four and stage five and stage six and stage seven, wherein in the first stage, the human subject is administered administering the bispecific anti-CD123 x anti-CD3 antibody four times per week for one week, wherein the first dose in the first phase is found in paragraph C, such as about 600 ng/kg to about 900 ng/kg between, such as about 750 ng/kg, and the second dose in the first stage is between about 100% to about 130%, such as about 120% to about 130% of the first dose in the first stage and the third dose in the first stage is between about 100% and about 130% of the second dose in the first stage, such as between about 120% and about 130%, wherein in the second stage , and the fourth dose in the first stage is between about 100% and about 130% of the third dose in the first stage, such as between about 120% and about 130%, wherein in the second stage, The bispecific antibody is administered to the human subject in a second dose of between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose in the first phase. CD123 x anti-CD3 antibody, once a week for one week, wherein in the third phase, in a first dose between about 100% and about 130% (eg, between about 120% and about 130%) of the second dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in three doses, once a week for one week, and wherein in the fourth phase, at about 100% to about 130% of the third dose The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fourth dose of between % (eg, between about 120% and about 130%) once a week for one week, and wherein In five stages, the bispecific antibody is administered to the human subject at a fifth dose that is between about 100% and about 130% (eg, between about 120% and about 130%) of the fourth dose. CD123 x anti-CD3 antibody, once a week for one week, and wherein in the sixth phase, between about 100% and about 130% (eg, between about 120% and about 130%) of the fifth dose administered The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject in a sixth dosing amount once a week for one week, and wherein in the seventh phase, at about 100% to about 100% of the sixth dosing amount A seventh dose of between 130% (eg, between about 120% and about 130%) administers the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week. In some embodiments, the duration of the seventh phase is between one week and four weeks. In some embodiments, the seventh stage continues until remission (eg, complete or partial), or until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein, or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times per week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg Between 800 ng/kg and about 1,000 ng/kg, and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is about Between 1,400 ng/kg and about 1,600 ng/kg, wherein in the second stage, between about 100% and about 130% (such as between about 120% and about 130% of the fourth dose administered in the first stage) A second dose of the bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject once a week for one week, wherein in the third phase, about 100% of the second dose is administered administering the bispecific anti-CD123 x anti-CD3 antibody to the human subject at a third dose of between about 130%, such as between about 120% and about 130%, once a week for one week, and wherein in the fourth stage, the dual dose is administered to the human subject in a fourth dose that is between about 100% and about 130% (eg, between about 120% and about 130%) of the third dose. Specific anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in the fifth stage, between about 100% and about 130% of the fourth dose (such as between about 120% and about 130%) The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at a fifth dosing amount during the % to about 130% (eg, between about 120% to about 130%) of the sixth dosing amount to administer the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week for one week, and wherein in the seventh stage, the human subject is administered the seventh dosing amount of between about 100% and about 130% (such as between about 120% and about 130%) of the sixth dosing amount. Bispecific anti-CD123 x anti-CD3 antibody once weekly until remission (eg, complete or partial), or up to until cancer has remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg Between 800 ng/kg and about 1,000 ng/kg, and the third dose in the first period is between about 1,100 ng/kg and about 1,300 ng/kg, and the fourth dose in the first period is about Between 1,400 ng/kg and about 1,600 ng/kg, wherein in the second phase, the bispecific is administered to the human subject at a second dose of between about 1,700 ng/kg and about 1,900 ng/kg Anti-CD123 x anti-CD3 antibody, once a week for one week, and wherein in a third phase, a third dose of between about 2,200 ng/kg to about 2,400 ng/kg is administered to the human subject The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein in a fourth phase, a fourth dose of between about 2,800 ng/kg and about 3,000 ng/kg is administered to human subjects are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, at a fifth dose of between about 3,500 ng/kg and about 3,700 ng/kg to The human subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein the sixth dose is between about 4,400 ng/kg to about 4,600 ng/kg in the sixth stage The bispecific anti-CD123 x anti-CD3 antibody is administered to the human subject at doses once a week for one week, and wherein in the seventh phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at a dose of between about 5,500 ng/kg to about 5,700 ng/kg The seventh dosing amount administers the bispecific anti-CD123 x anti-CD3 antibody to the human subject once a week until remission (eg, complete or partial), or for up to until the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In one embodiment, the method of treatment comprises a first stage and a second stage and a third stage and a fourth stage and a fifth stage and a sixth stage and a seventh stage, wherein in the first stage, the human subject is administered The bispecific anti-CD123 x anti-CD3 antibody is administered four times a week for one week, wherein the first dose in the first phase is about 750 ng/kg, and the second dose in the first phase is about 750 ng/kg 900 ng/kg, and the third dose in the first phase is about 1,200 ng/kg, and the fourth dose in the first phase is about 1,500 ng/kg, wherein in the second phase, the dose is about 1,800 ng The bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects at a second dose/kg once a week for one week, and wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at a third dose of about 2,300 ng/kg in the third phase. Dosing Amount The bispecific anti-CD123 x anti-CD3 antibody is administered to a human subject once a week for one week, and wherein in a fourth phase, the human subject is administered a fourth dosing amount of about 2,900 ng/kg The subject is administered the bispecific anti-CD123 x anti-CD3 antibody once a week for one week, and wherein in the fifth phase, the human subject is administered a fifth dose of about 3,600 ng/kg The bispecific anti-CD123 x anti-CD3 antibody is administered weekly for one week, and wherein the bispecific antibody is administered to human subjects in a sixth dose of about 4,500 ng/kg in a sixth phase CD123 x anti-CD3 antibody once a week for one week and wherein the bispecific anti-CD123 x anti-CD3 antibody is administered to human subjects in a seventh dose of about 5,600 ng/kg in a seventh phase , once a week until remission (eg, complete or partial), or for as long as the cancer is in remission. In one embodiment, once the cancer of CD123 is in remission, the method further comprises a maintenance dose of about the same administered amount for remission, according to the weekly dosing regimen described herein or the biweekly dosing regimen described herein or within about 10%, or about 20%, or about 30% (plus or minus) of the dose administered, provide the antibody (eg, XmAb14045) as maintenance therapy until no efficacy is determined, substandard observed toxicity levels, or discontinued by human subjects. The time of administration can independently be any described throughout the specification.

In some embodiments, the antibody comprises an intravenously administered bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045). In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody is administered by continuous infusion. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody is administered intravenously, by continuous infusion, or both. If there are more than two treatments, any combination of intravenous administration or continuous infusion can be used. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered until no efficacy is determined, an unsatisfactory level of toxicity is observed, or voluntary discontinuation by the human subject.

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is first-line therapy, second-line therapy, third-line therapy, fourth-line therapy, fifth-line therapy, or sixth-line therapy.

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) treats refractory leukemia. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is maintenance therapy. In one embodiment, for any of the methods described herein, when the cancer exhibits CD123 remission, such as partial remission and/or complete remission, the method further comprises a dosing regimen of every other week as described herein for remission ( The bispecific anti-CD123 x anti-CD3 antibody (e.g., XmAb14045) is provided in the same dose administered as a partial remission and/or complete remission until no efficacy is determined, an unqualified level of toxicity is observed, or it is voluntarily terminated by a human subject . In one embodiment, for any of the methods described herein, when the cancer exhibits CD123 remission, such as partial remission and/or complete remission, the method further comprises according to the weekly dosing regimen described herein or as described herein The once every three weeks dosing regimen or the once every four weeks dosing regimen described herein or the twice monthly dosing regimen described herein or the thrice monthly dosing regimen described herein or the monthly dosing regimen described herein Dosage regimen for remission (eg, partial remission and/or complete remission) at the same dose administered, or at about 10% (plus or minus) of this dose, or at (plus or minus) the dose Provide the bispecific anti-CD123 x anti-CD3 antibody (e.g. XmAb14045) within about 20%, or within about 30% (plus or minus) of the dose administered until no efficacy is determined, an unqualified level of toxicity is observed, or voluntarily terminated by human subjects.

A medical professional can readily determine and prescribe an effective amount of the desired antibody composition. For example, a physician may start dosing an agent used in the antibody composition at levels below that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. VII. Treatment by Blast Percent Inspiration

In another aspect, the present invention provides a method of treating certain populations of human subjects having cancer expressing CD123. In an exemplary embodiment, prior to administration of any of the CD123-expressing cancer treatment regimens described herein in the first stage, the percentage of blast cells in the bone marrow of the human subject is determined, and if the percentage is about 35% or less, or about 30% or less, or about 25% or less, or about 20% or less, or about 15% or less, or about 10% or less, or about 5% or less, proceed The treatment regimen for cancers expressing CD123. In an exemplary embodiment, the percentage of blast cells in the human subject's bone marrow is determined prior to administration of the first stage of a treatment regimen for any of the CD123-expressing cancers described herein, and if the percentage is about 25% or less , the treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, prior to administration of the first phase of any of the CD123-expressing cancer treatment regimens in the "Two Phases, wherein the First Phase is Dosed Three Times Weekly", the human subject is measured in bone marrow The percentage of blast cells, and if the percentage is about 25% or less, the treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, the human subject is measured in bone marrow prior to administration of any of the CD123-expressing cancer treatment regimens in the "Four Phases, wherein the First Phase is Dosed Three Times Weekly" in the first phase. The percentage of blast cells, and if the percentage is about 25% or less, the treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, the human subject's bone marrow is measured prior to administration of the first phase of any of the CD123-expressing cancer treatment regimens in the "Two Phases, wherein the First Phase is Dosed Four Times Weekly" section The percentage of mesoderm cells, and if the percentage is about 25% or less, the treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, the human subject's bone marrow is assayed prior to administration of the first phase of any of the CD123-expressing cancer treatment regimens in the "Four Phases, wherein the First Phase is Dosed Four Times Weekly" The percentage of mesoderm cells, and if the percentage is about 25% or less, the treatment regimen for the cancer expressing CD123 is performed.

In an exemplary embodiment, the present invention provides a method of improving the efficacy of treatment of a cancer expressing CD123, the method comprising: determining bone marrow mesoderm in a human subject (eg, a human subject having a cancer expressing CD123) Percentage of cells; where a percentage of 25% or less indicates the efficacy of the bispecific anti-CD123 x anti-CD3 antibody.

In an exemplary embodiment, the present invention provides a method of determining sensitivity to treatment of a cancer expressing CD123, the method comprising: measuring a human subject (eg, a human subject having a cancer expressing CD123) in bone marrow Percentage of blast cells; where a percentage of 25% or less indicates the efficacy of the bispecific anti-CD123 x anti-CD3 antibody.

In an exemplary embodiment, the present invention provides a method of selecting one or more human subjects having increased responsiveness to treatment of a cancer expressing CD123, the method comprising: assaying a human subject (eg, having A human subject with a cancer expressing CD123) the percentage of blasts in the bone marrow; wherein a percentage of 25% or less corresponds to an increase in the subject's responsiveness.

The percentage of blast cells in the bone marrow of a human subject can be determined by standard methods for AML diagnosis, such as bone marrow aspiration or bone marrow biopsy. VIII. Treatment by CD8+ PD-1+ Percent Inspiration

In another aspect, the present invention provides a method of treating certain populations of human subjects having cancer expressing CD123. In an exemplary embodiment, the percentage of CD8+ T cells (the CD8+ T cells being PD-1+) in the human subject is determined prior to administration of the first stage of a treatment regimen for any of the CD123-expressing cancers described herein, and if the percentage is about 35% or less, or about 30% or less, or about 25% or less, or about 20% or less, or about 15% or less, or about 10% or less low, or about 5% or less, a treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, the percentage of CD8+ T cells (the CD8+ T cells being PD-1+) in the human subject is determined prior to administration of the first stage of a treatment regimen for any of the CD123-expressing cancers described herein, And if the percentage is about 25% or less, then a treatment regimen for the cancer expressing CD123 is performed. In an exemplary embodiment, the human subject is determined to be in The percentage of CD8+ T cells that are PD-1+, and if the percentage is about 25% or less, then a treatment regimen for the cancer expressing CD123. In an exemplary embodiment, prior to administration of the first phase of the treatment regimen for any of the CD123-expressing cancers in the "Four Phases, wherein the First Phase is Dosed Three Times Weekly", the human subject is measured in The percentage of CD8+ T cells that are PD-1+, and if the percentage is about 25% or less, then a treatment regimen for the cancer expressing CD123. In an exemplary embodiment, the human subject is assayed prior to administration of the first phase of the treatment regimen for any of the CD123-expressing cancers in the "Two Phases, wherein the First Phase is Dosed Four Times Weekly" section The percentage of CD8+ T cells in which the CD8+ T cells are PD-1+, and if the percentage is about 25% or less, proceed with a treatment regimen for the cancer expressing CD123. In an exemplary embodiment, the human subject is assayed prior to administration of the first phase of the treatment regimen for any of the CD123-expressing cancers in the "Four Phases, wherein the First Phase is Dosed Four Times Weekly" The percentage of CD8+ T cells in which the CD8+ T cells are PD-1+, and if the percentage is about 25% or less, proceed with a treatment regimen for the cancer expressing CD123.

In an exemplary embodiment, the present invention provides a method of improving the efficacy of treatment of a cancer expressing CD123, the method comprising: determining CD8+ T in a human subject, such as a human subject having a cancer expressing CD123 Percentage of cells (the CD8+ T cells are PD-1+); where a percentage of 25% or less indicates the efficacy of the bispecific anti-CD123 x anti-CD3 antibody.

In an exemplary embodiment, the invention provides a method of determining sensitivity to treatment of a cancer expressing CD123, the method comprising: measuring CD8+ in a human subject (eg, a human subject having a cancer expressing CD123) Percentage of T cells (the CD8+ T cells are PD-1+); where a percentage of 25% or less indicates the efficacy of the bispecific anti-CD123 x anti-CD3 antibody.

In an exemplary embodiment, the invention provides a method of selecting one or more human subjects having increased responsiveness to treatment of a cancer expressing CD123, the method comprising: assaying a human subject (eg, having percentage of CD8+ T cells that are PD-1+ in human subjects with cancer expressing CD123); wherein a percentage of 25% or less corresponds to an increase in subject responsiveness.

The percentage of CD8+ T cells (the CD8+ T cells being PD-1+) in human subjects can be determined by standard methods, such as assessment by flow cytometry of peripheral blood and bone marrow aspirates. combination therapy

In certain instances, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with one or more (eg, another) therapeutic agents. As used herein, "combination" administration means the delivery of two (or more) different treatments to a subject during the course of the subject suffering from the disorder, eg, after the subject is diagnosed with the disorder And two or more treatments are delivered until the disorder is cured or eliminated, or until the treatment is terminated for other reasons. In some embodiments, the delivery of the first treatment is still in progress when the delivery of the second treatment begins, so there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous delivery" or "parallel delivery." In other embodiments, delivery of one therapy ends before delivery of another therapy begins. In some embodiments in each case, the treatment is more effective because it is administered in combination. For example, the second treatment is more effective than the results observed when the second treatment is administered in the absence of the first treatment, eg, an equivalent effect is observed with less of the second treatment, or the second treatment will A greater reduction in one or more symptoms, or similar to the first treatment was observed. In some embodiments, delivery results in a greater reduction in symptoms or other parameters associated with the disorder than would be observed when one treatment is delivered in the absence of another treatment. The effects of the two treatments can be partially additive, fully additive, or greater than additive. The delivery can be such that when the second treatment is delivered, the effects of the delivered first treatment are still detectable.

The bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) and the at least one other therapeutic agent can be administered simultaneously (in the same or separate compositions) or sequentially. For sequential administration, the bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be administered first, and the other therapeutic agent can be administered second, or it can be reversed.

The bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) and/or one or more other therapeutic agents, regimens or modalities can be administered during an activity disorder, or during a remission or less active disease. The bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) can be administered before the other therapy, concurrently with the therapy, after the therapy, or during the remission phase.

When administered in combination, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) and the one or more other agents (eg, a second or third agent) can be used more than either alone (eg, as a single agent) A higher, lower or the same amount or dose of each agent is administered. In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) and the one or more other agents (eg, the second or third agent) are administered in amounts or dose ratios used alone (eg, as monotherapy) in a low amount or dose of each agent (eg, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%). In other embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) and the one or more other agents (eg, second or third agent) result in a desired effect (eg, treatment of cancer) The amount or dose is lower (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%) than the amount or dose of each agent expected to achieve the same therapeutic effect alone (e.g., as a monotherapy) or at least about 50%).

In some embodiments, the antibody is combined with other therapeutic agents, such as anticancer agents, antiallergic agents, antinausea agents (or antiemetics), analgesics, cytoprotective agents, or any combination thereof. In some embodiments, the antibody is combined with other therapeutic agents, such as anti-allergic agents, anti-nausea agents (or anti-emetics), analgesics, cytoprotective agents, or any combination thereof.

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered to a human subject in combination with one or more of: an anti-TNF or anti-IL6 receptor antibody, a steroid, or an anti-TNF Histamines (such as Benadryl).

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered to a human subject in combination with an antihistamine. In one embodiment, the antagonist antihistamines line H _1. In one embodiment, the system of the first-generation antihistamine H ₁ antagonist. In one embodiment, the antihistamine is 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 antagonist antihistamines line H _1. In one embodiment, the H ₁ antagonist based acrivastine (acrivastine), azelastine (azelastine), Bilasiting (bilastine), bromobenzene diphenhydramine (bromodiphenhydramine), brompheniramine ( brompheniramine), buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemass clemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethylindine ( dimetindene), diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, benzindamine phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®), tripelenamine and triprolidine, or any combination thereof. In one embodiment, the antihistamine is Avastin. 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 line H ₁ antihistamines inverse agonist. In one embodiment, the inverse agonist, H ₁ based acrivastine, cetirizine 𠯤, levocetirizine 𠯤 (levocetirizine), desloratadine (desloratadine), pyrilamine (pyrilamine), or any combination thereof. In one embodiment, the system H ₂ antihistamines antihistamines. In one embodiment, the antihistamine H ₂ H ₂ antagonists based. In one embodiment, the antihistamine H ₂ H _2-based inverse agonist. In one embodiment, the system H ₂ antihistamine cimetidine (cimetidine), famotidine (famotidine), lafutidine (lafutidine), nizatidine (nizatidine), ranitidine ranitidine, roxatidine, and tiotidine, or any combination thereof.

In embodiments, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be administered in combination with at least one therapeutic agent that is an anticancer agent and/or a side effect improving agent. Combination therapy, anticancer agent

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be administered in combination with at least one therapeutic agent, the at least one therapeutic agent being an anticancer agent. In embodiments, the anticancer agent is a chemotherapeutic agent, radiation, or an antibody (eg, an antibody to a checkpoint inhibitor). In embodiments, the anticancer agent is an immunoablative agent (eg, alemtuzumab), an anti-TIM-3 antibody (eg, MBG45), other antibody therapy, a BCL-2 inhibitor (eg, venetoclax ( venetoclax), cyclophosphamide, fludarabine, rapamycin, mycophenolic acid, steroids, FR90165, interferon, radiation or peptide vaccines (eg Izumoto et al 2008 J Neurosurg [ Journal of Neurosurgery] 108:963-971, peptide vaccines). In an embodiment, the anticancer agent is an immunosuppressive agent. In an embodiment, the immunosuppressant is cyclosporin, azathioprine, methotrexate, mycophenolate, or FK506. Combination therapy, anticancer agent, radiation

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with radiation. Combination therapy, anticancer agent, chemotherapeutic agent

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein can be used in combination with an anticancer agent.

In an embodiment, the anticancer agent is a chemotherapeutic agent. In embodiments, the chemotherapeutic agent is selected from the group consisting of alkylating agents, antimetabolites, kinase inhibitors, proteasome inhibitors, vinca alkaloids, anthracyclines, antineoplastic antibiotics, aromatase inhibitors agents, topoisomerase inhibitors, mTOR inhibitors, and retinoic acid. Combination therapy, anticancer agent, alkylating agent

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is an alkylating agent. In embodiments, the alkylating agent is nitrogen mustard, nitrosourea, alkyl sulfonate, trisulfanium, aziridine, platinum complexes, or a non-classical alkylating agent.

In embodiments, the alkylating agent is nitrogen mustard. In an exemplary embodiment, the alkylating agent is nitrogen mustard, which is dichloromethyldiethylamine (dichloromethyldiethylamine hydrochloride), ifosfamide (IFEX), Alkeran , chlorambucil, cyclophosphamide or derivatives thereof. In an embodiment, the alkylating agent is nitrogen mustard, which is trofosfamide, estramustine, or derivatives thereof.

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 hydrochloride) or derivatives thereof. In an embodiment, the alkylating agent is a nitrosourea, which is semustine, fotemustine, nimustine, ranimustine, or the like derivative.

In embodiments, 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.

In an embodiment, the alkylating agent is tris. In an embodiment, the alkylating agent is trisulfanium, which is dacarbazine, mitozolomide, temozolomide (Temodar), or derivatives thereof.

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

In embodiments, 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.

In embodiments, the alkylating agent is a non-classical alkylating agent. In embodiments, the non-classical alkylating agent is procarbazine, hexamethylmelamine, or derivatives thereof. In an embodiment, the alkylating agent is trabectedin or a derivative thereof. Combination therapy, anticancer agent, antimetabolite

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is an antimetabolite. In embodiments, the antimetabolite is a pyrimidine analog, a purine analog, or a folate antagonist.

In embodiments, the antimetabolite is a pyrimidine analog. In an embodiment, the antimetabolite is a pyrimidine analog, which is a fluoropyrimidine. In an embodiment, the fluoropyrimidine is 5-fluorouracil, capecitabine, carmofur, floxuridine, doxifluridine, tegafur or its derivatives. In an embodiment, the antimetabolite is a pyrimidine analog, which is cytarabine, gemcitabine, decitabine, azacitidine, or derivatives thereof. In embodiments, the antimetabolite is an adenosine deaminase inhibitor.

In an embodiment, the antimetabolite is a purine analog. In an embodiment, the antimetabolite is a purine analog, which is fludarabine (also known as 2-fluoro-ara-amp), nelarabine, clofarabine, or its derivatives. In an embodiment, the purine analog is an adenosine analog. In an embodiment, the adenosine analog is fludarabine (eg, 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.

In an embodiment, the antimetabolite is a folic acid antagonist, which is methotrexate, pemetrexed, or a derivative thereof. Combination therapy, anticancer agent, kinase inhibitor

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is a kinase inhibitor. In embodiments, 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 (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 embodiments, the kinase inhibitor is zanubrutinib (also known as BGB-3111) (BeiGene), ibrutinib (eg, Imbruvica), ibrutinib ( evobrutinib) (EMD Serono) or acalabrutinib (Acerta/AstraZeneca). In embodiments, the kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor. In embodiments, the kinase inhibitor inhibits the tyrosine kinase domain of epidermal growth factor receptor (EGFR). In embodiments, the kinase inhibitor inhibits the tyrosine kinase domain of epidermal growth factor receptor (EGFR). In an embodiment, the kinase inhibitor is gefitinib (Iressa), erlotinib (Tarceva), pyrotinib (also known as HTI-1001) (Hengrui Therapeutics) company), 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 AG013736) (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 (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) (Riegel), gilteritinib (Astellas (Astellas). Astellas)). In an embodiment, the tyrosine kinase inhibitor is neratinib (HER2 Her1 Her4), toceranib, or a derivative thereof. In an embodiment, the kinase inhibitor is phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). In embodiments, the kinase inhibitor is idelalisib (eg, Zydelig) (Gilead) or alpelisib. In an embodiment, the kinase inhibitor is a Chk1 inhibitor. In an embodiment, the kinase inhibitor is rabusertib, also known as LY2603618 (Eli Lilly). Combination therapy, anticancer agent, proteasome inhibitor

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is a proteasome inhibitor. In an embodiment, the proteasome inhibitor is bortezomib (Velcade), carfilzomib, ixazomid, or a derivative thereof. Combination therapy, anticancer agent, vinca alkaloids

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is a vinca alkaloid. In an embodiment, the anticancer agent is a chemotherapeutic agent, which is a monoterpene indole alkaloid. In an embodiment, the anticancer agent is a vinca alkaloid, which is vinblastine, vinorelbine, vincristine, vindesine, or a derivative thereof. Combination therapy, anticancer agents, anthracyclines

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is an anthracycline. In embodiments, the anthracycline is daunorubicin (also known as daunomycin), doxorubicin (Adriamycin) (eg, liposomal doxorubicin) , epirubicin, idarubicin (Idamycin), valrubicin (valrubicin) or derivatives thereof. Combination therapy, anticancer agents, other antitumor antibiotics

In an embodiment, the anticancer agent is a chemotherapeutic agent, 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 mitomycin-C or a derivative thereof.

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is a microtubule agent. In embodiments, the microtubule agent is docetaxel, paclitaxel, or a derivative thereof. Combination therapy, anticancer agent, aromatase inhibitor

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is an aromatase inhibitor. In an embodiment, the aromatase inhibitor is a steroidal inhibitor. In an embodiment, the aromatase steroid inhibitor is exemestane (Aromasin), formestane or a derivative thereof. In embodiments, 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, anticancer agent, topoisomerase inhibitor

In an embodiment, the anticancer agent is a chemotherapeutic agent, 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, anticancer agent, mTOR inhibitor

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is an mTOR inhibitor. In an embodiment, the mTOR inhibitor is rapamycin or rapalog. In an embodiment, the mTOR inhibitor is temsirolimus (Torisel), everolimus (Afinitor), 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 an ATP-competitive mTORC1/mTORC2 inhibitor. In an embodiment, the ATP-competitive mTORC1/mTORC2 inhibitor is sapanisertib (sapanisertib) or a derivative thereof. Combination Therapy, Anticancer Agent, Retinoic Acid

In an embodiment, the anticancer agent is a chemotherapeutic agent, which is retinoic acid. In an embodiment, the retinoic acid is all-trans retinoic acid (retinoic acid), cis-retinoic acid (9-cis RA), bexarotene (Targretin), or derivatives thereof.

Exemplary chemotherapeutic agents include anthracenedione derivatives (eg, mitoxantrone), immune cell antibodies (eg, gemtuzumab, gemtuzumab ozogamicin) ), rituximab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, brentuximab), Anti-CD52 Abs (eg, alemtuzumab (Campath)). In an embodiment, the chemotherapeutic agent is tositumomab or aclacinomycin A or gliotoxin or pegaspargase.

Common chemotherapeutic agents considered for use in combination therapy include bleomycin sulfate (Blenoxane), busulfan (Myleran), capecitabine (Xeloda), N4-pentoxycarbonyl-5-deoxy-5-fluoro Cytidine, carboplatin (Paraplatin), carmustine (BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cladribine (Leustatin), cyclophosphamide (Cytoxan or Neosar), Glycocytidine liposome injection (DepoCyt), Dacarb (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, Efudex), gemcitabine (difludeoxycytidine), hydroxyurea (Hydrea), idarubicin (Idamycin), irinotecan (Camptosar), L-asparaginase (ELSPAR), leucovorin (leucovorin calcium), 6-mercaptopurine (Purinethol), methotrexate (Folex), paclitaxel (Taxol), teniposide (Vumon), tirapazamine (Tirazone), topotecan HCl 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 (yttrium 90/MX-DTPA), polyphenhydramine 20 with carmustine implant (Gliadel), and citric acid Tamoxifen (Nolvadex).

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein is administered to a subject in combination with one or more of the following therapeutic agents: methotrexate (eg, Abitrexate, methotrexate LPF, Mexate, Mexate-AQ, Folex, Folex PFS), Nelarabine (eg, Arranon), doxorubicin HCl, daunorubicin with cytarabine and anthracyclines or Combinations of idarubicin, clofarabine (eg, Clofarex or Clolar), cyclophosphamide (eg, Cytoxan, Neosar, Clafen), cytarabine (eg, Cytosar-U, Tarabine PFS), dasatinib ( For example, Sprycel) or other BCR-ABL and SRC tyrosine kinase inhibitors, asparaginase (Erwinaze) (eg, Asparaginase Erwinia Chrysanthemi), imatinib mesylate Gleevec (eg, Gleevec), Ponatinib HCl (eg, Iclusig), mercaptopurines (eg, Purinethol, Purixan), Pegaspargase (eg, Oncaspar), Ponatinib HCl, Prednisone, Vinca Sulfate New alkaloids, vincristine sulfate liposomes (eg, Marqibo), vincasar PFS, and Hyper-CVAD. In an embodiment, the subject in the preceding sentence has ALL.

In an embodiment, the subject is administered a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein in combination with one or more of the following therapeutic agents: daunorubicin hydrochloride (eg, Cerubidine or Rubidomycin) (combined as needed with cytarabine and anthracyclines such as daunorubicin or idarubicin), idarubicin hydrochloride (eg, Idamycin), Bcl2 inhibitors (eg, ABT-737, venetate Traquex (eg, Venclexta), cyclophosphamide (eg, Cytoxan, Clafen, Neosar), cytarabine (eg, Cytosar-U, Tarabine PFS), doxorubicin HCl, decitabine (low methylating agents), fludarabine (fludara), FLT3 inhibitors (eg, sunitinib, sorafenib, midostaurin, lestaurtinib) , quizartinib, crenolanib, PLX3397), GCSF (granular leukocyte-colony stimulating factor), IDH inhibitors (eg, IDH1 inhibitors such as AG120 or IDH305); IDH2 inhibitors , such as AG221; pan-IGH1/IGH2 inhibitors such as AG881), mitoxantrone hydrochloride, thioguanine (eg, Tabloid), azacytidine, or decitabine (eg, hypomethylating agents), sulfate Vincristine (eg, Vincasar PFS). In an embodiment, the subject in the preceding sentence has AML.

In an embodiment, the subject is administered a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein in combination with one or more of the following therapeutic agents: G100 (Immune Design) ), bosutinib (eg, Bosulif), busulfan (eg, Busulfex, Myleran), cyclophosphamide (eg, Clafen, Cytoxan, Neosar), cytarabine (eg, Cytosar-U, Tarabine PFS), Dasatinib (eg, Sprycel), imatinib mesylate (eg, Gleevec), hydroxyurea (eg, Hydrea), ponatinib HCl (eg, Iclusig), dichloromethyldiethylamine hydrochloride (eg, Mustargen) , nilotinib, homoharringtonine mesylate (eg, Synribo), and alpha interferon. In an embodiment, the subject in the preceding sentence has CML.

In embodiments, the subject is administered with CVP (a combination of cyclophosphamide, vincristine, and prednisone) and/or CHOP (cyclophosphamide, daunorubicin, Oncovin (vincristine) and prednisone) in combination, with or without etoposide (eg, VP-16) and/or cyclophosphamide and pentostatin and/or chlorambucil and prednisone The bispecifics described herein are administered in combination and/or in combination with fludarabine and cyclophosphamide and an immunomodulator such as thalidomide or a thalidomide derivative (eg, lenalidomide) Anti-CD123 x anti-CD3 antibody (eg, XmAb14045). Combination therapy, anticancer agents, inhibitors such as antibodies

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with the following inhibitors: PD1 inhibitor, PDL1 inhibitor, PDL2 inhibitor, TIM3 inhibitor, LAG3 inhibitor agent, CTLA4 inhibitor, TIGIT inhibitor, BTLA inhibitor, CD47 inhibitor or 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.

In an embodiment, the anticancer agent is an antibody, such as an immunoneoplastic agent. Combination therapy, anticancer agent, PD1

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with a PD1 inhibitor. In an embodiment, the PD1 inhibitor is a small molecule inhibitor. In an embodiment, the PD1 inhibitor is CA-170 (Corres), AUNP-12 (Aurigene) or a compound described in WO 2015/034820, especially BMS-1, BMS -2, BMS-79 and BMS-196.

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein can be used in combination with an anti-PD1 antibody. In an embodiment, the PD1 inhibitor is nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab (Madison/Pfizer), Spartalizumab (also known as PDR001), JNJ-63723283 (J&J), TSR-042 (Tesaro), cemiplimab (also known as REGN2810) ( Sanofi), AMP-224 (Aprimoon/GSK), MEDI0680 (also known as AMP-514) (AstraZeneca), MGA012 (MacroGene/Insett), MGD013 (Macro Gene Company), MGD019 (Macro Gene Company), SHR-1210 (Shanghai Hengrui Pharmaceutical Company/Insett Company), GLS-010 (Yuheng Pharmaceutical Company/WuXi Biologics Company), JS001 (Shanghai Junshi Biopharmaceutical Company) PharmaTech), tislelizumab (also known as BGB-A317) (BeiGene / Celgene), sintilimab (also known as IBI308) (Innovent Company), CX-188 (Sitomex Therapeutics) or CS1003 (CStone Pharmaceuticals).

Exemplary non-limiting anti-PD1 antibody molecules are disclosed in US 2015/0210769, published July 30, 2015, entitled "Antibody Molecules to PD1 and Uses Thereof" (by reference). incorporated in its entirety).

In embodiments, the anti-PD1 antibody molecule comprises at least one or two heavy chain variable domains (including a constant region as needed), at least one or two light chain variable domains (including a constant region as needed), or two or, it comprises the amino acid sequence of BAP049-Col-A, BAP049-Col-B, BAP049-Col-C, BAP049-Col-D or BAP049-Col-E; or as US 2015/0210769 described in Table 1 of, or encoded by the nucleotide sequences in Table 1; or substantially identical to any of the preceding sequences (e.g., having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identity). The anti-PD1 antibody molecule optionally comprises a leader sequence derived from a heavy chain, a light chain, or both as shown in Table 4 of US 2015/0210769; or a sequence substantially identical thereto.

In embodiments, the anti-PD1 antibody molecule comprises at least one, two or three complementarity determining regions (CDRs) from the heavy chain variable region and/or light chain variable region of the antibodies described herein For example an antibody selected from any of the following: BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10 , BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Collection-A, BAP049-Collection-B, BAP049-Collection-C, BAP049-Collection -D or BAP049-Cloning-E; or as described in Table 1, or encoded by a nucleotide sequence in Table 1; or substantially identical to any of the preceding sequences (eg, having at least 80%, 85% %, 90%, 92%, 95%, 97%, 98%, 99% or higher identity).

In embodiments, the anti-PD1 antibody molecule comprises at least one, two or three CDRs (or all CDRs in general) from a heavy chain variable region comprising those in Table 1 of US 2015/0210769 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, one or more of the CDRs (or all of the CDRs in general) are relative to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In an embodiment, the anti-PD1 antibody molecule comprises at least one, two or three CDRs (or all CDRs in general) from a light chain variable region comprising those in Table 1 of US 2015/0210769 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, one or more of the CDRs (or all of the CDRs in general) are relative to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions. In embodiments, the anti-PD1 antibody molecule comprises substitutions in the light chain CDRs, eg, one or more substitutions in CDR1, CDR2 and/or CDR3 of the light chain. In one embodiment, according to Table 1 (eg, SEQ ID NO: 16 or 24 of the murine or chimeric, unmodified sequence; or SEQ ID NO: 34, 42, 46, 54, 58, 62 of the modified sequence , 66, 70, 74, or 78), the anti-PD1 antibody molecule comprises a substitution in the light chain CDR3 at position 102 of the light chain variable region (eg, at position 102 of the light chain variable region substitution of cysteine for tyrosine, or substitution of cysteine for serine residues).

In an embodiment, the anti-PD1 antibody molecule comprises at least one, two, three, four, five or six CDRs (or all CDRs in general) from the heavy and light chain variable regions, the heavy chain and light chain variable regions comprise the amino acid sequences shown in Table 1 of US 2015/0210769 or the amino acid sequences encoded by the nucleotide sequences shown in Table 1. In embodiments, one or more of the CDRs (or all of the CDRs in general) are relative to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In embodiments, the anti-PD1 antibody molecule comprises: (a) a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 4, the VHCDR2 amino acid sequence of SEQ ID NO: 5, and the VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 13, the VLCDR2 amino acid sequence of SEQ ID NO: 14 and the VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed In Table 1 of US 2015/0210769; (b) a VH comprising the VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1; the VHCDR2 amino acid sequence of SEQ ID NO: 2; and the VHCDR3 amino acid sequence of SEQ ID NO: 3; and VL, It comprises the VLCDR1 amino acid sequence of SEQ ID NO: 10, the VLCDR2 amino acid sequence of SEQ ID NO: 11 and the VLCDR3 amino acid sequence of SEQ ID NO: 32, each disclosed in Table 1 of US 2015/0210769; (c) VH, which comprises the VHCDR1 amino acid sequence of SEQ ID NO: 224, the VHCDR2 amino acid sequence of SEQ ID NO: 5, and the VHCDR3 amino acid sequence of SEQ ID NO: 3; and VL, which comprises SEQ ID The VLCDR1 amino acid sequence of NO: 13, the VLCDR2 amino acid sequence of SEQ ID NO: 14, and the VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769; or (d) VH comprising the VHCDR1 amino acid sequence of SEQ ID NO: 224; the VHCDR2 amino acid sequence of SEQ ID NO: 2; and the VHCDR3 amino acid sequence of SEQ ID NO: 3; and VL comprising SEQ ID NO: 3 The VLCDR1 amino acid sequence of ID NO: 10, the VLCDR2 amino acid sequence of SEQ ID NO: 11, and the VLCDR3 amino acid sequence of SEQ ID NO: 32 are each disclosed in Table 1 of US 2015/0210769.

In an embodiment, the anti-PD1 antibody molecule comprises (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224 ; the VHCDR2 amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 5; and the VHCDR3 amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising SEQ ID NO : The VLCDR1 amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 13, the VLCDR2 amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 14 and the VLCDR3 amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33 , each disclosed in Table 1 of US 2015/0210769.

In an embodiment, the PD1 inhibitor is an anti-PD1 antibody selected from nivolumab, pembrolizumab, or pidilizumab. In other embodiments, the PD1 inhibitor is spartalizumab (PDR001).

In an embodiment, the anti-PD1 antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In an embodiment, the anti-PD1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind PD1 are disclosed in US 8,008,449 and WO 2006/121168. In an embodiment, the inhibitor of PD1 is nivolumab and has a sequence disclosed herein (or a sequence substantially identical or similar thereto, eg, at least 85%, 90%, 95%, or higher than a specified sequence) sequence of identity).

輕鏈

The heavy and light chain amino acid sequences of nivolumab are as follows: Heavy chain

light chain

In an embodiment, the anti-PD1 antibody is pembrolizumab. Pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA; Merck) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab and other humanized anti-PD1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2): 134-44, US 8,354,509 and WO2009/114335 . The heavy and light chain amino acid sequences of Pembrolizumab are as follows: Heavy Chain QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG 50 INPSNGGTNF NEKFKNRVTL TTDSTTTAY 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 NQVSTLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447 light chain EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50 LIYLASYLES GVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL 100 TFGGGTKVEI KRTVAAPSVF IFPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218'

In an embodiment, the inhibitor of PD1 is disclosed, for example, in US 8,354,509 and WO 2009/114335, and has a sequence disclosed herein (or a sequence substantially identical or similar thereto, eg, at least 85%, 90%, or 90% of the specified sequence). %, 95% or higher sequence identity) of pembrolizumab.

In an embodiment, the anti-PD1 antibody is pidilizumab. Pedilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD1 antibodies are disclosed in WO 2009/101611.

Other anti-PD1 antibodies include AMP 514 (Apple Moon Corporation) and the like, eg, the anti-PD1 antibodies disclosed in US 8,609,089, US 2010028330 and/or US 20120114649.

In embodiments, the PD1 inhibitor is an immunoadhesin (eg, an immunoadhesin comprising the extracellular or PD1 binding portion of PDL1 or PDL2 fused to a constant region (eg, the Fc region of an immunoglobulin sequence). In an embodiment, the PD1 inhibitor is AMP-224 (B7-DCIg; Apple Moon; eg, disclosed in WO 2010/027827 and WO 2011/066342), which blocks PD1 and B7-H1 The interaction between the PDL2 Fc-fused soluble receptor.

In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises another anticancer agent. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a chemotherapeutic agent. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a pyrimidine analog. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises cytarabine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises an anthracycline. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises idarubicin. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises daunorubicin. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises an anthracenedione. In an embodiment, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises gemtuzumab. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a FLT3 inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a topoisomerase inhibitor. In an embodiment, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a poisomerase II inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises etoposide. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises mitoxantrone. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises an adenosine analog. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises fludarabine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises cladribine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a kinase inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises a Bcr-Abl inhibitor. In an embodiment, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises imatinib or nilotinib or dasatinib or Bosutinib or ponatinib or a combination thereof. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PD1 inhibitor, the combination further comprises omacetaxine. In an embodiment, for any of the combinations described in this paragraph, the PDl inhibitor is spartalizumab. Combination therapy, anticancer agent, PDL1 or PDL2

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a PDL1 inhibitor. In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with a PDL2 inhibitor.

In an embodiment, the PDL1 inhibitor is an antibody molecule. In an embodiment, the anti-PDL1 inhibitor is atezolizumab (Tecentriq) (formerly known as YW243.55.S70 or MPDL3280A), avelumab (Bavencio) (EMD Serono) (formerly known as MSB-0010718C), durvalumab (Imfinzi; Midimuni/AstraZeneca) (formerly MEDI-4736), FAZ053, LY3300054 (Eli Lilly), ABBV-181 (AbbVie) , MSB2311 (Maybus Biopharmaceuticals), MDX-1105 (also known as BMS-936559), CS1001 (formerly WBP3155) (CStone Pharmaceuticals), KN035 (Corning & Jereh Biotech), CA-327 (Criss), CX-072 (Sitomex Therapeutics), M7824 (EMD Serono), HTI-1316 (Hengrui Therapeutics) or JS003 (Shanghai Junshi Biomedical Technology).

Exemplary, non-limiting PDL1 inhibitors are disclosed in US 2016/0108123, entitled "Antibody Molecules to PDL1 and Uses Thereof," published April 21, 2016 (by reference). incorporated in its entirety).

In an embodiment, the PDL1 inhibitor includes at least one or two heavy chain variable domains (including constant regions as needed), at least one or two light chain variable domains (including constant regions as needed), or both , which includes BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12 , BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Col-K, BAP058-Col-L, BAP058-Col-M, BAP058-Col-N or BAP058 - the amino acid sequence of any of Colony-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequence of Table 1; or substantially identical to any of the preceding sequences (eg, sequences having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or more identity).

In embodiments, the PDL1 inhibitor comprises at least one, two or three complementarity determining regions (CDRs) from the heavy chain variable region and/or the light chain variable region of an antibody described herein, such as An antibody selected from any of the following: BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058-hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-hum10, BAP058-hum11, BAP058-hum12, BAP058-hum13, BAP058-hum14, BAP058-hum15, BAP058-hum16, BAP058-hum17, BAP058-Col-K, BAP058-Col-L, BAP058-Col-M, BAP058 -Col-N or BAP058-Col-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequences in Table 1; or substantially identical to any of the preceding sequences ( For example, sequences having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identity).

In an embodiment, the PDL1 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a heavy chain variable region comprising those described in Table 1 of US 2016/0108123 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In an embodiment, the PDL1 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a light chain variable region comprising those described in Table 1 of US 2016/0108123 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions. In embodiments, the PDL1 inhibitor comprises substitutions in the light chain CDRs, eg, one or more substitutions in CDR1, CDR2 and/or CDR3 of the light chain.

In embodiments, the PDL1 inhibitor comprises at least one, two, three, four, five or six CDRs (or all CDRs in general) from the heavy and light chain variable regions, the heavy chain and The light chain variable region comprises the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 of US 2016/0108123. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In embodiments, the PDL1 inhibitor comprises: (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; the VHCDR2 amino acid sequence of SEQ ID NO: 2 sequence; and the 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) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 9, the VLCDR2 amino acid sequence of SEQ ID NO: 10 and the VLCDR3 amino acid sequence of SEQ ID NO: 11, Each is disclosed in Table 1 of US 2016/0108123.

In embodiments, the PDL1 inhibitor comprises: (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; the VHCDR2 amino acid sequence of SEQ ID NO: 5 Sequence and the 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) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13 and the VLCDR3 amino acid sequence of SEQ ID NO: 14, Each is disclosed in Table 1 of US 2016/0108123.

In an embodiment, the PDL1 inhibitor comprises the VHCDR1 amino acid sequence of SEQ ID NO:1. In an embodiment, the anti-PDL1 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.

輕鏈（如WO 2013/079174中所揭露的SEQ ID NO: 25） QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL。In an embodiment, the PDL1 inhibitor is MSB0010718C. MSB0010718C (also known as A09-246-2; Merck Serono) is a monoclonal antibody that binds PDL1. Pembrolizumab and other humanized anti-PDL1 antibodies are disclosed in WO2013/079174 and have sequences disclosed herein (or sequences substantially identical or similar, eg, at least 85%, 90%, 95% of the specified sequences) or sequences of higher identity). The heavy chain and light chain amino acid sequences of MSB0010718C include at least the following: Heavy chain (SEQ ID NO: 24 as disclosed in WO 2013/079174)

Light chain (SEQ ID NO: 25 as disclosed in WO 2013/079174) QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL.

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

In an embodiment, the PDL1 inhibitor is MDX-1105. MDX-1105 (also known as BMS-936559) is described in WO 2007/005874 and has the sequence disclosed therein (or a sequence substantially identical or similar thereto, eg at least 85%, 90%, 95%, % or higher sequence identity) anti-PDL1 antibody.

In an embodiment, the PDL1 inhibitor is MDPL3280A (Genentech/Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds PDL1. MDPL3280A and other human monoclonal antibodies to PDL1 are disclosed in US Patent No. 7,943,743 and US Publication No. 20120039906.

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; Apple Moon; eg, disclosed in WO 2010/027827 and WO 2011/066342) .

In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises another anticancer agent. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a chemotherapeutic agent. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a pyrimidine analog. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises cytarabine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises an anthracycline. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises idarubicin. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises daunorubicin. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises an anthracenedione. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises gemtuzumab. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a FLT3 inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a topoisomerase inhibitor. In an embodiment, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a poisomerase II inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises etoposide. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises mitoxantrone. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises an adenosine analog. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises fludarabine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises cladribine. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a kinase inhibitor. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises a Bcr-Abl inhibitor. In an embodiment, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises imatinib or nilotinib or dasatinib or Bosutinib or ponatinib or a combination thereof. In embodiments, for any combination of a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) and a PDL1 inhibitor, the combination further comprises omacetaxine. In embodiments, for any combination described in this paragraph, the combination further comprises a PD1 inhibitor. In an embodiment, for any of the combinations described in this paragraph, the PDl inhibitor is spartalizumab. Combination therapy, anticancer agent, TIM3

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a TIM3 inhibitor. In an embodiment, the TIM3 inhibitor is MGB453, INCAGN2390 (Inset), Sym023, TSR-022 (Tessalo) and LY3321367 (Eli Lilly).

Exemplary non-limiting TIM3 inhibitors are disclosed in US 2015/0218274, entitled "Antibody Molecules to TIM3 and Uses Thereof", published August 6, 2015 (by reference). incorporated in its entirety).

In an embodiment, the TIM3 inhibitor includes at least one or two heavy chain variable domains (including constant regions as needed), at least one or two light chain variable domains (including constant regions as needed), or both , which includes ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-hum10, ABTIM3-hum11, ABTIM3 - any of hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3-hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23 amino acid sequence; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequences in Tables 1-4; or substantially identical to any of the preceding sequences (eg, having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identity). 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.

In embodiments, the TIM3 inhibitor comprises at least one, two or three complementarity determining regions (CDRs) from the heavy chain variable region and/or the light chain variable region of an antibody described herein, such as An antibody selected from any of the following: ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3- hum10, ABTIM3-hum11, ABTIM3-hum12, ABTIM3-hum13, ABTIM3-hum14, ABTIM3-hum15, ABTIM3-hum16, ABTIM3-hum17, ABTIM3-hum18, ABTIM3-hum19, ABTIM3-hum20, ABTIM3-hum21, ABTIM3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US 2015/0218274; or encoded by the nucleotide sequences in Tables 1-4; or substantially identical to any of the preceding sequences (eg, having at least 80 %, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identity).

In an embodiment, the TIM3 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a heavy chain variable region comprising Tables 1-4 of US 2015/0218274 The amino acid sequences shown in or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4. In embodiments, one or more of the CDRs (or the totality of the amino acid sequences shown in Tables 1-4 or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4) All CDRs above) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions.

In an embodiment, the TIM3 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a light chain variable region comprising Tables 1-4 of US 2015/0218274 The amino acid sequences shown in or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4. In embodiments, one or more of the CDRs (or the totality of the amino acid sequences shown in Tables 1-4 or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4) All CDRs above) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions. In embodiments, the TIM3 inhibitor comprises substitutions in the light chain CDRs, eg, one or more substitutions in CDR1, CDR2 and/or CDR3 of the light chain.

In an embodiment, the TIM3 inhibitor comprises at least one, two, three, four, five or six CDRs (or all CDRs in general) from the heavy and light chain variable regions, the heavy chain and The light chain variable region comprises the amino acid sequences shown in Tables 1-4 of US 2015/0218274 or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4. In embodiments, one or more of the CDRs (or the totality of the amino acid sequences shown in Tables 1-4 or the amino acid sequences encoded by the nucleotide sequences shown in Tables 1-4) All CDRs above) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions.

In embodiments, the TIM3 inhibitor comprises: (a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and SEQ ID NO: The VHCDR3 amino acid sequence of 5; and the light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13, and the VLCDR2 amino acid sequence of SEQ ID NO: 14 VLCDR3 amino acid sequences, each disclosed in Tables 1-4 of US 2015/0218274; (b) a VH comprising a VHCDR1 amino acid sequence selected from the group consisting of 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 VL, It comprises the VLCDR1 amino acid sequence of SEQ ID NO: 6, the VLCDR2 amino acid sequence of SEQ ID NO: 7, and the VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274 middle; (c) VH comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 9; VHCDR2 amino acid sequence of SEQ ID NO: 25; and VHCDR3 amino acid sequence of SEQ ID NO: 5; and VL, which Comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13, and the VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274 ; (d) VH comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 3; VHCDR2 amino acid sequence of SEQ ID NO: 24; and VHCDR3 amino acid sequence of SEQ ID NO: 5; and VL, which Comprising the VLCDR1 amino acid sequence of SEQ ID NO: 6, the VLCDR2 amino acid sequence of SEQ ID NO: 7, and the VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274 ; (e) VH comprising the VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 9; the VHCDR2 amino acid sequence of SEQ ID NO: 31; and the VHCDR3 amino acid sequence of SEQ ID NO: 5; and VL, which Comprising the VLCDR1 amino acid sequence of SEQ ID NO: 12, the VLCDR2 amino acid sequence of SEQ ID NO: 13, and the VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274 ;or (f) a VH comprising the VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 3; the VHCDR2 amino acid sequence of SEQ ID NO: 30; and the VHCDR3 amino acid sequence of SEQ ID NO: 5; and VL, It comprises the VLCDR1 amino acid sequence of SEQ ID NO: 6, the VLCDR2 amino acid sequence of SEQ ID NO: 7, and the VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274 middle.

Exemplary TIM3 inhibitors are disclosed in US Patent No. 8,552,156, WO 2011/155607, EP 2581113, and US Publication No. 2014/044728. Combination therapy, anticancer agent, LAG3

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with a LAG3 inhibitor. In an embodiment, the LAG3 inhibitor is LAG525, TSR-033 (Tesaro), REGN3767 (Sanofi), etilagimod alpha (also known as IMP321) (Prima Bio Medicine (Prima BioMed), MGD013 (Macrogenes), FS118 (F-star/Merck), INCAGN2385 (Insett) or GSK2831781 (GSK).

Exemplary non-limiting LAG3 inhibitors are disclosed in US 2015/0259420, entitled "Antibody Molecules to LAG3 and Uses Thereof," published on September 17, 2015 (by reference). incorporated in its entirety).

In an embodiment, the LAG3 inhibitor includes at least one or two heavy chain variable domains (including constant regions as needed), at least one or two light chain variable domains (including constant regions as needed), or both , which includes BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12 , BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (for example, 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-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050 - the amino acid sequence of any one of colony-F, BAP050-colonization-G, BAP050-colonization-H, BAP050-colonization-I or BAP050-colonization-J; or as in the table of US 2015/0259420 1, or encoded by the nucleotide sequences in Table 1; or substantially identical to any of the preceding sequences (e.g., having at least 80%, 85%, 90%, 92%, 95%, 97% , 98%, 99% or higher identity).

In embodiments, the LAG3 inhibitor comprises at least one, two or three complementarity determining regions (CDRs) from the heavy chain variable region and/or the light chain variable region of an antibody described herein, such as An antibody selected from any of the following: BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (for example, 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-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050 -hum20-Ser), BAP050-Col-F, BAP050-Col-G, BAP050-Col-H, BAP050-Col-I or BAP050-Col-J; or as in Table 1 of US 2015/0259420 described in, or encoded by the nucleotide sequences in Table 1; or substantially identical to any of the preceding sequences (e.g., having at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identity).

In an embodiment, the LAG3 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a heavy chain variable region comprising those listed in Table 1 of US 2015/0259420 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In an embodiment, the LAG3 inhibitor comprises at least one, two or three CDRs (or all CDRs in general) from a light chain variable region comprising those described in Table 1 of US 2015/0259420 The amino acid sequence shown or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions. In embodiments, the anti-PDL1 antibody molecule comprises substitutions in the light chain CDRs, eg, one or more substitutions in CDR1, CDR2 and/or CDR3 of the light chain.

In embodiments, the LAG3 inhibitor comprises at least one, two, three, four, five or six CDRs (or all CDRs in general) from the heavy and light chain variable regions, the heavy chain and The light chain variable region comprises the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 of US 2015/0259420. In embodiments, with respect to the amino acid sequence shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions or deletions.

In embodiments, the LAG3 inhibitor comprises: (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; the VHCDR2 amino acid sequence of SEQ ID NO: 2 sequence; and the 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) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 10, the VLCDR2 amino acid sequence of SEQ ID NO: 11 and the VLCDR3 amino acid sequence of SEQ ID NO: 12, Each is disclosed in Table 1 of US 2015/0259420.

In another embodiment, the anti-LAG3 antibody molecule comprises: (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; the VHCDR2 amino acid sequence of SEQ ID NO: 5 The sequence and the 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) comprising the VLCDR1 amino acid sequence of SEQ ID NO: 13, the VLCDR2 amino acid sequence of SEQ ID NO: 14 and the VLCDR3 amino acid sequence of SEQ ID NO: 15, Each is disclosed in Table 1 of US 2015/0259420.

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.

In an embodiment, the anti-LAG3 antibody is relatlimab. Relimumab (also known as BMS-986016 or BMS986016; Bristol-Myers Squibb) is a monoclonal antibody that binds LAG3. Relimumab and other humanized anti-LAG3 antibodies are disclosed in US 2011/0150892, WO 2010/019570 and WO 2014/008218. Combination therapy, anticancer agent, CTLA4

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with a CTLA4 inhibitor.

Exemplary anti-CTLA4 antibodies include tremelimumab (an IgG2 monoclonal antibody, available from Midimonide, a subsidiary of AstraZeneca), formerly known as ticilimumab , CP-675,206); and Ipilimumab (Yervoy) (CTLA4 antibody, also known as MDX-010, CAS No. 477202-00-9). Other exemplary anti-CTLA4 antibodies are disclosed, eg, in US Pat. No. 5,811,097. Other exemplary anti-CTLA4 antibodies include abatacept (Orencia), IBI310 (Innovent), BMS-986249 (BMS/CytomX Therapeutics), or CS1002 (CStone).

In embodiments, a bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) described herein can be combined with an anti-PD1 antibody molecule (eg, as described herein) and an anti-CTLA4 antibody (eg, ipilimumab) used. Combination therapy, anticancer agent, TIGIT

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with a TIGIT inhibitor. In an embodiment, the TIGIT inhibitor is OMP-313M32 (OncoMed). Combination Therapy, Anticancer Agent, BTLA

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a BTLA inhibitor. Combination therapy, anticancer agent, CD47

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) 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, anticancer agent, IDO

In an embodiment, a bispecific anti-CD123 x anti-CD3 antibody described herein (eg, XmAb14045) can be used in combination with an IDO inhibitor. In embodiments, the IDO inhibitor is navoximod (also known as GDC-0919) (Genetech/NewLink Genetics), indomod or indomod German prodrugs such as NLG802 (NewLink Genetics), epacadostat (also known as INCB024360) (Inceit), HTI-1090 (also known as SHR9146) (constant Ray Therapeutics), BMS-986205 (BMS), or LY3381916 (Eli Lilly). Combination therapy, anticancer agent, GITR agonist

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a GITR agonist.

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a GITR agonist. In an embodiment, the GITR inhibitor is TRX518-001, GWN323, MEDI1873 (Midimone), OMP-336B11 (Oncomed) or ICAGN01876 (Insett).

Exemplary GITR agonists include, eg, GITR fusion proteins and anti-GITR antibodies (eg, bivalent anti-GITR antibodies); eg, GITR fusion proteins described in: US Patent No. 6,111,090, European Patent No. 0920505B1, US Patent No. 6,111,090 Patent Case No.: 8,586,023, PCT Publication Nos.: WO 2010/003118 and 2011/090754, or anti-GITR antibodies described, for example, in: US Patent Case No.: 7,025,962, European Patent Case No.: 1947183B1, US Patent Case No.: 7,812,135 , US Patent No.: 8,388,967, US Patent No.: 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683, US Patent No.: 8,709,424, PCT Publication No.: WO 2013/039954, International Publication No.: WO 2013/039954, US Publication No.: US2014/0072566, International Publication No.: WO2015/026684, PCT Publication No.: WO 2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication Case No.: WO 2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO 99/20758, U.S. Patent Case No.: 6,689,607, PCT Publication No.: WO 2006/083289, PCT Publication No.: WO 2005/115451, US Patent No.: 7,618,632, PCT Publication No.: WO 2011/051726, International Publication No.: WO 2004060319, and International Publication No.: WO 2014012479.

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a GITR agonist and a PD1 inhibitor, eg, as described in WO 2015/026684.

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with GITR agonists and TLR agonists, eg, as in WO 2004060319 and International Publication No.: WO 2014012479 described in.

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with a GITR agonist and a PD1 inhibitor, eg, as described in WO 2015/026684.

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with GITR agonists and TLR agonists, eg, as in WO 2004060319 and International Publication No.: WO 2014012479 described in. Combination therapy, anticancer agent, ICOS agonist

In embodiments, the bispecific anti-CD123 x anti-CD3 antibodies described herein (eg, XmAb14045) can be used in combination with an ICOS agonist. Combination therapy, administered to human subjects with ALL

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered to a human subject with ALL in combination with one or more of: methotrexate (eg, an antineoplastic agent, Methotrexate LPF, Mexate, Mexate-AQ, Folex, Folex PFS), nerabine (eg Arranon), doxorubicin hydrochloride, daunorubicin hydrochloride (eg Cerubidine, Rubidomycin) (with cytarabine and Anthracycline combination (daunorubicin or daunorubicin), mitoxantrone, fludarabine, cladribine, clofarabine (such as Clofarex or Clolar), cyclophosphamide (such as Cytoxan, Neosar, Clafen), cytarabine (e.g. Cytosar-U, Tarabine PFS), dasatinib (e.g. Sprycel), other Brc tyrosine kinase inhibitors, asparaginase (e.g. asparagine) Enzymes, Chrysanthemum rot), imatinib mesylate (eg, Gleevec), ponatinib hydrochloride (eg, Iclusig), inotuzumab ozogamicin, https://www.cancer.gov/ about-cancer/treatment/drugs/vincristine-sulfate-liposome, mercaptopurines (e.g. Purinethol, Purixan), pegaspargase (e.g. Oncaspar), ponatinib hydrochloride, prednisone, vincristine sulfate, vincristine sulfate Alkaline liposomes (eg Marqibo), vincristine PFS, hyper CVAD, or any combination thereof. This bispecific antibody can be administered to subjects undergoing histocompatibility leukocyte therapy, or who have previously undergone allogeneic stem cell transplantation Human subjects undergoing additional donor lymphocyte infusions. Combination therapy, administered to human subjects with AML

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered to a human subject with AML in combination with one or more of: daunorubicin hydrochloride (eg, daunorubicin Cerubidine or Rubidomycin) (in combination with cytarabine and anthracycline-daunorubicin or idarubicin as needed), Vyxeos, idarubicin hydrochloride (eg, Idamycin), BCL2 inhibitors (eg, Venclexta), cyclophosphamide (eg, Cytoxan, Clafen, Neosar), cytarabine (eg, Cytosar-U, Tarabine PFS), doxorubicin hydrochloride, decitabine ( hypomethylating agents), fludarabine (fludara), Flt3 inhibitors (eg, sunitinib, sorafenib, midostaurin, letatinib, quizatinib , Crenolanib, PLX3397), GCSF (granular leukocyte-colony stimulating factor), IDH inhibitors (eg, IDH1 inhibitors, such as AG120 or IDH305); IDH2 inhibitors, such as AG221; pan-IGH1/IGH2 Inhibitors (eg, AG881), mitoxantrone hydrochloride, thioguanine (eg, Tabloid), azacitidine (eg, Vidaza, hypomethylating agents), vincristine sulfate (eg, Vincristine) Base PFS), gemtuzumab ozogamicin, etoposide, ensidipine, or any combination thereof. Combination therapy, administered to human subjects with CML

In some embodiments, the bispecific anti-CD123 x anti-CD3 antibody (eg, XmAb14045) is administered to a human subject with CML in combination with one or more of: bosutinib (eg, Bosulif), Busulfan (eg, Busulfex), Cyclophosphamide (eg, Clafen, Cytoxan, Neosar), Cytarabine (eg, Cytosar-U, Tarabine PFS), Dasatinib (eg, Sprycel), Imatinib Mesylate Nitrogen (eg, Gleevec), hydroxyurea (eg, Hydrea), ponatinib (eg, Iclusig), mustard (eg, Mustargen), busulfan (eg, Myleran), nerotinib, omacitab Octyl mesylate (eg, Synribo), and alpha interferon, or any combination thereof. Combination Therapy: Side Effects Modifiers

In some embodiments, the bispecific antibody is administered to a human subject in combination with one or more side effect improving agents. In an exemplary embodiment, the one or more side effect improving agents are administered prior to the first administration of the bispecific antibody. In an exemplary embodiment, the one or more side effect improving agents are administered prior to each administration of the bispecific antibody.

Side effects associated with the administration of CD123 x CD3 bispecific antibodies include, but are not limited to, interferon release syndrome ("CRS"). Other possible side effects include lymphopenia (decreased lymphocyte count), increased blood gamma-glutamine transpeptidase (GGT), increased blood alanine transaminase (ALT), increased blood Increased levels of aspartate aminotransferase (AST), fever, vomiting, nausea, diarrhea, hypotension, hypoxia, rash, dysphagia, gastroparesis, capillary leak syndrome, hypophosphatemia, anemia , fatigue, and increased lipase in the blood.

Symptoms of CRS can include high fever, nausea, transient hypotension, and hypoxia. CRS can include clinical physical signs and symptoms such as fever, fatigue, anorexia, myalgia, dizziness, nausea, vomiting, and headache. CRS can include clinical skin signs and symptoms, such as a 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 shortness of breath and hypoxemia. CRS can include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased (early) cardiac output, and potentially decreased cardiac output. CRS can include clinical signs and symptoms of coagulation, 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 neurological signs and symptoms, such as headache, altered mental status, confusion, madness, difficulty with word-calling or marked aphasia, hallucinations, tremors, dysmetria, gait changes, and seizures.

In an exemplary embodiment, administration of XmAb14045 described herein to a human subject produces a low rate of one or more of the symptoms of CRS described herein. In an exemplary embodiment, administration of XmAb14045 described herein to a human subject produces low levels of one or more of the symptoms of CRS described herein. In an exemplary embodiment, administration of XmAb14045 described herein to a human subject produces a low grade (eg, Grade 1 or Grade 2) of one or more of the symptoms of CRS described herein. In an exemplary embodiment, administration of XmAb14045 described herein to a human subject produces a low grade (eg, Grade 1 or Grade 2) CRS.

In one embodiment, the one or more side effect modifying agents include steroids, antihistamines, antiallergic agents, antinausea agents (or antiemetics), analgesics, antipyretics, cytoprotective agents, vasopressors , an anticonvulsant, an anti-inflammatory agent, or any combination thereof. Combination therapy : side effect modifiers, steroids

In one embodiment, the side effect improving agent is a steroid. In one embodiment, the steroid is a corticosteroid. In one embodiment, the corticosteroid is a glucocorticosteroid. In one embodiment, the corticosteroid is becortisol, dexamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone, or any combination thereof. In one embodiment, the corticosteroid is corticosterone, corticosterone, ethamethasoneb, or any combination thereof. In one embodiment, the steroid is corticosterone. In one embodiment, the steroid is dexamethasone. Combination therapy: Side effect modifiers, antihistamines

In one embodiment, the side effect improving agent is an antihistamine. In one embodiment, the antagonist antihistamines line H _1. In one embodiment, the H ₁ antagonist is atorvastatin, azelastine, bilastine, bromdiphenhydramine, brompheniramine, buxil, carbinoxamine, cetirizine 𠯤 (Zyrtec®), Chlorphenhydramine, Chlorpheniramine, Clemastine, Cyclidine Diphenhydramine, Doxylamine, Ebastine, Embramine, Fexofenadine (Allegra®), Hydroxy (Vistaril®), Lolatadine (Claritin®), Chlorobenzyl 𠯤, mirtazapine, olopatadine, orphenadrine, benzindene, pheniramine, phentoxamine, isopropyl 𠯤, quetiapine (Seroquel®), rupatadine (Alergoliber®), Tripinamine, triplitine, or any combination thereof.

In one embodiment, the antihistamine is Avastin. 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 line H ₁ antihistamines inverse agonist. In one embodiment, the inverse agonist, H ₁ based acrivastine, cetirizine 𠯤, 𠯤 levocetirizine, desloratadine, pyrilamine, or any combination thereof.

In one embodiment, the system H ₂ antihistamines antihistamines. In one embodiment, the antihistamine H ₂ H ₂ antagonists based. In one embodiment, the antihistamine H ₂ H _2-based inverse agonist. In one embodiment, the system H ₂ antihistamine cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, or random combination. Combination therapy: Side effect improver, antiallergic agent

In one embodiment, the side effect improving agent is an antiallergic agent. In one embodiment, the side effect-modifying agent is an antihistamine, glucocorticoid, epinephrine (adrenaline), obesity cell stabilizer, antileukotriene, anticholinergic, decongestant, or any combination thereof. In one embodiment, the side effect improving agent is a decongestant. In one embodiment, the side effect improving agent is an epinephrine releasing agent. In one embodiment, the side effect improving agent is levamylamine, phenylpropanolamine, Benzedrex®, loratadine, or any combination thereof. In one embodiment, the side effect improving agent is an alpha-adrenergic receptor agonist. In one embodiment, the side effect improving agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetrahydrozoline, tramazoline, bubenazoline, or any combination thereof. Combination therapy: Side effect modifiers, anti-nausea agents (or antiemetics)

In one embodiment, the side effect improving agent is an anti-nausea agent. In one embodiment, the side effect improving agent is an antiemetic. In one embodiment, the side effect-improving agent based 5-HT ₃ receptor antagonists. In one embodiment, the side effect improving agent is dolasetron (Anzemet®), granisetron (Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®) ), palonosetron (Aloxi®), mirtazapine (Remeron®), or any combination thereof. In one embodiment, the side effect improving agent is a dopamine antagonist. In one embodiment, the side effect-improving agent based 5-HT ₃ receptor antagonists. In one embodiment, the side effect improving agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, proclorazine, alipride, prochloraz Lazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®), or any combination thereof. In one embodiment, the side effect improving agent is an NK1 receptor antagonist. In one embodiment, the side effect improving agent is aprepitant or fosaprepitant (Emend®), casopitant, rolapitant (Varubi®), or any combination thereof. In one embodiment, the side effect improving agent is an anticholinergic drug. In one embodiment, the side effect improving agent is scopolamine. Combination therapy: Side effect modifiers, analgesics and/or antipyretics

In one embodiment, the side effect improving agent is an analgesic. In one embodiment, the side effect improving agent is an antipyretic agent. In one embodiment, the side effect improving 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, salalicylate, 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 improving agent is aspirin. In one embodiment, the side effect improving agent is acetaminophen, any derivative thereof. In one embodiment, the side effect improving 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 profen, 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. In one embodiment, the NSAID is an enolic acid derivative. In one embodiment, the NSAID is piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, 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 improving agent is phenazone, metamizole, nabumetone, any derivative thereof, or any combination thereof. In one embodiment, the side effect improving agent is an opiate. In one embodiment, the side effect improving agent is codeine, morphine, oxymorphol, phentanyl, or any combination thereof. In one embodiment, the side effect improving agent is dihydrocodeine, oxymorphone, oxycodone, metropone, or any combination thereof. Combination therapy: side effect improving agent, cytoprotective agent

In one embodiment, the side effect improving agent is a cytoprotective agent. In one embodiment, the side effect improving agent is an aminothiol compound. In one embodiment, the side effect improving agent is amifostine. In one embodiment, the side effect improving agent is bleomycin, dexrazoxane, coenzyme M, or any combination thereof. Combination therapy: Side effect modifiers, vasopressors

In one embodiment, the side effect improving agent is a vasopressor. In one embodiment, the vasopressor is norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or any combination thereof. In one embodiment, the vasopressor is dobutamine, midodrine, amezinium, or any combination thereof. Combination therapy: side effect modifiers, anticonvulsants

In one embodiment, the side effect improving agent is an anticonvulsant. In one embodiment, the anticonvulsant is an aldehyde. In one embodiment, the aldehyde is paraldehyde. In one embodiment, the anticonvulsant is aromatic allyl alcohol. In one embodiment, the aromatic allyl alcohol is stiripentol. In one embodiment, the anticonvulsant is a barbiturate. In one embodiment, the barbiturate is phenobarbital, primidone, mebitol, barbexaclone, or any combination thereof. In one embodiment, the anticonvulsant is a benzodiazepine. In one embodiment, the benzodiazepine is clobazam, clonazapine, clorazepate, dizapine, midazolam, lorazepam lorazepam, nitrazepam, temazepam, nimetazepam, or any combination thereof. In one embodiment, the anticonvulsant is formamide. In one embodiment, the formamide 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 valproate. In one embodiment, the valproate salt is valproic acid, sodium valproate, sodium divalproex, or any combination thereof. In one embodiment, the valproate is amine hexenoic acid, progabe, 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 hydantoin. In one embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, fosphenytoin, or any combination thereof. In one embodiment, the anticonvulsant is oxazolidinedione. In one embodiment, the oxazolidinedione is methylethyldione, trimethylenedione, oxadione, or any combination thereof. In one embodiment, the anticonvulsant is propionate. In one embodiment, the anticonvulsant is a pyrimidinedione. In one embodiment, the anticonvulsant is 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 succinimide. In one embodiment, the succinimide is ethosuximide, phensuximide, methosuximide, or any combination thereof. In one embodiment, the anticonvulsant is sulfamide. In one embodiment, the succinimide is acetazolamide, sutiamide, methazolamide, zonisamide, or any combination thereof. In one embodiment, the anticonvulsant is Tris. In one embodiment, the tris are lamosans. In one embodiment, the anticonvulsant is urea. In one embodiment, the urea is benzyl urea, phenethyl urea, or any combination thereof. In one embodiment, the anticonvulsant is valprodamide. In one embodiment, the anticonvulsant is valprodamide. In one embodiment, the valproamide is valproamide, valproamide, or any combination thereof. In one embodiment, the anticonvulsant is perampanel, stiripentol, pyridoxine, or any combination thereof. Combination therapy: Side effect improver, TNFα inhibitor

In one embodiment, the side effect improving agent is an anti-inflammatory agent. In one embodiment, the side effect improving agent is a TNF-α inhibitor. In one embodiment, the TNF-alpha inhibitor is an antibody. Examples of anti-TNFα antibody molecules are, for example, infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), or any combination thereof. Another example of a TNFα inhibitor is a fusion protein such as etanercept (Enbrel®). In one embodiment, the TNF-alpha inhibitor is a small molecule. Small molecule inhibitors of TNFα include, but are not limited to, xanthine derivatives (eg, pentoxifylline), bupropion, or any combination thereof. Combination therapy: Side effect improver, IL6 inhibitor

In one embodiment, the side effect improving agent is an anti-inflammatory agent. In one embodiment, the side effect improving agent is an IL-6 inhibitor. Examples of IL-6 inhibitors are anti-IL-6 antibody molecules such as tocilizumab (toc), 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.

The methods described herein can include administering to a human subject a bispecific antibody described herein, and further administering one or more agents to control the elevated levels of soluble factors caused by bispecific antibody treatment. In one embodiment, the soluble factor elevated in the human subject is one or more of IFN-γ, TNFα, 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. Accordingly, the agent administered to treat this side effect may be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of the soluble forms is an antibody or antigen-binding fragment thereof. Examples of such agents include, but are not limited to, steroids (eg, corticosteroids), TNFα inhibitors, IL-1R inhibitors, and IL-6 inhibitors. Examples include anakinra or rilonacept or canakinumab.

In one embodiment, the side effect improving agent is an agent that reduces immune-mediated side effects. Exemplary immune-mediated side effects include, but are not limited to, pneumonia, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, and endocrinopathy (eg, hypophysitis, type 1 diabetes, and thyroid disorders (eg, thyroid). Hypothyroidism and hyperthyroidism)). In one embodiment, the side effect improving agent reduces embryo-fetal toxicity.

In embodiments, an antipyretic agent can be administered to the human subject. In embodiments, an analgesic can be administered to the human subject. Side Effects Combinations and Amounts

In one embodiment, the steroid is administered before the bispecific antibody. In one embodiment, the steroid is administered in an amount between about 5 mg and about 30 mg. In one embodiment, the steroids described herein are administered in an amount between about 5 mg and about 25 mg. In one embodiment, the steroid is administered in an amount between about 5 mg and about 15 mg. In one embodiment, the steroid is administered in an amount between about 8 mg and about 12 mg. In one embodiment, the steroid is administered in an amount 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 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 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 XmAb14045. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes prior to each administration of XmAb14045. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes prior to each administration of XmAb14045.

In one embodiment, the antihistamine is administered prior to the bispecific antibody. In one embodiment, the antagonist antihistamines line H _1. In one embodiment, the system of the first generation of H ₁ antagonists H ₁ antagonist. In one embodiment, the antihistamine is ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbisoxamine, 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 between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount 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 between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount 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 is between about 20 mg and 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 prior to each administration of XmAb14045. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes prior to each administration of XmAb14045. In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes prior to each administration of XmAb14045.

In one embodiment, acetaminophen is administered prior to the bispecific antibody. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg. In one embodiment, acetaminophen is administered in an amount 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 between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount 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, acetaminophen is administered between about 15 minutes and about 45 minutes prior to each administration of XmAb14045. In one embodiment, acetaminophen is administered about 30 minutes prior to each administration of XmAb14045. In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of XmAb14045.

In one embodiment, the steroid is administered prior to the bispecific antibody, H ₁ antagonist, and acetaminophen. In one embodiment, the bispecific antibody administration prior to dexamethasone, H ₁ antagonist, and acetaminophen. In one embodiment, the 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 to about 20 mg, diphenhydramine is administered in an amount of about 25 mg, and diphenhydramine is administered in an amount of about 650 mg prior to the bispecific antibody with acetaminophen.

In one embodiment, the anti-nausea agent is administered prior to the bispecific antibody. In one embodiment, the anti-nausea agent-based 5-HT ₃ receptor antagonists. In one embodiment, the amount of between 30 mg to about 5 mg administered to the 5-HT ₃ receptor antagonists. In one embodiment, the amount of between 15 mg to about 5 mg administered to 5-HT ₃ receptor antagonists. In one embodiment, the amount of between 10 mg to about 5 mg administered to 5-HT ₃ receptor antagonists. In one embodiment, the amount of about 8 mg is administered in 5-HT ₃ receptor antagonists. In one embodiment, the amount administered 8 mg of 5-HT ₃ receptor antagonists. In one embodiment, the 5-HT ₃ receptor antagonist is ondansetron lines.

In one embodiment, the NK1 receptor antagonist is administered prior to the bispecific antibody. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 100 mg and 300 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount between about 125 mg and 200 mg. In one embodiment, the NK1 receptor antagonist is administered in an amount 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 a combination thereof. In one embodiment, the NK1 receptor antagonist is fosaprepitant meglumine.

Specific embodiments of the invention have been described above for purposes of illustration, however it will be understood by those skilled in the art that many changes in detail may be made without departing from the invention as set forth in the appended claims.

Specific embodiments of the invention have been described above for purposes of illustration, however it will be understood by those skilled in the art that many changes in detail may be made without departing from the invention as set forth in the appended claims. example

Examples are provided below to illustrate the methods described throughout. These examples are not intended to limit the method to any particular application or theory of operation. For all constant region positions discussed, numbering is according to the EU index in Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed., United States Public Health Service, National Institutes of Health [US Public Health Agency, National Institutes of Health], Bethesda, incorporated by reference in its entirety). The skilled artisan will appreciate that this convention consists of non-consecutive numbering of specific regions of the immunoglobulin sequence, thereby enabling standardization of references to conserved positions within the immunoglobulin family. Thus, the position of any given immunoglobulin as defined by the EU index will not necessarily correspond to its sequential sequence.

General and specific scientific techniques are outlined in US Patent Publication Nos. 2015/0307629, 2014/0288275, 2014/294823, 2016/0229924, and 2016/0355608. Example 1 XmAb14045 Therapeutic Program

This is a multicenter, open-label, multiple-dose, single-arm, Phase 1, dose-escalation study of XmAb14045. The dose of XmAb14045 will be administered intravenously (IV) over a 2 hour infusion period. The dose infusion period can be varied based on any observed infusion toxicity.

XmAb14045 is a humanized bsAb that binds both CD123 and CD3. The XmAb14045 pharmaceutical composition is a sterile liquid provided in single-use glass vials. Each vial is filled with 1.1 mL of a pharmaceutical composition containing 10 mM sodium citrate, 150 mM sodium chloride, and 0.04% (w/v) polysorbate-80 (pH 5.5) 1.0 mg/mL (± 5%) of XmAb14045. Each product vial should provide 1.0 mL of drug solution.

The IV solution stabilizer will be supplied in single-use glass vials. Each vial contains 10.5 mL of a solution (pH 5.5) containing 250 mM sodium citrate and 1.0% (w/v) polysorbate-80. Each product vial should provide 10.0 mL of drug solution.

Prior to administration, XmAb14045 will be administered in 10 mL of USP in one or more ethylene/polypropylene copolymer infusion bags (Excel™, B. Braun) to the desired final concentration. After dilution, the bag containing XmAb14045 should be gently inverted 2 to 3 times to mix the solution. The bag should not be shaken.

Before each dose of XmAb14045, human subjects should receive: • Inject 10-20 mg of dexamethasone IV approximately 1 hour before the weekly dose of XmAb14045 in Parts A and B. In Part C, dexamethasone should be administered prior to the C1D1 and C1D15 doses and may be omitted in subsequent doses unless overt symptoms of CRS occur. • Oral acetaminophen 650 mg approximately 30 minutes before infusion • Diphenhydramine 25 mg PO or IV 30-60 minutes before infusion

The study will be conducted in 5 parts: Part A, establishing a dosing cohort of MTD/RD for the first infusion; Part B, after human subjects receive their first infusion of the doses identified in Part A Establish dosing cohort for MTD/RD for the second (and subsequent infusion); Part C, Establish dosing cohort for MTD/RD for the following dosing regimen: 3 times weekly for the first 2 weeks of continuous therapy ( Induction), followed by weekly dosing (consolidation); and Parts D and E, establishing dosing cohorts for MTD/RD for the following dosing regimens: 3 (Part D) or 4 (Part E) weekly The first week of continuous therapy (induction), followed by increasing weekly dosing (consolidation) by using continuous escalating dosing during Cycle 1 (Days 1-28), and into Cycle 2 if tolerated and needed.

Part A: human subjects will be enrolled into the groups as many as 15 consecutive doses (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 µg/kg), and initial accelerated titration was used for the first 3 cohorts. The first 3 cohorts will each consist of 1 human subject until there is evidence of ≥ grade 2 toxicity, and the remaining cohorts will each enroll at least 3 human subjects into the classic 3+3 dose escalation regimen. Human subjects will be admitted for 3 days at the first and fourth doses (and at the second dose if admission is necessary for collection of serum interferons and inflammatory factors at the 8-hour post-infusion time point 2 days) for observation, PK, PD and laboratory assessment. Within each escalating dose cohort (Cohorts 1A-8A), human subjects will be administered XmAb14045 intravenously (IV) over 2 hours, every 7 days, for a total of 4 doses in each 28-day cycle . The initial treatment period will consist of 2 cycles.

Part B : For second and subsequent drug infusions, escalation to higher doses will be attempted. As in Part A, human subjects will be admitted at the first and fourth doses, but also at the escalating second dose (Day 8) for observation, PK, PD, and interleukin assessments .

Part C : Human subjects will be enrolled in up to 8 consecutive dose cohorts, and the initial dose level will be based on the highest tolerated dose level achieved in either Part A or B at that time. Administration of XmAb14045 will be divided into an induction phase (C1D1-C1D14) and a consolidation phase (C1D15 and beyond). Induction will consist of six 2-hour infusions (Days 1, 3, 5, 8, 10, and 12) starting at one-third of the weekly maximum dose level in Part A, which begins at Part C Has been assessed as tolerable/safe by DERC, and consolidation will consist of weekly 2-hour infusions (C1D15 and C1D22, and all subsequent infusions) at the full weekly dose from Part A, which is Part C has been assessed as tolerable/safe by DERC at the outset.

The Part C cohort will recruit at least 3 human subjects, each on a classic 3+3 dose escalation schedule. Human subjects will be hospitalized for 3 days at doses 1 through 2 and also at dose 8 for observation, PK, PD, and laboratory assessments.

If all 3 human subjects tolerated the initial Part C cohort without undergoing DLT (and DERC agreed), recruitment would begin on the next higher cohort, as determined in Table 4. The initial treatment period will consist of 2 cycles. After reaching the MTD and/or RD dose, the cohort can be expanded to up to an additional 12 subjects to obtain additional safety data. If MTD/RD is identified during the consolidation phase, increments during the induction phase can continue until MTD/RD is also identified.

Parts D and E: Human subjects can be included in Parts D and E dose cohorts according to Tables 5 and 6, respectively. Treatment will be divided into an induction phase (C1D1-C1D7) and a consolidation phase (C1D8 and beyond). 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)) , which begins with a C1D1 dose of 0.75 mcg/kg, and consolidation will consist of weekly 2-hour infusions (days 8, 15, and 22) and all subsequent infusions. During Cycle 1 (Days 1-28), unless Grade 3 CRS is observed, each dose will be increased by 50% from the previous dose. Recruitment of Part D cohorts can be performed in parallel with Parts A, B, C, and E. Part E cohorts can be recruited in parallel with Parts A, B, C, and D, but cohort 1E will not be opened until DERC finds cohort 1D tolerable.

If all 3 human subjects tolerate Cohort 1D without undergoing DLT (and DERC agrees), recruitment will begin on the next higher Part D Cohort (2D) or alternatively Cohort 1E as in as determined in Tables 5 and 6. The initial treatment period will consist of 2 cycles. For Part D or Part E, after reaching the MTD and/or RD dose, the cohort can be expanded to up to an additional 12 subjects to obtain additional safety data. If MTD/RD is identified during the consolidation phase, increments during the induction phase can continue until MTD/RD is also identified.

Doses to be administered to human subjects will be calculated for all cohorts based on baseline (Day -1) body weight measurements (in kg). Following the first dose, subsequent doses will be modified only if the human subject's body weight changes by more than 10% compared to Day -1 body weight, at which time the dose will be recalculated using the current body weight for the day of infusion. For human subjects weighing more than 100 kg, the dose of XmAb14045 will be calculated based on the body weight of 100 kg, not the actual body weight of the human subject.

The single dose level cohort of Part A and the sequentially increasing second and subsequent infusion dosing cohorts of Part B will use a dose escalation schedule. Dose escalation in both Parts A and B will continue until the MTD and/or RD for further study is identified, or until a dose of 35.0 mcg/kg is reached, whichever comes first.

Human subjects will receive two 28-day cycles of therapy (8 weekly doses in Parts A and B; 3 weekly doses x 2 weeks, followed by 6 weekly doses in Part C; 3 weekly doses Dose × 1 week, followed by 7 weekly doses of Part D; or 4 doses × 1 week, followed by 7 weekly doses of Part E). In the absence of unacceptable study drug-related toxicity, human subjects may receive additional treatment cycles if there is clinical benefit (as assessed by the investigator). Doses will be administered on Day 1, Day 8, Day 15, and Day 22 of each cycle unless otherwise stated in Sections C, D, and E. In the presence of drug-related toxicity, administration can be delayed. Completion of 4 doses of Parts A and B, 8 doses of Part C, 6 doses of Part D, or 7 doses of Part E of XmAb14045 and have undergone a planned safety assessment through Day 22 (+ up to 2 days to allow for small schedule changes and dosing delays) human subjects will be considered to have sufficient safety data/visit to identify DLT. If the MTD and/or RD are not reached, the dose will be escalated to the next dose cohort after review by DERC. Visit human subjects for a minimum of 4 weeks following cessation of treatment or until disease progression requires treatment, stem cell transplantation, or death occurs, whichever occurs first. The study website will collect information on disease status and survival by outpatient visits, email, or telephone contact for 6 and 12 months after the last study visit, or until death. A portion of the dose escalation scheme

In Part A, dose level escalation will first be performed according to an accelerated titration design (see Table 1 ). By implementing conservative triggering of cohort expansion during the accelerated escalation phase, this design allows for more efficient dose escalation while maintaining safety standards, and the design can limit exposure to potential subtherapeutic doses of XmAb14045 in human subjects quantity. [ Table 1 ] . Study Cohorts - Part A group planned dose human subjects A part 1A 3 ng/kg (0.003 µg/kg) 1 (+2+3) 2A 10 ng/kg (0.01 µg/kg) 1 (+2+3) 3A 30 ng/kg (0.03 µg/kg) 1 (+2+3) 4A 75 ng/kg (0.075 µg/kg) 3 (+3) 5A 150 ng/kg (0.150 µg/kg) 3 (+3) 6A 300 ng/kg (0.3 µg/kg) 3 (+3) 7A 500 ng/kg (0.5 µg/kg) 3 (+3) 8A 750 ng/kg (0.75 µg/kg) 3 (+3) 9A 1.3 µg/kg 3 (+3) 10A 2.3 µg/kg 3 (+3) 11A 4.0 µg/kg 3 (+3) 12A 7.0 µg/kg 3 (+3) 13A 12.0 µg/kg 3 (+3) 14A 20.0 µg/kg 3 (+3) 15A 35.0 µg/kg 3 (+3) extension-A at MTD or recommended first infusion dose up to 12 MTD = maximum tolerated dose.

During the initial accelerated dose escalation period (Cohorts 1A, 2A, and 2A), after treatment of 1 human subject per cohort, if there were no Grade ≥ 2 toxicities during Cycle 1 and that human subject Doses can be escalated if the minimum safety assessment requirements have been met (see Table 3 ). When human subjects experience ≥ Grade 2 toxicity during the dose escalation safety assessment period, the accelerated escalation period will end, the standard dose escalation period will begin, and the cohort of one or more events will be expanded to a total of at least 3 human subjects (2 additional human subjects will be recruited). [ Table 2 ] . Dose escalation schedule accelerated dose escalation period Number of human subjects with at least one event ≥ Grade 2 Number of human subjects recruited and evaluable for safety after four doses of XmAb14045 incremental decision 0 1 Escalation to next higher dose level 1 1 Two additional human subjects were recruited at the same dose level and were assigned to the following standard dose escalation (3 + 3) design. Standard dose escalation period Number of human subjects with at least one DLT Number of human subjects recruited and evaluable for safety after four doses of XmAb14045 incremental decision 0 3 Escalation to next higher dose level 1 3 Recruit 3 additional human subjects at the same dose level 1 6 Escalation to next higher dose level 2 3 or 6 Dose escalation may not occur; MTD has been exceeded. Should be extended to the next lower dose level. DLT = dose-limiting toxicity; MTD = maximum tolerated dose

After this cohort (or from Cohort 4A [0.075 µg/kg], whichever comes first), the standard 3 + 3 dose escalation rule will apply:

If zero out of 3 human subjects have DLT, the dose will be escalated to the next level.

If 1 out of 3 human subjects has DLT, the cohort will be further expanded to a total of 6 human subjects, or until a second human subject in the cohort undergoes DLT. If no additional human subjects have DLT, the dose will be escalated to the next higher dose level.

The MTD was defined as the highest dose level at which no more than 1 of the 6 human subjects at which toxicity could be assessed experienced a DLT. Any cohort with 2 or more human subjects experiencing DLT will exceed the MTD and no further dose escalation will occur. Dose levels below cohorts with DLT of 2 or more human subjects will be extended to at least 6 to delineate the MTD.

At least 1 human subject (during the accelerated dose escalation phase of the study) or 3 human subjects (during the standard escalation phase of the study) must meet all requirements for a dose escalation safety assessment before a dose escalation decision can be reached.

To determine the incidence of DLT and to define the MTD and/or recommended dosing of XmAb14045 for further studies, only human subjects undergoing DLT and those with sufficient safety data/visit will be evaluated. Human subjects who have completed 4 doses of XmAb14045 and have undergone a planned safety assessment through Day 22 (up to +2 days to account for minor program changes and dosing delays) will be considered adequately safe Sexual data/visits. Human subjects who withdraw from the study before Day 22 of completion of treatment for reasons unrelated to study drug toxicity will be considered to have insufficient data to support dose escalation. In such cases, a replacement human subject will be recruited to receive the same dose of XmAb14045 as the prematurely withdrawn human subject.

The DERC will decide to proceed to the next cohort level after reviewing all required dose escalation safety assessment data from human subjects in the cohort. During safety assessments, PK and ADA data are not normally used because these samples can be analyzed in batches to allow for a more uniform drug exposure analysis and ADA analysis across all study samples. However, if human subject safety concerns arise and the treating physician believes that information on drug exposure and/or ADA analysis is useful in determining treatment planning for human subjects, then the human subjects collected to date may be assessed. Subject samples were subjected to PK and ADA analysis.

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

Based on the availability of PK and PD data in this trial and the type and severity of toxicities observed, the dose escalation regimen may be modified with DERC consent (eg, smaller increases or decreases in dose levels may be permitted, which may be Recruiting additional human subjects, infusion duration and schedule can be modified). Dose Escalation Protocol - Part B

In Part B, the dose on Day 1 will be fixed at the level established in Part A. The second dose will be escalated and maintained in subsequent doses. Dosing cohorts will be defined relative to the MTD/RD determined in Part A. [ Table 3 ] : Study Cohorts - Part B group Day 1 Day 8 Day 15 Day 22 human subjects Part B -1B X X X+1 X+1 3 ( +3 ) 1B X X+1 X+1 X+1 3 (+3) 2B X X+2 X+2 X+2 3 (+3) 3B X X+3 X+3 X+3 3 (+3) 4B X X+4 X+4 X+4 3 (+3) 5B X X+5 X+5 X+5 3 (+3) 6B X X+6 X+6 X+6 3 (+3) 7B X X+7 X+7 X+7 3 (+3) extension-B Group in MTD or RD up to 12 MTD = maximum tolerated dose; RD = recommended dose; X = part A MTD/RD

Dose escalation will be as described for the standard 3+3 regimen described in Part A, and at 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 mcg/kg), however the infusion dose on Day 1 will always be the MTD/RD determined in Part A (denoted as "X" in Table 3). Dose escalation for each Part B cohort will be based on this starting point. For example, if the MTD/RD from Part A was 0.03 mcg/kg, the first infusion in cohort 1B would be 0.03 mcg/kg, and the second and subsequent infusions would be 0.075 mcg/kg (ie, X + 1).

A minimum of 3 human subjects will be recruited in each cohort. As in Part A, no two human subjects will begin treatment with XmAb14045 on the same day. If all 3 human subjects tolerated the cohort without undergoing DLT (and DERC agreed), recruitment would begin on the next higher cohort. If a DLT occurs at any time until Day 22 (up to +2 days, to account for small schedule changes and dosing delays), or if the medical monitor determines that additional safety data is required for a given dose cohort, the cohort 3 additional human subjects will be added. If there are additional DLTs in the cohort of 6 human subjects, the previous dosing cohort will be expanded to 6 to establish MTD and/or RD. If this happens on cohort 1B, the next 3 human subjects will be recruited to cohort-1B. If there are no additional DLTs in these 3 additional human subjects, an additional 3 human subjects will be added to the cohort. If there are additional DLTs, the MTD/RD and schedule established in Part A will be recommended for further study.

Based on available PK and PD data and the type and severity of observed toxicities, the dose escalation regimen may be modified with DERC consent (eg, smaller increases or decreases in dose levels may be permitted, additional cohorts may be recruited human subjects, infusion duration and schedule can be modified). Dose Escalation Protocol - Part C

Accrual for Part C cohorts will begin as soon as possible. Administration of XmAb14045 will be divided into an induction phase (C1D1-C1D14) and a consolidation phase (C1D15 and beyond). Induction 3 weekly infusions (cycle 1, days 1, 3, 5, 8, 10, and 12) (induction dose) administered IV over 2 hours. Beginning with C1D15, once a week (consolidation), it is also voted for 2 hours. The induction phase of the first Part C cohort will begin at one third of the highest weekly dose level of Part A (not to exceed a C1D1 dose of 0.75 μg/kg), which has been assessed as tolerable/safe by DERC (0.43 μg/kg) and consolidation will consist of once-weekly 2-hour infusions (C1D15 and C1D22, and all subsequent infusions) at the full once-weekly dose level of Part A (which was assessed by DERC as tolerable/safe) ( 1.3 μg/kg) composition.

See Table 4 for specific doses and planned cohort dose escalation. [ Table 4 ] : Study Cohorts - Part C group C1D1 dose ( µg/kg ) Induction dose ( µg/kg ) Consolidation dose ( µg/kg ) human subjects Part C 8C 0.25 0.25 0.75 3 (+3) 9C 0.43 0.43 1.3 3 (+3) 10C 0.75 0.77 2.3 3 (+3) 11C 0.75 1.3 4.0 3 (+3) 12C 0.75 2.3 7.0 3 (+3) 13C 0.75 4.0 12.0 3 (+3) 14C 0.75 6.7 20.0 3 (+3) 15C 0.75 11.7 35.0 3 (+3) extension-C MTD or RD in Part C up to 12

A minimum of 3 human subjects will be recruited in each cohort. As in Parts A and B, no two human subjects will begin treatment with XmAb14045 on the same day. If all 3 human subjects tolerated the cohort without undergoing DLT (and DERC agreed), recruitment would begin on the next higher cohort. If a DLT occurs at any time until Day 22 (up to +2 days, to account for small schedule changes and dosing delays), or if the medical monitor determines that additional safety data is required for a given dose cohort, the cohort 3 additional human subjects will be added. If there are additional DLTs in the cohort of 6 human subjects, the previous dosing cohort will be expanded to 6 to establish MTD and/or RD.

Based on available PK and PD data and the type and severity of observed toxicities, the dose escalation regimen may be modified with DERC consent (eg, smaller increases or decreases in dose levels may be permitted, additional cohorts may be recruited human subjects, infusion duration and schedule can be modified).

Changes that can only be made through protocol modification include: • Dose escalation in the induction or consolidation phase is faster than shown in Table 4. • Administration by infusion over 4 times per week • Administration over 2 weeks beyond once weekly administration • Exceeding the highest tolerated C1D1 dose achieved in Part A as the C1D1 induction dose in Part C. Dose escalation scheme -D section and section E

Parts D and E combine reduced C1D1 doses 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 issues; and will escalate to The drug limit is a 50% or less increase. Accruals for Part D will begin immediately, accruals for Part E may begin after DERC finds that Cohort 1D or Modified 1D is tolerable, and accruals for Parts D and E may occur simultaneously. Accruals for Parts A, B, and C are currently suspended.

Human subjects will initially be recruited into cohort 1D (Table 5). Treatment will be divided into an induction phase (C1D1-C1D7) and a consolidation phase (C1D8 and beyond). Induction will consist of 3 doses (Part D) or 4 doses (Part E; Table 6) per week by 2-hour infusion (the first week of Cycle 1 (Days 1, 3, and 5 or Days 1, 3, and 4) and 5 days) period), which starts with a C1D1 dose of 0.75 mcg/kg, and the consolidation of part D or E will consist of weekly 2-hour infusions (days 8, 15, and 22) and all subsequent infusions. During Cycle 1 (Days 1-28), each dose will be increased by 50% from the previous dose. Human subjects can be recruited into the modified 1D. [ Table 5 ] : Study Cohort - Part D Escalation Cohort (dose escalation increments of 50% ) First cycle Second cycle group Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 Day 1 Day 8 Day 15 + 1D 0.75 1.1 - 1.7 2.5 3.8 5.7 5.7 5.7 5.7 2D 0.75 1.1 - 1.7 2.5 3.8 5.7 8.5 8.5 8.5 3D 0.75 1.1 - 1.7 2.5 3.8 5.7 8.5 12.8 12.8 4D 0.75 1.1 - 1.7 2.5 3.8 5.7 8.5 12.8 19.2 Note: The escalating dosing in Part D may continue beyond Cohort 4D, where dose increments are approximately 50%. Decrease escalation cohort (if Grade 3 CRS is observed, dose escalation increments of 25% ) group First cycle The second period + Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 -1D 0.75 0.9 - 1.2 1.5 1.8 2.3 2.3 CRS = Interferon Release Syndrome. All doses are in µg/kg. Modified Part D Increment Group First cycle Second cycle group Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 Day 1 Day 8 Day 15 + Modified 1D 0.43 0.75 - 1.1 1.7 1.7 1.7 1.7 1.7 1.7 Decrease escalation cohort (if Grade 3 CRS is observed, dose escalation increments of 25% ) group First cycle The second period + Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 -1D 0.43 0.542 - 0.678 0.848 1.060 1.060 1.060 CRS = Interferon Release Syndrome. All doses are in µg/kg. [ Table 6 ] : Study Cohort - Part E Escalation Cohort (dose escalation increments of 50% ) First cycle Second cycle group Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 Day 1 Day 8 Day 15 + 1E 0.75 1.1 1.7 2.5 3.8 5.7 8.5 8.5 8.5 8.5 2E 0.75 1.1 1.7 2.5 3.8 5.7 8.5 12.8 12.8 12.8 3E 0.75 1.1 1.7 2.5 3.8 5.7 8.5 12.8 19.2 19.2 Note: The escalating dosing in Part E may continue beyond Cohort 3E, where dose increments are approximately 50%. Decrease escalation cohort (if Grade 3 CRS is observed, dose escalation increments of 25% ) group First cycle The second period + Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 -1E 0.75 0.9 1.2 1.5 1.8 2.3 2.9 2.9 CRS = Interferon Release Syndrome. All doses are in µg/kg. Modified Section E Incrementing Groups First cycle Second cycle group Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 Day 1 Day 8 Day 15 + Modified 1E 0.433 0.75 1.1 1.7 2.5 2.5 2.5 2.5 2.5 2.5 Decrease escalation cohort (if Grade 3 CRS is observed, dose escalation increments of 25% ) group First cycle The second period + Day 1 Day 3 Day 4 Day 5 Day 8 Day 15 Day 22 -1E 0.433 0.542 0.678 0.848 1.060 1.060 1.060 1.060 CRS = Interferon Release Syndrome. All doses are in µg/kg.

A minimum of 3 human subjects will be recruited in each cohort. As in Parts A, B, and C, no 2 human subjects will begin treatment with XmAb14045 on the same day. If all 3 human subjects tolerated Cohort 1D without undergoing DLT and DERC agreed that further dose escalation was necessary, recruitment would begin on Cohort 2D or 1E or modified 1E as needed.

If cohorts ID and/or IE tolerated, further escalation of DERC may be considered. This will happen in the following way: • Dose escalation can occur at C2D1 and can be increased by 50% over the previous cohort acceptable to DERC. • At least 3 subjects are recruited in each cohort and no 2 subjects will begin treatment with increasing doses of XmAb14045 on the same day. • The DLT period can be extended to include the day of the escalation dose plus an additional 2 days. • If all 3 human subjects tolerate the cohort without undergoing DLT and DERC agrees that further dose escalation is necessary, then C2D8 will be dose escalated by 50% over C2D1 and the DLT period can be extended again to escalated doses day plus 2 days (C2D10). • Continue escalation in a manner acceptable to DERC, but may not continue escalation beyond 35 µg/kg.

If group 1D or 1E is intolerant, DERC may consider the following options: • If excess CRS is observed at the C1D1 dose, it may be administered in divided doses (ie, a total dose of 0.75 mcg/kg can be administered as two 2-hour infusions on C1D1 and C1D2). • If excess CRS is found in dosing after C1D1, recruitment of the decremented cohort-1D can be initiated. If excess toxicity persists, a reduction to cohort-2D is possible. • DERC may make other changes to dose and schedule according to the guidelines below.

If a DLT occurs at any time until Day 22 (up to +2 days, to account for small schedule changes and dosing delays), or if the medical monitor determines that additional safety data is required for a given dose cohort, the cohort 3 additional human subjects will be added. If additional DLTs occur in the cohort of 6 human subjects, the previous dosing cohort will be expanded to 6 human subjects to establish MTD and/or RD.

Based on available PK and PD data and the type and severity of observed toxicities, the dose escalation regimen may be modified with DERC consent (eg, smaller increases or decreases in dose levels may be permitted, up to An additional 12 human subjects were obtained for additional safety data; infusion duration and schedule can be modified (including split dosing as determined above).

Changes that can only be made through protocol revisions include the following: • Dose escalation in the induction or consolidation phase is faster than indicated in Table 5 or Table 6. • Administration by infusion over 4 times per week • Administration over 2 weeks with greater than weekly administration Results:

At data cutoff, 95 human subjects had been treated, 94 with relapsed/refractory AML and 1 with B-ALL. Human subjects had a median age of 62 years (range 18-85 years) and were heavily pre-treated (median 3 [range 1-8] for prior treatment). CRS or its constituent symptoms were the most common treatment-emergent adverse events (TEAEs). CRS episodes occurred within approximately 1-4 hours of starting the drug infusion and occurred in 76 of 95 human subjects (80%). Grade ≥ 3 CRS occurred only at the 1,300 ng/kg or 2,300 ng/kg dose and at the first dose, with one exception. Myelosuppression requiring dose adjustment was not observed. Two human subjects had signs of mild tumor lysis syndrome.

Based on data published in December 2018, from a subset of these human subjects administered in Cohorts 9A, 10A, 1B and 2B, single agent anti-leukemia activity at the two highest dose levels studied to date (1300 ng/kg or 2300 ng/kg weekly) 5 out of 18 human subjects (CR/CRi ratio 27.8%) were recorded as best CR(2) or CRi(3) Responses; at low doses, no CR, CRi, or morphological leukemia-free status (MLFS) responses were observed. Antileukemic activity occurred rapidly; all responders had achieved at least MLFS response after 4 doses (1 cycle). Disease stabilization lasting more than 3 months occurred in 3 additional human subjects. Bone marrow blast reduction occurred in 56% of human subjects. Three responders transitioned to stem cell transplantation. The median response time was 15.4 weeks (range 9.1-20.3+). Excluding CRS-related events, other TEAEs in >10% of human subjects included: chills (39%), fever (27%), tachycardia (21%), elevated 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 subjects and was managed with analgesics. Grade 3 transaminase elevations occurred within 24 hours after infusion of XmAb14045, with complete remission within 7 days, and occurred most often with the first dose of XmAb14045 in 5 human subjects. Only one human subject developed hyperbilirubinemia (grade 1). 66 human subjects in the data subgroup published in December 2018; median age 61 years (range 18-85 years); 46% female; 100% had an AML diagnosis; median time since first diagnosis was 49 weeks (range 3-879); median prior treatment was 3 (range 1-8); 30% of human subjects had a history of hematopoietic stem cell transplantation; 86% were refractory to last treatment; 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 unfavorable; 9% of human subjects had an ELN risk category Category is unknown. 11% had secondary leukemia. As can be seen from the data, XmAb14045 was well tolerated at the doses and regimens studied and was clinically active in relapsed AML. Antibody constructs with full length Fc regions allow weekly dosing. Interferon release syndrome is the major toxicity of XmAb14045; premedication and management with activating doses and escalating dosing are effective in limiting its severity. Even after chronic administration, no obvious signs of myelosuppression were observed. Significant clinical responses have been achieved in relapsed/refractory AML allowing allogeneic stem cell transplantation.

Based on data published in December 2018, from a subgroup of these human subjects, the severity of infused CRS (cohorts 9A-2B) is shown in Figure 17. Cohorts 1A-3A were not premedicated. Cohort 4A added standard premedication (75 ng/kg): IV 10-20 mg dexamethasone; po 50 mg diphenhydramine; po 500 mg acetaminophen. All CRS episodes begin within 1-4 hours after drug infusion and usually resolve within 1-4 hours. CRS was generally more severe at the initial dose, accounting for most grade ≥ 3 episodes.

Based on the data published in December 2018, a subset of those from human subjects, peak serum IL-6 by infusion as shown in FIG. 18. Percentage change based on data published in December 2018, a subgroup from those of a human subject, from the pretreatment baseline bone marrow blasts 19 as shown in FIG. Based on the data published in December 2018, a subgroup from those of a human subject to treatment discontinuation time as shown in Figure 20. Based on the data published in December 2018, a subgroup from those of a human subject, CR, and CRi respondent data as shown in FIG. 21. Embryonic cells based on data published in December 2018, from a subgroup of those human subjects, the respondents compared to respondents without CD123 expression as shown in Figure 22.

Based on data as of (October 28, 2020), 112 subjects have been dosed. Human subjects had a median age of 64 years (range 18-85 years) and were heavily pre-treated (median 3 [range 0-8] for prior treatment). 53% of human subjects were women. The time since first diagnosis was 48 weeks [range 3-896 weeks]. The major toxicity was cytokine release syndrome (CRS) and occurred in 60.7% of human subjects. The efficacy analysis included all patients who: a) had completed at least the first cycle (4 doses in Parts A and B; 8 doses in Part C; 6 doses in Part D; 7 doses in Part E); and b) have at least one post-treatment disease assessment (occurring at the end of odd-numbered cycles). Fifty-four human subjects in cohorts 8A-1D were evaluable. Objective response rate (CR + CRi + MLFS + PR) = 14.8% (8/54 human subjects) at ≥ 0.75 µg/kg. ORR = 25.9% in the population with blast count ≤ 25% (7/27 human subjects). An additional 38 human subjects had stable disease (70.4%). Bone marrow blast reduction occurred in 52% of human subjects.

IL-6 levels in human subjects can be used as a predictive biomarker for CRS, especially when IL-6 levels are greater than 1000 pg/mL. In the cohort with the initial dose of 0.75 microg/kg and the weekly escalating dose, IL-6 peaks were observed at both the initial dose and the weekly escalating dose. In the cohort with an initial dose of 0.75 microg/kg and dosing every other day, CRS was observed at this initial dose.

In the cohort with an initial dose of 0.75 microg/kg or less, the IL-6 inhibitor (tocilizumab) was administered to approximately half of the patients following this initial dose. After this initial dose, the IL-6 inhibitor (tocilizumab) was not administered to patients in the cohort with the initial dose of 0.5 microg/kg or less.

Based on data as of (October 28, 2020), 19 human subjects have been recruited into Cohort 1D. Efficacy was evaluable for 10 of the 19 human subjects. The following table provides efficacy and DLT: group 1D CR+CRi+MLFS+PR (1 cr) Evaluable (<= 25% blasts) 2 CR+CRi+MLFS+PR (<= 25%) (1) DLT Gr 3 DIC; LFTs; amylase; extravasation; ARDS amylase/lipase Xencor Presents Updated Data From Phase 1 Study of Victorinumab in Acute Myeloid Leukemia at ASH Annual Meeting 2020

MONROVIA, Calif.--(BUSINESS WIRE)--Xencor, Inc. (NASDAQ:XNCR) is a clinical-stage biopharmaceutical company developing treatments for Engineered Monoclonal Antibodies for Cancer and Autoimmune Diseases, today announced that its ongoing Phase 1 CD123 x CD3 bispecific antibody velkumab (XmAb® 14045) in patients with relapsed or refractory acute myeloid Recent data from a dose escalation study in leukemia (AML) patients. At the 62nd Annual Meeting of the American Society of Hematology (ASH), Farhad Ravandi, MD, professor of medicine and chief of the Division of Acute Myeloid Leukemia in the Leukemia Department at the University of Texas MD Anderson Cancer Center, presented in an oral session. such data.

“Vektuzumab has meaningful clinical activity in relapsed AML, and the response appears to be associated with a lower baseline disease burden, driven by a lower percentage of blasts and PD1 expression on CD8+ and CD4+ T cells in patients Lower indication. This suggests a possible strategy for selecting patients who are likely to be most responsive," Dr. Ravandi said. "Responses including CR and CRi are durable, lasting many months in some patients."

"Furthermore, we continued to observe that the severity of the major toxicity (CRS) of velkimab was generally mild to moderate when observed, and that our mitigation strategy, including a combination of dose modification measures, has effectively limited its severity," said Allen Yang, MD, Ph.D., senior vice president and chief medical officer. "With a manageable configuration and promising potential in certain patient populations such as myelodysplastic syndrome and AML with minimal residual disease, we are now planning to develop with our partner Novartis Victorinumab for these patients.” Key Highlights of the Presentation

In data as of October 28, 2020, 112 patients with relapsed or refractory AML had received velociraptor. The patients had a median age of 64 years and had undergone extensive pretreatment (a median of three prior treatments and 30% of patients with a history of allogeneic hematopoietic stem cell transplantation (n = 34)). 86% of patients (n = 96) were refractory to their last treatment and 62% (n = 69) were classified as poor risk by the European Leukemia Network (ELN 2017) system. The study is ongoing and more patients are being recruited.

Interferon release syndrome (CRS) was the most common toxicity in 61% of patients (n = 68), and 9% of patients (n = 10) experienced grade 3 or higher CRS. Most CRS was observed in the first dose and was usually manageable with premedication. Other mitigation measures include choosing a lower initial dose, avoiding weekly dose escalation, and dosing more frequently in the first week to allow for higher cumulative exposure and avoid potential CD123 antigen silencing. There is no evidence of drug-related myelosuppression. Neurologic events were rare and were predominantly grade 1 and 2 headaches.

The efficacy analysis included 54 evaluable patients who received a dose of at least 0.75 mcg/kg, completed at least one treatment cycle, and had at least one post-treatment disease assessment. Two patients achieved complete remission (CR), and three patients achieved CR (incomplete hematologic recovery). In addition, two patients achieved morphological leukemia-free status and one patient experienced a partial response, as assessed by the investigator. The overall response rate (ORR) was 15% (n = 8/54).

Biomarker analysis indicated that low baseline leukemia burden and low expression of PD-1 on CD4+ and CD8+ T cells were independent predictors of response. Seven respondents had baseline blast counts less than or equal to 25% of blasts in the bone marrow. When this threshold was used to identify groups with low disease burden for analysis, the ORR increased to 26% (n = 7/27).

The presentation will be documented under "Events and Presentations" in the investor section of the company's website www.xencor.com. About Victorinumab

Veltuzumab (XmAb® 14045) is a tumor-targeting antibody in Phase 1 clinical trials for acute myeloid leukemia (AML) and other hematological malignancies expressing CD123, comprising a CD123 binding domain and a cytotoxic T cell binding domain (CD3). The XmAb bispecific Fc domain acts as a scaffold for these two antigen-binding domains, and confers long circulating half-life, stability, and ease of manufacture to Victorinumab. CD123 is highly expressed on AML cells and leukemia stem cells, and it is associated with poor prognosis in AML patients. Binding of velociraptor to CD3 activates T cells for efficient and targeted killing of tumor cells expressing CD123. About Suncor Corporation

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

Statements contained in this release that are not historical facts are forward-looking statements within the meaning of applicable securities laws, including, but not limited to, citations by Sencor's Chief Medical Officer and references to the timing, expectations and success of clinical trials, product candidates and Sencor Any statement related to the company's research and development program. Such statements involve known and unknown risks, uncertainties and other factors that could cause actual results, performance or achievements and the timing of events to differ materially from those implied by such statements and therefore Statements such as these should not be considered guarantees of future performance or results. Such risks include, but are not limited to, risks associated with the process of discovering, developing, manufacturing and commercializing drugs that are safe and effective for use as human treatments, as well as other risks described in Suncor's public securities filings. For a discussion of these and other factors, please see Suncor's annual report on Form 10-K for the year ended December 31, 2019 and Suncor's subsequent filings with the Securities and Exchange Commission. All forward-looking statements are based on Suncor's current information and beliefs and assumptions made by Suncor. We caution you not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. The warning was issued under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements in their entirety are qualified by this cautionary statement, and Suncor undertakes no obligation to revise or update this release to reflect events or circumstances after the date hereof, except as required by law. Example 2 In vitro antitumor efficacy

The T cell-dependent cytotoxicity of XmAb14045 against CD123-positive (KG1a and Kasumi-3) and CD123-negative (Ramos) cell lines was examined using purified PBMCs or T-cell-depleted PBMCs as effector cells. In addition, T cell activation was assessed by quantifying CD69 induction (a marker of lymphocyte activation) on CD4+ and CD8+ T cells. XENP13245 (anti-RSV x anti-CD3 bsAb) was used as a control. In CD4 + and CD8 + T cells when human PBMC supplied as effector populations, XmAb14045 (not XENP13245) showed CD123 ⁺ KG-1a (EC ₅₀ of 0.28 ng / mL; see FIG. 8), and Kasumi-3 (EC ₅₀ at 0.01 ng/mL) cell lines with potent and potent killing and potent induction of CD69. However, when T cells were depleted from PBMCs ( Figure 8 ), XmAb14045 was unable to induce killing or induce CD69 expression on T cells. XmAb14045 without inducing CD123 ^- cytotoxic Ramos B cell line, does not induce CD69 expression as measured by T cell activation.

A series of studies were performed to assess the function of T cells derived from PBMCs derived from human subjects with AML. Specifically, the ability of XmAb14045 to mediate RTCC against various target populations (found within or added to AML samples) was investigated. _{This target population includes: 1) the CD123 hi} CD33 _hi population that appears in both AML PBMC and healthy PBMC after several days of incubation in culture; 2) putative AML identified in samples by flow cytometry blast cells; and 3) added KG1a AML cells. CD123-dependent T cell activation was measured by upregulation of CD25 and Ki-67 on T cells. CD123-dependent target cell killing was monitored using annexin-V staining and by monitoring the reduction in counted blast cells.

For XmAb14045-induced target cell killing and T cell activation, multiple AML human subject PBMC and normal PBMC samples were tested. Both AML and normal PBMC contain CD123 _high and CD33 _high (CD123 _hi CD33 _hi ) cells; thus, this population may not represent leukemic blasts, but does serve as a useful surrogate target population. Incubating PBMCs with XmAb14045 for 6 days induced a dose-dependent partial depletion of _{CD123 hi} CD33 _hi cells, as well as activation and proliferation of ^{CD4+ and CD8+ T cells, in AML human subject-derived PBMCs.}

In a second set of studies, a modified staining method was used to detect leukemic blasts in PBMCs from human subjects with AML. AML PBMCs or PBMCs from normal control donors were incubated with XmAb14045 at concentrations of 9 or 90 ng/mL for 24 or 48 hours and putative blast numbers were obtained by flow cytometry. XmAb14045 reduced blast numbers by approximately 80% at 48 hours ( Figure 11 ). As expected, blast cells were not observed in normal donor PBMCs. This result was extended by evaluating a total of 6 human subjects with AML. XmAb14045 (at a concentration of 9 or 90 ng/mL) or XENP13245 (anti-RSV x anti-CD3) served as negative controls. At 48 hours, XmAb14045 depleted this putative blast population in AML PBMCs by approximately 20% to 90%, with no apparent dependence on the number of target cells or T cells in the sample (see Figure 12 ). Depletion is again associated with activation and proliferation of T cells.

In a third set of studies, killing of AML tumor cell lines by T cells from human subjects with AML was evaluated. PBMCs from one AML donor were mixed with the CD123 expressing cell line KG-1a for 48 hours in the presence of XmAb14045 (see Figure 13 ). At 48 hours, XmAb14045 induced robust apoptosis (approximately 50% Annexin-V positive) in AML human subject-derived PBMCs, although still slightly lower than cells induced in normal PBMCs apoptosis. XmAb14045 again induced robust proliferation of CD4+ and CD8+ T cells in AML human subjects and healthy donors.

^{In conclusion, XmAb14045 induced killing of allogeneic CD123+} KG-1a tumor cells by AML human subject-derived PBMC and normal PBMC. More importantly, XmAb14045 induced autologous leukemic blast cell killing in PBMCs from multiple AML human subject samples, suggesting that it can also stimulate leukemic blast cell depletion in AML human subjects. ^{Furthermore, XmAb14045 induced CD4+} and CD8 ⁺ T cell activation in both PBMCs and normal PBMCs of AML human subjects in the presence of CD123 ⁺ target cells, suggesting that the AML human subject T cell line is fully functional and able to respond to XmAb14045. Example 3 Antitumor activity in a mouse AML xenograft model

The antitumor activity of different doses of XmAb14045 was examined in NSG mice systemically implanted with KG1aTrS2 cells and normal human PBMC. KG1aTrS2 cells are derived from the AML cell line KG1a and have been engineered to express luciferase, allowing quantification of tumor burden. Mice received 1 x 10 ⁶ cells in KG1aTrS2 th day 0 intravenously. KG1aTrS2 twenty days post cell injection, mice to intraperitoneal (IP) implanted 10 x 10 ⁶ PBMCs th, and treated with 0.03,0.1,0.3, or 1.0 mg / kg or vehicle treatment of XmAb14045, once a week, 3 weeks in a row. Tumor burden was monitored by in vivo imaging throughout the study ( Figure 14 ). As shown in FIG. 14 and FIG. 15, accepted KG1a cells alone or the cells plus PBMC KG1a mice exhibit a steadily increasing over time AML load. In contrast, XmAb14045 at all dose levels tested began to reduce tumor burden approximately 3 days after the initial dose, eventually reducing burden by approximately 3 orders of magnitude relative to the KG1a-only control group and significantly compared to the KG1a plus huPBMC group reduce. No significant differences in antitumor activity were observed across the XmAb14045 dose range, suggesting that even lower doses may exhibit antitumor activity.

Peripheral blood samples were analyzed by flow cytometry. At day 11, the number of CD4+ and CD8+ T cells was reduced in treated mice compared to controls, but by day 20 this difference was no longer evident and the T cell counts trended upward, suggesting that XmAb14045 mediates T cells Cell activation and expansion ( Figure 16 ). PD1 expression, another marker of T cell activation, was consistently higher on T cell samples from the XmAb14045-treated group. However, it is unclear from this study whether the increase in PD1 expression interferes with the activity of XmAb14045.

none

[ Figure 1 ] depicts a useful bispecific antibody in a format known as a "corkscrew". XmAb14045 is in this bottle opener format. It should be noted that the scFv and Fab domains can be swapped (eg, anti-CD3 as Fab, anti-CD123 as scFv).

[ Figure 2 ] depicts the sequences of the three polypeptide chains that make up XmAb14045, a bispecific anti-CD123 x anti-CD3 antibody. CDRs are underlined, and junctions between domains are indicated by slashes ("/"). The charged scFv linker is double underlined; the linker can be replaced by other linkers, for example, the linker described in Figure 7 of US Patent Application Publication No. 2014/0288275 or other uncharged linkers such as the US SEQ ID NO: 441 of Patent Application Publication No. 2014/0288275.

[ FIG. 3 ] depicts different anti-CD123 Fab constructs designed to increase affinity to human CD123 and increase the stability of the 7G3 H1L1 construct (see, eg, US Patent Application Publication No. 2016/0229924, Figure 136 , SEQ ID NOs: 455 and 456). Changes in amino acid sequence are shown.

[ Figure 4 ] depicts the affinity and stability properties of optimized humanized variants of the parental 7G3 murine antibody (see, e.g., US Patent Application Publication No. 2016/0229924, Figure 136, SEQ ID NOs: 453 and 454 ).

[ Figures 5A-5B ] depict additional anti-CD123 Fab sequences with CDRs underlined.

[ Figure 6 ] depicts additional anti-CD123 x anti-CD3 sequences. CDRs are underlined, and junctions between domains are indicated by slashes ("/"). The charged scFv linker is double underlined; the linker can be replaced by other linkers, for example, the linker described in Figure 7 of US Patent Application Publication No. 2014/0288275 or other uncharged linkers such as the US SEQ ID NO: 441 of Patent Application Publication No. 2014/0288275.

[ Figures 7A-7D ] depict additional bispecific formats, as generally described in Figure 1 of US Patent Application Publication No. 2016/0229924 and the accompanying legends and supporting text.

[ FIG. 8 ] depicts RTCC with intact or T cell depleted PBMCs against KG-1a target cells. Effector cells (400 k) (intact or magnetically depleted PBMCs) were incubated with carboxyluciferin succinimidyl ester-labeled KG-1a target cells (10 k) for 24 hr and treated with Annexin V for cell death dyeing.

[ FIG. 9 ] depicts CD123hiCD33hi depletion over a dose range of XmAb14045 in PBMCs of AML human subjects. Five AML human subject PBMC samples were incubated with a range of doses of XmAb14045 (0.12 to 90 ng/mL) for 6 days and viable cells were gated to count CD123hiCD33hi target cells. The lowest concentration (0.04 ng/mL) point is for the no-drug control plotted on a logarithmic scale. Each point was normalized to account for cell count variability.

[ FIG. 10 ] depicts Ki67 levels in T cells from AML human subject PBMC as a function of XmAb14045. Five AML human subject PBMC samples were incubated with a range of doses of XmAb14045 (0.12 to 90 ng/mL) for 6 days, and viable cells were gated for CD4+ and CD8+ T cells to count Ki67+ cells. The lowest concentration (0.04 ng/mL) point is for the no-drug control plotted on a log scale.

[ FIG. 11 ] depicts the number of AML blasts in PBMCs of human subjects treated with XmAb14045. PBMCs from single AML human subjects were incubated with 9 or 90 ng/mL XmAb14045 for 24 or 48 hours and blast cell counts were plotted. Normal donor PBMCs were also used as controls.

[ FIG. 12 ] depicts leukemic blasts in PBMCs of AML human subjects. PBMCs from six AML human subjects were incubated with antibodies for 48 hours and blasts were counted and plotted. One donor (AML #1) was not treated with XENP13245, and each line was a single donor.

[ FIG. 13 ] depicts apoptosis of KG-1a tumor cells of AML PBMCs. Carboxyluciferin succinimidyl-labeled CD123+ KG-1a cells were added to PBMCs to examine the cytotoxicity of target cells stimulated by AML effector T cells. After 48 hours of incubation, KG-1a cell death was detected using the apoptosis marker Annexin V staining.

[ FIG. 14 ] depicts the effect of XmAb14045 on tumor burden over time in a mouse xenograft model of AML.

[ FIG. 15 ] depicts the reduction in tumor burden following 3 weekly doses of XmAb14045.

[ FIG. 16 ] depicts the effect of XmAb14045 on T cell numbers in a mouse xenograft model of AML. Peripheral blood CD45+CD8+ events were monitored by flow cytometry. Sampling was performed on days 11 and 20 after administration of XmAb14045.

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

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

[ FIG. 19 ] depicts the percent change in bone marrow blasts from pre-treatment baseline from a subgroup of tested human subjects.

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

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

[ FIG. 22 ] depicts blast CD123 expression for responders versus non-responders from a subset of tested human subjects.

[ Figure 23 ] The line is presented under the heading: Response to Vibecotamab (XmAb® 14045) (CD123 x CD3 T cell engaging bispecific antibody) in patients with relapsed/refractory acute myeloid leukemia (AML) Complete response to weekly dosing regimen; results from Phase 1 study. Regarding the figure titled "XmAb® 14045 (SQZ622): CD123 x CD3 Bispecific Antibody," XmAb 14045 is a bispecific full-length immunoglobulin molecule targeting CD3 on T cells and CD123 on AML blasts. The α-subunit of the CD123 or IL-3 receptor is expressed on the surface of early hematopoietic precursor cells and various hematological cancers, including AML blasts. XmAb14045 has a long half-life associated with its full-length immunoglobulin structure, allowing it to be administered by short infusions. It recruits and activates T cells, resulting in the killing of CD123-expressing blast cells. Ablation of Fc-gamma receptor binding eliminates the possibility of nonspecific activation of T cells. Regarding the first figure titled "XmAb14045 Phase 1 Design," the Phase 1 study was designed to determine the maximum tolerated dose and safety of the first and subsequent infusions of XmAb14045, as well as various other secondary and exploratory goals. Patients with relapsed and refractory AML or ALL with adequate performance status and adequate organ function are eligible to participate. Regarding the second figure titled "XmAb14045 Phase 1 Design," 114 patients have been enrolled as of October 2020. The safety analysis cohort included those who had received at least 1 dose. Efficacy analyses included all patients who completed at least one cycle or 28 days of treatment. Five dosing regimens have been evaluated, including an initial weekly dosing regimen. The latest regimen includes a first cycle dose escalation strategy with weekly dose escalation. Each dose was administered by IV infusion over 2 hours. Regarding the graph titled "Demographics (Safety Population)", 112 patients with AML were evaluable for safety. The analysis did not include 2 patients with blast-stage ALL and CML. The median # of prior therapy was 3 and 30% of patients had received prior allogeneic stem cell transplantation. Most patients had unfavorable ELN risk profiles. Regarding the graph titled "Safety Data: Relevant TEAEs Occurring in ≥ 10% of Subjects' AML Safety Population (N = 112)", as expected, the most significant TEAEs were CRS, which occurred in approximately 61 % of patients, most had between grade 1 and 2 events. There is no evidence of drug-related myelosuppression. Neurologic events were also rare and were predominantly grade 1 and 2 headaches. Regarding the graph titled "Safety Data: Initial Dose, Dosing Visit, and IL-6 Levels", as expected, a significant increase in IL-6 was seen after the initial dose, which gradually subsided with subsequent dosing , but rose again to high levels with weekly dosing, especially after a significant weekly dose increase. Regarding the figure titled "Safety Data: Weekly Dosing and IL-6 Levels," elevations in IL-6 correlated with the incidence and severity of CRS. On the left side of the graph, in all cohorts, 4.5% of the weekly stable dosing had high IL-6 levels, which were associated with few grade 2 or higher CRS. On the right side of the graph, 15% of weekly escalation events had greater than 1000 pg/mL of IL-6, and this was associated with a higher incidence of grade 2 or higher CRS. Regarding the graph titled "Safety Data: Dosing Visits and CRS," a higher frequency and severity were similarly found with the initial dose of 0.75 mcg/kg compared to 0.43 mcg/kg. Regarding the figure titled "Safety Data: CRS Strategies for Future Cohorts and Trials," the above data provide important information for designing dosing strategies to reduce the incidence and severity of CRS while maintaining efficacy. This is by choosing a lower initial dose, dosing more frequently in the first week to allow for higher cumulative exposure, and avoiding potential antigen sinks and by avoiding weekly dose escalation. Regarding the graph titled "Efficacy Data," among the 54 patients who received doses of at least 0.75 mcg/kg or higher, the objective response rate was 14.8%. However, among the 27 patients with blast % less than 25%, the response rate was 25.9%. Overall, an additional 38 patients had stable disease, with 52% of whom had reduced bone marrow blasts. Regarding the graph titled "Efficacy Data: Time to Treatment Discontinuation", responses including CR and CRi were durable, lasting several months in some patients. Regarding the figure titled "XmAb14045/SQZ622 Cohort Data," this table provides response information for the treatment cohort. Overall responses were reported in most cohorts regardless of the cumulative dose in Week 1 of Cycle 1. Cohort IE with lower initial dose and stable dosing without weekly escalation is ongoing. Regarding the graph titled "Responders associated with low absolute blast counts", it is important to note that, in general, responses were associated with lower percentages of peripheral blood and bone marrow blasts. Regarding the graph titled "Responders associated with low PD-1 expression on CD8 and CD4 T cells," it is important to note that responses have been associated with low PD-1 expression on ^CD8+ and CD4 ^{+ T cells.} Regarding the graph titled "AML blast count % in bone marrow vs ^{PD1+ % CD8+} cells in blood", it is important to note that low blast percentage in bone marrow and low PD-1 on ^{circulating CD8+ T cells} Performance appears to be a predictor of response. This suggests a possible strategy for selecting patients most likely to respond.

none

Claims (112)

A method for treating a cancer expressing CD123 in a human subject in need of treatment, the method comprising administering to the human subject a bispecific in at least a first stage, a second stage, a third stage and a fourth stage Anti-CD123 x Anti-CD3 Antibody, wherein during the first period, the bispecific anti-CD123 x anti-CD3 antibody is administered in first, second, and third doses three times a week for one week, wherein the first dose is about 750 ng/kg, the second dose is between about 140% and 180% of the first dose, and the third dose is between about 130% and 160% of the second dose %between, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at an amount between about 120% and 160% of the third dose in the first phase once a week, for a week, wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the amount administered in the second phase, once a week for one week , wherein during the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the amount administered in the third phase, once a week, for at least a week, Thus, the cancer expressing CD123 is treated. The method of claim 1, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours during the first and/or second phase. The method of claim 1 or 2, wherein the duration of the fourth stage is between one week and four weeks. The method of claim 1 or 2, wherein the fourth stage is maintained until remission. The method of any one of claims 1 to 4, further comprising administering a maintenance dose. The method of claim 5, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the fourth phase. The method of claim 5 or 6, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 5 to 7, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of any one of claims 1 to 8, further comprising a fifth stage, wherein the human is administered an amount between about 120% and 160% of the amount administered in the fourth stage Subjects are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for at least one week. The method of claim 9, wherein during the fifth stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. The method of claim 9 or 10, wherein the duration of the fifth stage is one or two weeks. The method of claim 9 or 10, wherein the fifth stage is maintained until remission. The method of any one of claims 6 to 13, further comprising administering a maintenance dose. The method of claim 13, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the fifth phase. The method of claim 13 or 14, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 13 to 16, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of any one of claims 11 to 16, further comprising a sixth stage, wherein the human is administered an amount between about 120% and 160% of the amount administered in the fifth stage Subjects are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for at least one week. The method of claim 17, wherein within the sixth stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. The method of claim 17 or 18, wherein the sixth stage is maintained until remission. The method of any one of claims 14 to 19, further comprising administering a maintenance dose. The method of claim 20, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the sixth phase. The method of claim 20 or 21, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 20 to 22, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of any one of claims 18 to 23, further comprising a seventh stage, wherein the human is administered an amount between about 120% and 160% of the amount administered in the sixth stage Subjects are administered the bispecific anti-CD123 x anti-CD3 antibody once a week for at least one week. The method of claim 24, wherein within the seventh stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. The method of claim 24 or 25, wherein the seventh stage is maintained until remission. The method of any one of claims 21 to 26, further comprising administering a maintenance dose. The method of claim 27, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the seventh phase. The method of claim 27 or 28, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 27 to 29, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. A method as claimed in any one of claims 1 to 8, wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the second phase dose is about 2,500 ng/kg, wherein the dose administered in the third phase is about 3,800 ng/kg, and Wherein this fourth phase is administered at about 5,700 ng/kg until remission. A method as claimed in any of claims 9-23, wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the second phase dose is about 2,500 ng/kg, wherein the dose of the third phase is about 3,800 ng/kg, wherein the fourth phase dose is about 5,700 ng/kg, and Wherein the fifth stage dose is about 8,500 ng/kg until remission. A method as claimed in any of claims 23-30, wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the second phase dose is about 2,500 ng/kg, wherein the dose of the third phase is about 3,800 ng/kg, wherein the dose of the fourth phase is about 5,700 ng/kg, wherein the fifth stage dose is about 8,500 ng/kg, and Wherein the sixth phase dose is about 12,800 ng/kg until remission. The method of any of claims 23-30, which consists essentially of a first stage, a second stage, a third stage, a fourth stage, a fifth stage, a sixth stage, and a seventh stage wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the second phase dose is about 2,500 ng/kg, wherein the dose of the third phase is about 3,800 ng/kg, wherein the dose of the fourth phase is about 5,700 ng/kg, wherein the dose of the fifth stage is about 8,500 ng/kg, wherein the dose of the sixth stage is about 12,800 ng/kg, The dose of this seventh phase is about 19,200 ng/kg until remission. A method as claimed in any one of claims 1-8, wherein the second dose of the first stage is about 900 ng/kg, wherein the first-stage third dose is about 1,200 ng/kg, wherein the second phase dose is about 1,500 ng/kg, wherein the dose administered in the third phase is about 1,800 ng/kg, and The dose of this fourth phase is about 2,300 ng/kg until remission. The method of any one of the preceding claims, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered intravenously. The method of any one of the preceding claims, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours during the third and/or fourth phase. A method for treating a cancer expressing CD123 in a human subject in need thereof, the method comprising administering to the human subject a bispecific anti-CD123 during at least a first, second, third and fourth stage x anti-CD3 antibody, wherein during the first phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in first, second, third, and fourth doses four times a week for one week, wherein the first dose is administered The dose is about 750 ng/kg, and the second dose is between about 120% and 160% of the first dose, and the third dose is between about 120% and 160% of the second dose between about 120% and 160%, and the fourth dose is between about 120% and 160% of the third dose, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the fourth dose in the first phase once a week, for a week, wherein in the third phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the amount administered in the second phase, once a week for one week , wherein during the fourth phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the amount administered in the third phase, once a week, for at least a week, Thus, the cancer expressing CD123 is treated. The method of claim 38, wherein the bispecific anti-CD123 x anti-CD3 is administered over about two hours within the first and/or second and/or third and/or fourth stage antibody. A method as claimed in claim 38 or 39, wherein the duration of the fourth stage is between one week and four weeks. The method of claim 38 or 39, wherein the fourth stage is maintained until remission. The method of claim 41, further comprising administering a maintenance dose. The method of claim 42, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the fourth phase. The method of claim 42 or 43, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 42 to 44, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of claim 40, further comprising a fifth stage, wherein the bispecific anti-CD123x is administered in an amount between about 120% and 160% of the amount administered in the fourth stage Anti-CD3 antibodies once a week for at least one week. The method of claim 46, wherein during the fifth stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. A method as claimed in claim 46 or 47, wherein the duration of the fifth stage is one or two weeks. The method of claim 46 or 47, wherein the fifth stage is maintained until remission. The method of any one of claims 46 to 49, further comprising administering a maintenance dose. The method of claim 50, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the fifth phase. The method of claim 50 or 51, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 50 to 52, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of any one of claims 46 to 53, further comprising a sixth stage, wherein the dose is administered in an amount between about 120% and 160% of the amount administered in the fifth stage Bispecific anti-CD123 x anti-CD3 antibody once weekly for at least one week. The method of claim 54, wherein within the sixth stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. The method of claim 54 or 55, wherein the sixth stage is maintained until remission. A method as claimed in claim 55 or 56, wherein the duration of the sixth stage is one or two weeks. The method of any one of claims 54 to 57, further comprising administering a maintenance dose. The method of claim 58, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the sixth phase. The method of claim 58 or 59, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 58 to 60, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of claim 57, further comprising a seventh stage, wherein the bispecific anti-CD123x is administered in an amount between about 120% and 160% of the amount administered in the sixth stage Anti-CD3 antibodies once a week for at least one week. The method of claim 62, wherein within the seventh stage, the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours. The method of claim 62 or 63, wherein the seventh stage is maintained until remission. The method of any one of claims 62-64, further comprising administering a maintenance dose. The method of claim 65, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the seventh phase. The method of claim 65 or 66, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 65 to 67, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. The method of any of claims 1-68, wherein the second dose of the first stage is about 1,100 ng/kg, wherein the third dose of the first stage is about 1,700 ng/kg, wherein the fourth dose of the first stage is about 2,500 ng/kg, wherein the dose administered in the second phase is about 3,800 ng/kg, wherein the dose administered in the third phase is about 5,700 ng/kg, Wherein this fourth phase is administered at about 8,500 ng/kg until remission. A method as claimed in any of claims 14-68, wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the fourth dose of the first stage is about 2,500 ng/kg, wherein the dose administered in the second phase is about 3,800 ng/kg, wherein the dose administered in the third phase is about 5,700 ng/kg, wherein the dose of the fourth phase is about 8,500 ng/kg, The dose of this fifth phase is about 12,800 ng/kg until remission. A method as claimed in any of claims 17-68, wherein the second dose of the first phase is about 1,100 ng/kg, wherein the first-stage third dose is about 1,700 ng/kg, wherein the fourth dose of the first stage is about 2,500 ng/kg, wherein the dose administered in the second phase is about 3,800 ng/kg, wherein the dose administered in the third phase is about 5,700 ng/kg, wherein the dose of the fourth phase is about 8,500 ng/kg, wherein the dose of the fifth stage is about 12,800 ng/kg, Wherein the sixth phase dose is about 19,200 ng/kg until remission. A method for treating a cancer expressing CD123 in a human subject in need thereof, the method comprising administering to the human subject a bispecific anti-CD123 x anti-CD3 antibody in at least a first stage and a second stage, wherein during the first phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in first, second, third, and fourth doses four times a week for one week, wherein the first dose is administered The dose is about 430 ng/kg, the second dose is between about 140% and 180% of the first dose, and the third dose is between about 140% and 180% of the second dose between 130% and 160%, and the fourth dose is between about 130% and 160% of the third dose, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in an amount between about 120% and 160% of the fourth dose in the first phase once a week, for a week, Thus, the cancer expressing CD123 is treated. The method of claim 72, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours during the first and/or second phase. A method as claimed in claim 72 or 73, wherein the duration of the second phase is between one week and four weeks. The method of claim 72 or 73, wherein the second stage is maintained until remission. The method of any one of claims 72 to 75, further comprising administering a maintenance dose. The method of claim 76, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the second phase. The method of claim 76 or 77, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 76 to 78, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. A method as claimed in any one of claims 72 to 79, wherein the second dose of the first stage is about 750 ng/kg, wherein the first stage third dose is about 1,100 ng/kg, wherein the fourth dose of the first stage is about 1,700 ng/kg, Wherein the second phase dose is about 2,500 ng/kg until remission. A method as claimed in any of claims 72-79, wherein the second dose of the first stage is about 542 ng/kg, Wherein the third dose of the first stage is about 678 ng/kg, Wherein the fourth dose of the first stage is about 848 ng/kg, Wherein the second phase dose was about 1,060 ng/kg until remission. A method for treating a cancer expressing CD123 in a human subject in need thereof, the method comprising administering to the human subject a bispecific anti-CD123 x anti-CD3 antibody in at least a first stage and a second stage, wherein during the first phase, the bispecific anti-CD123 x anti-CD3 antibody is administered in first, second, and third doses four times a week for one week, wherein the first dose is About 433 ng/kg, the second dose is between about 140% and 180% of the first dose, and the third dose is between about 130% and 180% of the second dose between 160%, wherein in the second phase, the bispecific anti-CD123 x anti-CD3 antibody is administered at an amount between about 120% and 160% of the third dose in the first phase once a week, for a week, Thus, the cancer expressing CD123 is treated. The method of claim 82, wherein the bispecific anti-CD123 x anti-CD3 antibody is administered over about two hours during the first and/or second phase. A method as claimed in claim 82 or 83, wherein the duration of the second phase is between one week and four weeks. The method of claim 82 or 83, wherein the second stage is maintained until remission. The method of any one of claims 82 to 85, further comprising administering a maintenance dose. The method of claim 86, wherein the maintenance dose comprises the same amount of the bispecific anti-CD123 x anti-CD3 antibody administered in the second phase. The method of claim 86 or 87, wherein the maintenance dose is administered biweekly for at least one dose. The method of any one of claims 86 to 88, wherein the maintenance dose is administered every three weeks or every four weeks or monthly for at least one dose. A method as claimed in any one of claims 82 to 89, wherein the second dose of the first stage is about 750 ng/kg, wherein the first stage third dose is about 1,100 ng/kg, Wherein the second phase dose is about 1,700 ng/kg until remission. A method as claimed in any one of claims 82 to 89, wherein the second dose of the first stage is about 542 ng/kg, Wherein the third dose of the first stage is about 678 ng/kg, The dose of this second phase is about 848 ng/kg until remission. The method of any one of claims 1 to 91, wherein the cancer expressing CD123 is a hematological cancer. The method of any one of claims 1 to 92, wherein the cancer expressing CD123 is leukemia. The method of any one of claims 1 to 93, wherein the cancer expressing CD123 is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia ( ALL) and hairy cell leukemia (HCL). The method of any one of claims 1 to 94, wherein the cancer expressing CD123 is acute myeloid leukemia (AML). The method of claim 95, wherein the acute myeloid leukemia (AML) is a blastocytic plasmacytoid dendritic cell tumor (BPDCN). The method of any one of claims 1 to 96, wherein the cancer expressing CD123 is acute lymphoblastic leukemia, and the acute lymphoblastic leukemia is B-cell acute lymphoblastic leukemia (B-ALL). The method of any one of claims 1 to 97, wherein the remission is a reduction in the number of CD123-expressing cancer cells or a reduction in the growth rate of CD123-expressing cancer cells. The method of any one of claims 1 to 98, wherein the remission is increased T cell activation or increased IFN pathway upregulation. The method of any one of claims 1 to 99, wherein the remission is a partial remission of the CD123 expressing cancer. The method of any one of claims 1 to 100, wherein the bispecific anti-CD123 x anti-CD3 antibody comprises heavy chain 1 (HC1) (Fab-Fc) shown in SEQ ID NO: 1, SEQ ID NO : Heavy chain 2 (HC2) (scFv-Fc) shown in SEQ ID NO: 2 and light chain shown in SEQ ID NO: 3. The method of claim 101, wherein the bispecific anti-CD123 x anti-CD3 antibody is composed of heavy chain 1 (HCl) (Fab-Fc) shown in SEQ ID NO: 1, heavy chain 1 (HCl) (Fab-Fc) shown in SEQ ID NO: 2 Chain 2 (HC2) (scFv-Fc) and the light chain set forth in SEQ ID NO:3. The method of any one of claims 1 to 102, further comprising assessing the body weight of the human subject prior to administering the bispecific anti-CD123 x anti-CD3 antibody in the first phase. The method of any one of claims 1-103, further comprising administering to the human subject one or more therapeutic agents prior to administering the bispecific anti-CD123 x anti-CD3 antibody in the first stage . The method of claim 104, wherein the one or more therapeutic agents ameliorate one or more side effects of administration of the bispecific anti-CD123 x anti-CD3 antibody. The method of claim 105, wherein the one or more therapeutic agents are steroids, antihistamines, antiallergic, antinausea (or antiemetic), analgesic, antipyretic, cytoprotective, vascular Compressive agents, anticonvulsants, anti-inflammatory agents, or any combination thereof. The method of any one of claims 104-106, wherein the one or more therapeutic agents are a combination of corticosteroids, diphenhydramine, and acetaminophen. The method of any one of claims 1 to 107, further comprising determining the percentage of blast cells in the human subject's bone marrow prior to the first stage administration, and if the percentage is 25% or more is low, the first-stage investment is carried out. The method of any one of claims 1 to 107, further comprising, prior to the first stage administration, determining the percentage of CD8+ T cells in the human subject, the CD8+ T cells being PD-1 +, and if the percentage is 25% or less, make this first-stage investment. A method of improving therapeutic efficacy of treating cancer expressing CD123, the method comprising: Determining the percentage of blast cells in the bone marrow of a human subject having a cancer expressing CD123, or determining the percentage of CD8+ T cells that are PD-1+ in a human subject having a cancer expressing CD123 ; A percentage of 25% or less is indicative of the efficacy of the bispecific anti-CD123 x anti-CD3 antibody. A method of determining sensitivity to treatment of a cancer expressing CD123, the method comprising: Determining the percentage of blast cells in the bone marrow of a human subject having a cancer expressing CD123, or determining the percentage of CD8+ T cells that are PD-1+ in a human subject having a cancer expressing CD123 ; A percentage of 25% or less is indicative of the efficacy of the bispecific anti-CD123 x anti-CD3 antibody. A method of selecting one or more human subjects having increased responsiveness to treatment of a cancer expressing CD123, the method comprising: Determining the percentage of blast cells in the bone marrow of a human subject having a cancer expressing CD123, or determining the percentage of CD8+ T cells that are PD-1+ in a human subject having a cancer expressing CD123 ; A percentage of 25% or less corresponds to an increase in subject responsiveness.

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