Antibody variable domains targeting CD33, and use thereof

Abstract

To provide methods of treating a CD33-expressing cancer.SOLUTION: The invention provides: proteins with antibody heavy chain and light chain variable domains that can be paired to form an antigen binding site targeting CD33 (Siglec-3) on a cell, pharmaceutical compositions comprising the proteins, and therapeutic methods based on the proteins and pharmaceutical compositions, including the treatment of cancer.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 632,756, filed February 20, 2018, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002] This application contains an electronically submitted Sequence Listing in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy, created on February 19, 2019, is titled DFY_050WO_SL25.txt and is 571,095 bytes in size.

[0003] The present invention provides proteins having an antibody heavy chain variable domain and a light chain variable domain that can pair to form an antigen-binding site that targets CD33 (Siglec-3) on a cell, pharmaceutical compositions containing the proteins, and therapeutic methods using the proteins and pharmaceutical compositions, including the treatment of cancer. [Background technology]

[0004] Cancer remains a significant health problem despite considerable research efforts and scientific advances reported in the literature regarding the treatment of this disease. Some of the most frequently diagnosed cancers in adults include prostate, breast, and lung cancer. Hematologic malignancies, while less common than solid tumors, have lower survival rates. Current treatment options for these cancers are not effective for all patients and / or may have significant adverse side effects. Other types of cancer also remain difficult to treat using existing treatment options.

[0005] Cancer immunotherapy is desirable because it is highly specific and can use a patient's own immune system to promote the destruction of cancer cells. Fusion proteins, such as bispecific T cell engagers, are a well-documented cancer immunotherapy that bind to tumor cells and T cells to promote tumor cell destruction. T cells are the primary effectors of the adaptive immune system, attacking not only foreign cells but also host cells that present mutated or misexpressed peptides. Cells targeted by T cells can be virally infected cells that express foreign proteins or malignant cells that may express mutant proteins. T cells recognize target cells via T cell receptors (TCRs), which bind intracellular peptides presented by major histocompatibility complex proteins on the target cells. While individual T cells typically recognize target cells bearing specific MHC-peptide complexes, novel agents are being developed that hijack and amplify this natural process for therapeutic benefit. Bispecific T cell engagers link the antigen-binding site(s) of a tumor-associated antigen with the antigen-binding site(s) of a component of the TCR complex, directing T cell activity toward the desired target cell independent of wild-type peptide-MHC recognition. For example, Blincyto is an FDA-approved T cell engager that targets CD19 on malignant B cells.

[0006] T cells can also be engineered to express chimeric antigen receptors (CARs), thereby endowing the T cells with the target recognition capabilities of the CAR. CARs contain antigen binding sites (multiple) for tumor-associated antigens linked to a T cell activation domain. These CAR-T cells can also be used to target malignant cells, some of which have been approved by the FDA for use against B-cell malignancies.

[0007] Antibodies that bind to specific tumor-associated antigens and specific immune cells have been described in the literature. See, for example, WO2016 / 134371 and WO2015 / 095412. Antibody-drug conjugates or immunocytokines that use antigen-binding sites that target tumor-associated antigens to deliver toxic substances or immunomodulatory cytokines to specific target cells.

[0008] Natural killer (NK) cells are components of the innate immune system and account for approximately 15% of circulating lymphocytes. NK cells infiltrate virtually all tissues and were originally characterized for their ability to kill tumor cells without the need for prior sensitization. Activated NK cells kill target cells in a manner similar to that of cytotoxic T cells, namely, via cytolytic granules containing perforin and granzymes, and via death receptor pathways. Activated NK cells also secrete proinflammatory cytokines, such as IFN-gamma and chemokines, which promote the recruitment of other leukocytes to target tissues.

[0009] NK cells respond to signals through various activating and inhibitory receptors on their surface. For example, when NK cells encounter healthy autologous cells, their activity is suppressed by activation of killer cell immunoglobulin-like receptors (KIRs). Alternatively, when NK cells encounter foreign or cancer cells, they are activated through activating receptors (e.g., NKG2D, NCR, DNAM1). NK cells are also activated by the constant regions of some immunoglobulins via the CD16 receptor on their surface. The overall sensitivity of NK cells to activation depends on the sum of stimulatory and inhibitory signals.

[0010] CD33 is a member of the sialic acid-binding immunoglobulin-like lectin family. CD33 is a transmembrane receptor primarily expressed on myeloid cells, and regulates inflammatory and immune responses through its inhibitory effects on tyrosine kinase-induced signaling pathways. For example, CD33 has been shown to constitutively suppress the production of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-8, by human monocytes.

[0011] CD33 is associated with hematopoietic cancers. CD33 is widely expressed on blast cells of almost all acute myeloid leukemia (AML). Furthermore, stem and / or progenitor cells of hematopoietic cancers express CD33. + This suggests that CD33-directed therapy may be able to eradicate stem and / or progenitor cells when they are malignant, while sparing normal hematopoietic stem cells. In addition to its expression in AML, CD33 is also found in other myeloid neoplasms (e.g., myelodysplastic syndromes and myeloproliferative neoplasms) and a subset of B-cell and T-cell acute lymphoblastic leukemia (ALL) / lymphoblastic lymphoma. This expression pattern has led to the use of CD33-directed therapy in patients with malignancies, including AML, myelodysplastic syndromes, chronic myelomonocytic leukemia, myeloid blast crisis of chronic myeloid leukemia, and ALL. Summary of the Invention

[0012] In one aspect, the present invention provides antigen-binding sites that bind to epitopes on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33. In one aspect, the present invention provides antigen-binding sites that recognize and bind to one or more conformational epitopes on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33. In one aspect, the present invention provides antigen-binding sites that recognize and bind to one or more conformational epitopes on the extracellular domain of human CD33, but do not recognize and / or bind to one or more conformational epitopes on the extracellular domain of cyno CD33. In one aspect, the present invention provides antigen-binding sites that bind to human CD33 of the R69G allele. In one aspect, the present invention provides antigen-binding sites that bind to wild-type human CD33 (e.g., having the amino acid sequence identified by NCBI Reference Sequence: NP_001763.3) but do not bind to human CD33 of the R69G allele. In one aspect, the present invention provides an antigen-binding site that binds to an epitope of human CD33 that includes R69. In one aspect, the present invention provides an antigen-binding site comprising a heavy chain variable domain that binds to the extracellular domain of human CD33 and / or cyno CD33, regardless of the glycosylation profile of the target CD33.

[0013] In certain embodiments, the present invention provides antigen-binding sites that bind to the extracellular domain of human CD33 and / or cyno CD33 such that the epitope is unique compared to the epitopes targeted by one or more anti-CD33 antibodies known in the art. In certain embodiments, the present invention provides antigen-binding sites that bind to the extracellular domain of human CD33 and / or cyno CD33 and exhibit cross-reactivity with human or cyno CD33 and high affinity binding to the target CD33.

[0014] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 1]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable domain comprises the amino acid sequence FTFSSYGMS [SEQ ID NO:21] of SEQ ID NO:1 as the first complementarity determining region 1 ("CDR1"), NIKQDGSEKYYVDSVKG [SEQ ID NO:22] as the second CDR ("CDR2"), and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO:23] as the third CDR ("CDR3"). In some embodiments, the heavy chain variable domain comprises the amino acid sequence SYGMS [SEQ ID NO:434] of SEQ ID NO:1 as the first complementarity determining region 1 ("CDR1"), NIKQDGSEKYYVDSVKG [SEQ ID NO:22] as the second CDR ("CDR2"), and EGGPYYDSSGYFVYYGMDV [SEQ ID NO:435] as the third CDR ("CDR3"). In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYESFPTFGGGTKVEIK [SEQ ID NO: 2]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 2 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 24] of SEQ ID NO: 2 as CDR1, DASSLES [SEQ ID NO: 25] as CDR2, and QQYESFPT [SEQ ID NO: 26] as CDR3.

[0015] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2; or an antibody comprising heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 21, 22, and 23, respectively, or heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 434, 22, and 435, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 24, 25, and 26, respectively.

[0016] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 3]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSYWMS [SEQ ID NO: 27] of SEQ ID NO: 3 as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 28] as CDR2, and ARPLNAGELDV [SEQ ID NO: 29] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 3, SYWMS [SEQ ID NO: 181], as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 28], as CDR2, and PLNAGELDV [SEQ ID NO: 436], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3 has the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFA It can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to TYYCQQLESYPLTFGGGTKVEIK [SEQ ID NO: 4]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:3 is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:4. and the antibody light chain variable domain is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 4 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 30] as CDR1, EASSLES [SEQ ID NO: 31] as CDR2, and QQLESYPLT [SEQ ID NO: 32] as CDR3.

[0017] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4; or an antibody having the sequences of SEQ ID NOs: 27, 28, and 29, respectively, or having heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 181, 28, and 436, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 30, 31, and 32, respectively.

[0018] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGFTFSKYTMSWVRQAPGKGLEWVSAIVGSGESTYFADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 5]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 5. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:5 FTFSKYTMS [SEQ ID NO:33] as CDR1, AIVGSGESTYFADSVKG [SEQ ID NO:34] as CDR2, and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO:35] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:5 KYTMS [SEQ ID NO:183] as CDR1, AIVGSGESTYFADSVKG [SEQ ID NO:34] as CDR2, and EGGPYYDSSGYFVYYGMDV [SEQ ID NO:184] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDDLPTFGGGTKVEIK [SEQ ID NO: 6]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 6 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 36] of SEQ ID NO: 6 as CDR1, KASSLES [SEQ ID NO: 37] or KASSLE [SEQ ID NO: 185] as CDR2, and QQYDDLPT [SEQ ID NO: 38] as CDR3.

[0019] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 6; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 33, 34, and 35, respectively, or having the sequences of SEQ ID NOs: 183, 34, and 184, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 36, 37, and 38, respectively, or CDR1-3 having the sequences of SEQ ID NOs: 36, 185, and 38, respectively.

[0020] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFSDYYMHWVRQAPGQGLEWMGMINPSWGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREAADGFVGERYFDLWGRGTLVTVSS [SEQ ID NO:7]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:7. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:7 YTFSDYYMH [SEQ ID NO:39] as CDR1, MINPSWGSTSYAQKFQG [SEQ ID NO:40] as CDR2, and AREAADGFVGERYFDL [SEQ ID NO:41] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:7 DYYMH [SEQ ID NO:437] as CDR1, MINPSWGSTSYAQKFQG [SEQ ID NO:40] as CDR2, and EAADGFVGERYFDL [SEQ ID NO:438] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:7, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 7 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQDVALPITFGGGTKVEIK [SEQ ID NO: 8]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 7 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 8 and comprises the amino acid sequence RSSQSLLYSNGYNYLD [SEQ ID NO: 42] of SEQ ID NO: 8 as CDR1, LGSNRAS [SEQ ID NO: 43] as CDR2, and MQDVALPIT [SEQ ID NO: 44] as CDR3.

[0021] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8; or an antibody comprising heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 39, 40, and 41, respectively, or having the sequences of SEQ ID NOs: 437, 40, and 438, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 42, 43, and 44, respectively.

[0022] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFGSYWMSWVRQAPGKGLEWVATIKQDGSEKSYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 9]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 9. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFGSYWMS [SEQ ID NO: 45] of SEQ ID NO: 9 as CDR1, TIKQDGSEKSYVDSVKG [SEQ ID NO: 46] as CDR2, and ARPLNAGELDV [SEQ ID NO: 47] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:9 SYWMS [SEQ ID NO:181] as CDR1, TIKQDGSEKSYVDSVKG [SEQ ID NO:46] as CDR2, and RPLNAGELDV [SEQ ID NO:182] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:9, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSQSYPPITFGGGTKVEIK [SEQ ID NO: 10]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 10 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 48] of SEQ ID NO: 10 as CDR1, EASSLES [SEQ ID NO: 49] as CDR2, and QQSQSYPPIT [SEQ ID NO: 50] as CDR3.

[0023] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 10; or an antibody comprising heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 45, 46, and 47, respectively, or heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 181, 46, and 182, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 48, 49, and 50, respectively.

[0024] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFPSYWMSWVRQAPGKGLEWVATIKRDGSEKGYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 11]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 11. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 11, FTFPSYWMS [SEQ ID NO: 51], as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52], as CDR2, and ARPLNAGELDV [SEQ ID NO: 53], as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 11, SYWMS [SEQ ID NO: 181], as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52], as CDR2, and PLNAGELDV [SEQ ID NO: 439], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSQSYPPITFGGGTKVEIK [SEQ ID NO: 12]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 12 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 54] of SEQ ID NO: 12 as CDR1, EASSLES [SEQ ID NO: 55] as CDR2, and QQSQSYPPIT [SEQ ID NO: 56] as CDR3.

[0025] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 12; or an antibody comprising heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 51, 52, and 53, respectively, or having the sequences of SEQ ID NOs: 181, 52, and 439, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 54, 55, and 56, respectively.

[0026] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFGTYYMHWVRQAPGQGLEWMGIINPSRGSTVYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGAGYDDEDMDVWGKGTTVTVSS [SEQ ID NO: 13]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 13. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence YTFGTYYMH [SEQ ID NO:57] of SEQ ID NO: 13 as CDR1, IINPSRGSTVYAQKFQG [SEQ ID NO:58] as CDR2, and ARGAGYDDEDMDV [SEQ ID NO:59] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence TYYMH [SEQ ID NO:440] of SEQ ID NO: 13 as CDR1, IINPSRGSTVYAQKFQG [SEQ ID NO:58] as CDR2, and GAGYDDEDMDV [SEQ ID NO:441] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGIDSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHSYPLTFGGGTKVEIK [SEQ ID NO: 14]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 14 and comprises the amino acid sequence RASQGIDSWLA [SEQ ID NO: 60] as CDR1, AASSLQS [SEQ ID NO: 61] as CDR2, and QQAHSYPLT [SEQ ID NO: 62] as CDR3 of SEQ ID NO: 14.

[0027] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 57, 58, and 59, respectively, or heavy chain CDR1-3 having the sequences of SEQ ID NOs: 440, 58, and 441, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 60, 61, and 62, respectively.

[0028] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSISSSSEGIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 15]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 15. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSAMS [SEQ ID NO: 63] of SEQ ID NO: 15 as CDR1, SISSSSEGIYYADSVKG [SEQ ID NO: 64] as CDR2, and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO: 65] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYAMS [SEQ ID NO: 442] of SEQ ID NO: 15 as CDR1, SISSSSEGIYYADSVKG [SEQ ID NO: 64] as CDR2, and EGGPYYDSSGYFVYYGMDV [SEQ ID NO: 443] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASNSISSWLAWYQQKPGKAPKLLIYEASSTKSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDDLPTFGGGTKVEIK [SEQ ID NO: 16]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 16 and comprises the amino acid sequence RASNSISSWLA [SEQ ID NO: 66] as CDR1, EASSTKS [SEQ ID NO: 67] as CDR2, and QQYDDLPT [SEQ ID NO: 68] as CDR3 of SEQ ID NO: 16.

[0029] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 63, 64, and 65, respectively, or heavy chain CDR1-3 having the sequences of SEQ ID NOs: 442, 64, and 443, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 66, 67, and 68, respectively.

[0030] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINTDGSEVYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDVGPGIAYQGHFDYWGQGTLVTVSS [SEQ ID NO: 17]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 17. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 17 FTFSSYWMS [SEQ ID NO: 69] as CDR1, NINTDGSEVYYVDSVKG [SEQ ID NO: 70] as CDR2, and ARDVGPGIAYQGHFDY [SEQ ID NO: 71] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 17 SYWMS [SEQ ID NO: 181] as CDR1, NINTDGSEVYYVDSVKG [SEQ ID NO: 70] as CDR2, and DVGPGIAYQGHFDY [SEQ ID NO: 444] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQVIYSYLNWYQQKPGKAPKLLIYAASSLKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYDTPLTFGGGTKVEIK [SEQ ID NO: 18]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18 and comprises the amino acid sequence RASQVIYSYLN [SEQ ID NO: 72] as CDR1, AASSLKS [SEQ ID NO: 73] as CDR2, and QQVYDTPLT [SEQ ID NO: 74] as CDR3 of SEQ ID NO: 18.

[0031] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 18; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 69, 70, and 71, respectively, or having the sequences of SEQ ID NOs: 181, 70, and 444, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 72, 73, and 74, respectively.

[0032] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QLQLQESGPGLVKPSETLSLTCTVSGGSISSTDYYWGWIRQPPGKGLEWIGSIGYSGTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARETAHDVHGMDVWGQGTTVTVSS [SEQ ID NO: 19]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 19. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 19, GSISSTDYYWG [SEQ ID NO: 75] as CDR1, SIGYSGTYYNPSLKS [SEQ ID NO: 76] as CDR2, and ARETAHDVHGMDV [SEQ ID NO: 77] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 19, STDYYWG [SEQ ID NO: 445] as CDR1, SIGYSGTYYNPSLKS [SEQ ID NO: 76] as CDR2, and ETAHDVHGMDV [SEQ ID NO: 446] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence EIVLTQSPATLSLSPGERATLSCRASHSVYSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYDNLPTFGGGTKVEIK [SEQ ID NO: 20]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 20 and comprises the amino acid sequence RASHSVYSYLA [SEQ ID NO: 78] as CDR1, DASNRAT [SEQ ID NO: 79] as CDR2, and QQYDNLPT [SEQ ID NO: 80] as CDR3 of SEQ ID NO: 20.

[0033] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 20; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 75, 76, and 77, respectively, or having the sequences of SEQ ID NOs: 445, 76, and 446, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 78, 79, and 80, respectively.

[0034] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 266. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYAMS [SEQ ID NO: 304] of SEQ ID NO: 266 as CDR1, AISASGGSTYYADSVKG [SEQ ID NO: 305] as CDR2, and PRAYYDSSGFKVNYGMDV [SEQ ID NO: 306] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSAMS [SEQ ID NO:528] of SEQ ID NO:266 as CDR1, AISASGGSTYYADSVKG [SEQ ID NO:305] as CDR2, and ARPRAYYDSSGFKVNYGMDV [SEQ ID NO:529] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:266, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267 and comprises the amino acid sequence RASQSVSSSFLA [SEQ ID NO: 307] of SEQ ID NO: 267 as CDR1, GASSRAT [SEQ ID NO: 308] as CDR2, and QQASSSPPT [SEQ ID NO: 309] as CDR3.

[0035] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 266 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 267; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 304, 305, and 306, respectively, or having the sequences of SEQ ID NOs: 528, 305, and 529, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 307, 308, and 309, respectively.

[0036] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 268. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYAMS [SEQ ID NO: 310] of SEQ ID NO: 268 as CDR1, GISGSGGGSTYYADSVKG [SEQ ID NO: 311] as CDR2, and EGHSSSYYDHAFDI [SEQ ID NO: 312] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSAMS [SEQ ID NO:530] of SEQ ID NO:268 as CDR1, GISGSGGGSTYYADSVKG [SEQ ID NO:311] as CDR2, and AREGHSSSYYDHAFDI [SEQ ID NO:531] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:268, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:268 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:269.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 269 and comprises the amino acid sequence RASQSVSSDYLA [SEQ ID NO: 313] as CDR1, GASSRAT [SEQ ID NO: 314] as CDR2, and QQHSSAPPT [SEQ ID NO: 315] as CDR3 of SEQ ID NO: 269.

[0037] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 268 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 269; or an antibody comprising heavy chain CDRs 1-3 having the sequences of SEQ ID NOs: 310, 311, and 312, respectively, or having the sequences of SEQ ID NOs: 530, 311, and 531, respectively, and light chain CDRs 1-3 having the sequences of SEQ ID NOs: 313, 314, and 315, respectively.

[0038] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 270. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYYWS [SEQ ID NO: 316] of SEQ ID NO: 270 as CDR1, SIYYSGSTNYNPSLKS [SEQ ID NO: 317] as CDR2, and VGGVYSTIETYGMDV [SEQ ID NO: 318] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 270, GSISSYYWS [SEQ ID NO: 532], as CDR1, SIYYSGSTNYNPSLKS [SEQ ID NO: 317], as CDR2, and ARVGGVYSTIETYGMDV [SEQ ID NO: 533], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271 and comprises the amino acid sequence RASQSVSSNLA [SEQ ID NO: 319] of SEQ ID NO: 271 as CDR1, GASTRAT [SEQ ID NO: 320] as CDR2, and QQYTVYPPT [SEQ ID NO: 321] as CDR3.

[0039] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 270 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 271; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 316, 317, and 318, respectively, or having the sequences of SEQ ID NOs: 532, 317, and 533, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 319, 320, and 321, respectively.

[0040] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 272. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GYYWS [SEQ ID NO: 322] of SEQ ID NO: 272 as CDR1, EIDHSGSTNYNPSLKS [SEQ ID NO: 323] as CDR2, and QGIHGLRYFDL [SEQ ID NO: 324] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GSFSGYYWS [SEQ ID NO:534] of SEQ ID NO:272 as CDR1, EIDHSGSTNYNPSLKS [SEQ ID NO:323] as CDR2, and ARQGIHGLRYFDL [SEQ ID NO:535] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:272, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273 and comprises the amino acid sequence RASQSVSSYLA [SEQ ID NO: 325] of SEQ ID NO: 273 as CDR1, DASNRAT [SEQ ID NO: 326] as CDR2, and QQDHNFPYT [SEQ ID NO: 327] as CDR3.

[0041] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 272 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 273; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 322, 323, and 324, respectively, or having the sequences of SEQ ID NOs: 534, 323, and 535, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 325, 326, and 327, respectively.

[0042] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 274. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYWMS [SEQ ID NO: 328] of SEQ ID NO: 274 as CDR1, NINQDGSEKYYVDSVKG [SEQ ID NO: 329] as CDR2, and EANYYGNVGDDY [SEQ ID NO: 330] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 274 FTFSSYWMS [SEQ ID NO: 536] as CDR1, NINQDGSEKYYVDSVKG [SEQ ID NO: 329] as CDR2, and AREANYYGNVGDDY [SEQ ID NO: 537] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275 and comprises the amino acid sequence RASQSISSYLN [SEQ ID NO: 331] as CDR1, AASSLQS [SEQ ID NO: 332] as CDR2, and QQQYVTPIT [SEQ ID NO: 333] as CDR3 of SEQ ID NO: 275.

[0043] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 274 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 275; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 328, 329, and 330, respectively, or having the sequences of SEQ ID NOs: 536, 329, and 537, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 331, 332, and 333, respectively.

[0044] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 276. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYWMS [SEQ ID NO: 334] of SEQ ID NO: 276 as CDR1, NINQDGSEKYYVDSVKG [SEQ ID NO: 335] as CDR2, and EGGDSWYHAFDI [SEQ ID NO: 336] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 276 FTFSSYWMS [SEQ ID NO: 538] as CDR1, NINQDGSEKYYVDSVKG [SEQ ID NO: 335] as CDR2, and AREGGDSWYHAFDI [SEQ ID NO: 539] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277 and comprises the amino acid sequence RASQGISSWLA [SEQ ID NO: 337] as CDR1, AASNLQS [SEQ ID NO: 338] as CDR2, and QQKLSLPLT [SEQ ID NO: 339] as CDR3 of SEQ ID NO: 277.

[0045] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 276 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 277; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 334, 335, and 336, respectively, or having the sequences of SEQ ID NOs: 538, 335, and 539, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 337, 338, and 339, respectively.

[0046] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 278. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SGGYYWS [SEQ ID NO: 340] of SEQ ID NO: 278 as CDR1, SIYYSGSTYYNPSLKS [SEQ ID NO: 341] as CDR2, and DRLDYSYNYGMDV [SEQ ID NO: 342] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 278 GSISSGGYYWS [SEQ ID NO: 540] as CDR1, SIYYSGSTYYNPSLKS [SEQ ID NO: 341] as CDR2, and ARDRLDYSYNYGMDV [SEQ ID NO: 541] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:278 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:279.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 279 and comprises the amino acid sequence RASQSISSYLN [SEQ ID NO: 343] as CDR1, GASSLQS [SEQ ID NO: 344] as CDR2, and QQVYSAPFT [SEQ ID NO: 345] as CDR3 of SEQ ID NO: 279.

[0047] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 278 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 279; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 340, 341, and 342, respectively, or having the sequences of SEQ ID NOs: 540, 341, and 541, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 343, 344, and 345, respectively.

[0048] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 280. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SGYYWG [SEQ ID NO: 346] of SEQ ID NO: 280 as CDR1, SIYHSGSTNYNPSLKS [SEQ ID NO: 347] as CDR2, and LPPWFGFSYFDL [SEQ ID NO: 348] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence YSISSGYYWG [SEQ ID NO:542] of SEQ ID NO:280 as CDR1, SIYHSGSTNYNPSLKS [SEQ ID NO:347] as CDR2, and ARLPPWFGFSYFDL [SEQ ID NO:543] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:280, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281 and comprises the amino acid sequence RASQSVSSYLA [SEQ ID NO: 349] of SEQ ID NO: 281 as CDR1, DASNRAT [SEQ ID NO: 350] as CDR2, and QQVDNYPPT [SEQ ID NO: 351] as CDR3.

[0049] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 280 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 281; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 346, 347, and 348, respectively, or having the sequences of SEQ ID NOs: 542, 347, and 543, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 349, 350, and 351, respectively.

[0050] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 282. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYWMS [SEQ ID NO: 352] of SEQ ID NO: 282 as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 353] as CDR2, and DVGPGIAYQGHFDY [SEQ ID NO: 354] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSYWMS [SEQ ID NO:544] of SEQ ID NO:282 as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO:353] as CDR2, and ARDVGPGIAYQGHFDY [SEQ ID NO:545] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:282, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283 and comprises the amino acid sequence RASQSISSYLN [SEQ ID NO: 355] as CDR1, AASSLQS [SEQ ID NO: 356] as CDR2, and QQVYDTPLT [SEQ ID NO: 357] as CDR3 of SEQ ID NO: 283.

[0051] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 282 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 283; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 352, 353, and 354, respectively, or having the sequences of SEQ ID NOs: 544, 353, and 545, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 355, 356, and 357, respectively.

[0052] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 284. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SSSYYWG [SEQ ID NO: 358] of SEQ ID NO: 284 as CDR1, SIYYSGSTYYNPSLKS [SEQ ID NO: 359] as CDR2, and ETAHDVHGMDV [SEQ ID NO: 360] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GSISSSSYYWG [SEQ ID NO:546] of SEQ ID NO: 284 as CDR1, SIYYSGSTYYNPSLKS [SEQ ID NO:359] as CDR2, and ARETAHDVHGMDV [SEQ ID NO:547] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285 and comprises the amino acid sequence RASQSVSSYLA [SEQ ID NO: 361] of SEQ ID NO: 285 as CDR1, DASNRAT [SEQ ID NO: 362] as CDR2, and QQYDNLPT [SEQ ID NO: 363] as CDR3.

[0053] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 284 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 285; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 358, 359, and 360, respectively, or having the sequences of SEQ ID NOs: 546, 359, and 547, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 361, 362, and 363, respectively.

[0054] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 286. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYAIS [SEQ ID NO: 364] of SEQ ID NO: 286 as CDR1, SIIPIFGTANYAQKFQG [SEQ ID NO: 365] as CDR2, and EVGYGWYTKIAFDI [SEQ ID NO: 366] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GTFSSYAIS [SEQ ID NO:548] of SEQ ID NO:286 as CDR1, SIIPIFGTANYAQKFQG [SEQ ID NO:365] as CDR2, and AREVGYGWYTKIAFDI [SEQ ID NO:549] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:286, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287 and comprises the amino acid sequence RASQSVSSYLA [SEQ ID NO: 367] as CDR1, DASKRAT [SEQ ID NO: 368] as CDR2, and QQSSNHPST [SEQ ID NO: 369] as CDR3 of SEQ ID NO: 287.

[0055] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 286 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 287; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 364, 365, and 366, respectively, or having the sequences of SEQ ID NOs: 548, 365, and 549, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 367, 368, and 369, respectively.

[0056] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 288. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYYMH [SEQ ID NO: 370] of SEQ ID NO: 288 as CDR1, IINPSGGSTTYAQKFQG [SEQ ID NO: 371] as CDR2, and EAADGFVGERYFDL [SEQ ID NO: 372] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 288 YTFTSYYMH [SEQ ID NO: 550] as CDR1, IINPSGGSTTYAQKFQG [SEQ ID NO: 371] as CDR2, and AREAADGFVGERYFDL [SEQ ID NO: 551] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:288 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:289.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 289 and comprises the amino acid sequence RSSQSLLHSNGYNYLD [SEQ ID NO: 373] of SEQ ID NO: 289 as CDR1, LGSNRAS [SEQ ID NO: 374] as CDR2, and MQALGVPLT [SEQ ID NO: 375] as CDR3.

[0057] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 288 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 289; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 370, 371, and 372, respectively, or having the sequences of SEQ ID NOs: 550, 371, and 551, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 373, 374, and 375, respectively.

[0058] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 290. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GYYMH [SEQ ID NO: 376] of SEQ ID NO: 290 as CDR1, MINPYGGSTRYAQKFQG [SEQ ID NO: 377] as CDR2, and EAADGFVGERYFDL [SEQ ID NO: 378] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 290, YTFSGYYMH [SEQ ID NO: 552], as CDR1, MINPYGGSTRYAQKFQG [SEQ ID NO: 377], as CDR2, and AREAADGFVGERYFDL [SEQ ID NO: 553], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:290 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:291.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 291 and comprises the amino acid sequence RSSQSLLYSNGYNYLD [SEQ ID NO: 379] of SEQ ID NO: 291 as CDR1, LGSNRAS [SEQ ID NO: 380] as CDR2, and MQDVALPIT [SEQ ID NO: 381] as CDR3.

[0059] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 290 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 291; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 376, 377, and 378, respectively, or having the sequences of SEQ ID NOs: 552, 377, and 553, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 379, 380, and 381, respectively.

[0060] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 292. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence IYYMH [SEQ ID NO: 382] of SEQ ID NO: 292 as CDR1, IINPSSGSTVYAQKFQG [SEQ ID NO: 383] as CDR2, and GAGYDDEDMDV [SEQ ID NO: 384] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 292 YTFEIYYMH [SEQ ID NO: 554] as CDR1, IINPSSGSTVYAQKFQG [SEQ ID NO: 383] as CDR2, and ARGAGYDDEDMDV [SEQ ID NO: 555] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:292 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:293.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 293 and comprises the amino acid sequence RASQGIDSWLA [SEQ ID NO: 385] as CDR1, AASSLQS [SEQ ID NO: 386] as CDR2, and QQAHSYPLT [SEQ ID NO: 387] as CDR3 of SEQ ID NO: 293.

[0061] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 292 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 293; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 382, ​​383, and 384, respectively, or having the sequences of SEQ ID NOs: 554, 383, and 555, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 385, 386, and 387, respectively.

[0062] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 294. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GYWMS [SEQ ID NO: 388] of SEQ ID NO: 294 as CDR1, NINQDGSEEYYVDSVKG [SEQ ID NO: 389] as CDR2, and EANYYGNVGDDY [SEQ ID NO: 390] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFGGYWMS [SEQ ID NO:556] of SEQ ID NO:294 as CDR1, NINQDGSEEYYVDSVKG [SEQ ID NO:389] as CDR2, and AREANYYGNVGDDY [SEQ ID NO:557] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:294, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:294 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:295.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 295 and comprises the amino acid sequence RASQSIYNYLN [SEQ ID NO: 391] of SEQ ID NO: 295 as CDR1, AASNLHS [SEQ ID NO: 392] as CDR2, and QQAFHVPIT [SEQ ID NO: 393] as CDR3.

[0063] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 294 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 295; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 388, 389, and 390, respectively, or having the sequences of SEQ ID NOs: 556, 389, and 557, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 391, 392, and 393, respectively.

[0064] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 296. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GYWMS [SEQ ID NO: 394] of SEQ ID NO: 296 as CDR1, NINQDGSEVYYVDSVKG [SEQ ID NO: 395] as CDR2, and EANYYGNVGDDY [SEQ ID NO: 396] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFPGYWMS [SEQ ID NO:558] of SEQ ID NO:296 as CDR1, NINQDGSEVYYVDSVKG [SEQ ID NO:395] as CDR2, and AREANYYGNVGDDY [SEQ ID NO:559] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:296, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:296 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:297.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 297 and comprises the amino acid sequence RASQSIYNYLN [SEQ ID NO: 397] as CDR1, AASSTQS [SEQ ID NO: 398] as CDR2, and QQAFHVPIT [SEQ ID NO: 399] as CDR3 of SEQ ID NO: 297.

[0065] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 296 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 297; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 394, 395, and 396, respectively, or having the sequences of SEQ ID NOs: 558, 395, and 559, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 397, 398, and 399, respectively.

[0066] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 298. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYWMS [SEQ ID NO: 400] of SEQ ID NO: 298 as CDR1, NINQDGSEVYYVDSVKG [SEQ ID NO: 401] as CDR2, and DVGPGIAYQGHFDY [SEQ ID NO: 402] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 298 FTFSSYWMS [SEQ ID NO: 560] as CDR1, NINQDGSEVYYVDSVKG [SEQ ID NO: 401] as CDR2, and ARDVGPGIAYQGHFDY [SEQ ID NO: 561] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:298 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:299.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 299 and comprises the amino acid sequence RASQSIYYYLN [SEQ ID NO: 403] as CDR1, AASSRQS [SEQ ID NO: 404] as CDR2, and QQVYDTPLT [SEQ ID NO: 405] as CDR3 of SEQ ID NO: 299.

[0067] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 298 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 299; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 400, 401, and 402, respectively, or having the sequences of SEQ ID NOs: 560, 401, and 561, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 403, 404, and 405, respectively.

[0068] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 300. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence NYYMH [SEQ ID NO: 406] of SEQ ID NO: 300 as CDR1, WINPFSGGTRYAQKFQG [SEQ ID NO: 407] as CDR2, and DVGSSAYYYMDV [SEQ ID NO: 408] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 300 YTFSNYYMH [SEQ ID NO: 562] as CDR1, WINPFSGGTRYAQKFQG [SEQ ID NO: 407] as CDR2, and ARDVGSSAYYYMDV [SEQ ID NO: 563] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301 and comprises the amino acid sequence EASKGISSWLA [SEQ ID NO: 409] of SEQ ID NO: 301 as CDR1, AASDLQS [SEQ ID NO: 410] as CDR2, and QQAFLFPPT [SEQ ID NO: 411] as CDR3.

[0069] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 300 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 301; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 406, 407, and 408, respectively, or having the sequences of SEQ ID NOs: 562, 407, and 563, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 409, 410, and 411, respectively.

[0070] In certain embodiments, the invention provides an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 302. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYWIG [SEQ ID NO: 412] of SEQ ID NO: 302 as CDR1, SIYPGDSDTRYSPSFQG [SEQ ID NO: 413] as CDR2, and ELAYGDYKGGVDY [SEQ ID NO: 414] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence YSFTSYWIG [SEQ ID NO:564] of SEQ ID NO:302 as CDR1, SIYPGDSDTRYSPSFQG [SEQ ID NO:413] as CDR2, and ARELAYGDYKGGVDY [SEQ ID NO:565] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:302, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303 and comprises the amino acid sequence RASQSVSSSFLA [SEQ ID NO: 415] of SEQ ID NO: 303 as CDR1, GASSRAT [SEQ ID NO: 416] as CDR2, and QQLDSPPPT [SEQ ID NO: 417] as CDR3.

[0071] In certain embodiments, the antigen-binding site is contained within an antibody, e.g., a monoclonal antibody, e.g., an antibody comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 302 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 303; or an antibody comprising heavy chain CDR1-3 having the sequences of SEQ ID NOs: 412, 413, and 414, respectively, or having the sequences of SEQ ID NOs: 564, 413, and 565, respectively, and light chain CDR1-3 having the sequences of SEQ ID NOs: 415, 416, and 417, respectively.

[0072] The antibody heavy chain variable domain of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, and / or 302 can optionally be joined to an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an antibody constant region, such as an IgG constant region comprising a hinge, CH2, and CH3 domain, with or without a CH1 domain. In some embodiments, the amino acid sequence of the constant region is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an antibody constant region such as a human antibody constant region, a human IgG1 constant region, a human IgG2 constant region, a human IgG3 constant region, or a human IgG4 constant region. In some other embodiments, the amino acid sequence of the constant region is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an antibody constant region derived from another mammal, such as a rabbit, dog, cat, mouse, or horse. The constant region may incorporate one or more mutations compared to the human IgG1 constant region, for example, at Q347, Y349, L351, S354, E356, E357, K360, Q362, S364, T366, L368, K370, N390, K392, T394, D399, S400, D401, F405, Y407, K409, T411 and / or K439.Exemplary substitutions include, for example, Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, T350V, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, and T366S. , L368E, L368A, L368D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, T394W, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I, Y407V, K409F, K409W, K409D, T411D, T411E, K439D, and K439E.

[0073] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 1 (Ab1-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 2 (Ab1-V L ) is included.

[0074] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 3 (Ab2-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 4 (Ab2-V L ) is included.

[0075] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 5 (Ab3-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 6 (Ab3-V L ) is included.

[0076] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 7 (Ab4-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 8 (Ab4-VL ) is included.

[0077] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 9 (Ab5-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 10 (Ab5-V L ) is included.

[0078] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 11 (Ab6-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 12 (Ab6-V L ) is included.

[0079] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 13 (Ab7-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 14 (Ab7-V L ) is included.

[0080] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 15 (Ab8-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 16 (Ab8-V L ) is included.

[0081] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 17 (Ab9-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 18 (Ab9-V L ) is included.

[0082] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 19 (Ab10-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 20 (Ab10-V L ) is included.

[0083] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 266 (Ab11-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 267 (Ab11-V L ) is included.

[0084] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 268 (Ab12-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 269 (Ab12-V L ) is included.

[0085] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 270 (Ab13-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 271 (Ab13-V L ) is included.

[0086] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 272 (Ab14-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 273 (Ab14-V L ) is included.

[0087] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 274 (Ab15-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 275 (Ab15-V L ) is included.

[0088] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 276 (Ab16-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 277 (Ab16-V L ) is included.

[0089] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 278 (Ab17-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 279 (Ab17-V L ) is included.

[0090] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 280 (Ab18-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 281 (Ab18-V L ) is included.

[0091] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 282 (Ab19-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 283 (Ab19-V L ) is included.

[0092] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 284 (Ab20-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 285 (Ab20-V L ) is included.

[0093] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 286 (Ab21-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 287 (Ab21-V L ) is included.

[0094] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 288 (Ab22-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 289 (Ab22-V L ) is included.

[0095] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 290 (Ab23-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 291 (Ab23-V L ) is included.

[0096] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 292 (Ab24-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 293 (Ab24-V L ) is included.

[0097] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 294 (Ab25-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 295 (Ab25-V L ) is included.

[0098] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 296 (Ab26-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 297 (Ab26-V L ) is included.

[0099] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 298 (Ab27-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 299 (Ab27-V L ) is included.

[0100] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 300 (Ab28-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 301 (Ab28-V L ) is included.

[0101] In certain embodiments, the immunoglobulin heavy chain variable region has the amino acid sequence of SEQ ID NO: 302 (Ab29-V H ), and the immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 303 (Ab29-V L ) is included.

[0102] In specific embodiments, the invention provides proteins comprising a human CD33 antigen-binding site comprising a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, or 302, and further comprising a second antigen-binding site that is identical to or different from the antigen-binding site that binds human CD33.

[0103] In certain embodiments, any of the foregoing isolated antibodies has a K of 1 nM or less, 5 nM or less, or 12 nM or less against the extracellular domain of human CD33, as measured by surface plasmon resonance (SPR) (e.g., using the Biacore method described in Example 1 below) or biolayer interferometry (BLI) (e.g., using the Octet method described in Example 1 below). D and / or binds to CD33 derived from a subject's body fluids, tissues, and / or cells. In certain embodiments, any of the foregoing isolated antibodies has a specific activity of 1×10 or more as measured by SPR (e.g., using the Biacore method described in Example 1 below) or BLI (e.g., using the Octet method described in Example 1 below). -5 , 1×10 -4 , 1×10 -3 , 5×10 -3 , 0.01, 0.02, or 0.05 1 / s or less K d (i.e., dissociation rate, K off (also called

[0104] In specific embodiments of any of the antibodies or binding fragments thereof provided herein, the antibody is a monoclonal antibody, chimeric antibody, diabody, Fab fragment, Fab' fragment, or F(ab')2 fragment, Fv, bispecific antibody, bispecific Fab2, bispecific (mab)2, humanized antibody, artificially generated human antibody, bispecific T cell engager, bispecific NK cell engager, single-chain antibody (e.g., single-chain Fv fragment or scFv), triomab, knob-into-hole (kih) IgG with a common light chain, crossmab, ortho-Fab IgG, DVD-Ig, two-in-one IgG, IgG-scFv, sdFv2-Fc, bi-nanobody, tandAb, dual affinity retargeting antibody (DART), DART-Fc, scFv-HSA-scFv (where HSA = human serum albumin), or dock-and-lock (DNL)-Fab3.

[0105] In another aspect, the invention provides one or more isolated nucleic acids comprising sequences encoding the immunoglobulin heavy chain variable region and / or the immunoglobulin light chain variable region of any one of the aforementioned antibodies. The invention provides one or more expression vectors that express the immunoglobulin heavy chain variable region and / or the immunoglobulin light chain variable region of any one of the aforementioned antibodies. Similarly, the invention provides host cells comprising one or more of the aforementioned expression vectors and / or isolated nucleic acids.

[0106] Also provided are formulations comprising any of the proteins comprising a CD33 binding domain described herein, as well as methods of using these proteins and / or formulations to increase tumor cell death.

[0107] In another aspect, the present invention provides a method of treating cancer, e.g., a CD33-associated cancer, in a subject, comprising administering to the subject an effective amount of a protein containing any of the CD33-binding domains described herein, e.g., an anti-CD33 antibody, to treat the cancer in the subject.

[0108] In another aspect, the present invention provides a method for inhibiting cancer growth, e.g., the growth of a CD33-associated cancer, in a subject, comprising exposing the subject to an effective amount of a protein containing any of the CD33-binding domains described herein, e.g., an anti-CD33 antibody, to inhibit cancer growth in the subject.

[0109] Another aspect of the present invention provides a method of treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of any of the CD33-binding domain-containing proteins described herein. Exemplary cancers for treatment using the proteins include, for example, those wherein the cancer is selected from the group consisting of AML, myelodysplastic syndrome, chronic myelomonocytic leukemia, myeloid blast crisis of chronic myeloid leukemia, and ALL.

[0110] In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 Provided is a protein as disclosed herein comprising a sequence selected from sequence number 459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, SEQ ID NO:484, SEQ ID NO:485, SEQ ID NO:486, SEQ ID NO:487, and SEQ ID NO:488.

[0111] In certain embodiments, the invention provides a protein disclosed herein comprising an scFv linked to an antibody Fc domain, wherein the scFv linked to the antibody Fc domain is represented by a sequence selected from SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:242, and SEQ ID NO:243.

[0112] In certain embodiments, the present invention provides a protein as disclosed herein comprising a sequence selected from SEQ ID NO:189, SEQ ID NO:196, SEQ ID NO:244, and SEQ ID NO:245.

[0113] In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461 , SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO: 458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO: 458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.

[0114] In certain embodiments, the invention provides a protein disclosed herein comprising a sequence that is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an amino acid sequence selected from SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:242, and SEQ ID NO:243. In certain embodiments, the present invention provides a protein as disclosed herein comprising a sequence at least 95% identical to an amino acid sequence selected from SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:242, and SEQ ID NO:243. In certain embodiments, the present invention provides a protein disclosed herein comprising a sequence at least 99% identical to an amino acid sequence selected from SEQ ID NO:187, SEQ ID NO:197, SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:231, SEQ ID NO:232, SEQ ID NO:233, SEQ ID NO:234, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:237, SEQ ID NO:238, SEQ ID NO:239, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:242, and SEQ ID NO:243.

[0115] Another aspect of the present invention provides a formulation comprising a protein disclosed herein and a pharmaceutically acceptable carrier.

[0116] Another aspect of the invention provides a nucleic acid encoding a chimeric antigen receptor (CAR), wherein the nucleic acid is selected from the group consisting of SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, the nucleic acid sequence encoding a CD33-binding scFv comprising a sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an amino acid sequence selected from SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484; a nucleic acid sequence encoding a transmembrane domain; and a nucleic acid sequence encoding an intracellular signaling domain.

[0117] Another aspect of the present invention is directed to SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463 , SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484; a CD33-binding scFv comprising a sequence at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to an amino acid sequence selected from:

[0118] In certain embodiments of the nucleic acid or CAR, the CD33 binding scFv is selected from the group consisting of SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID NO: 449, SEQ ID NO: 450, SEQ ID NO: 451, SEQ ID NO: 452, SEQ ID NO: 453, SEQ ID NO: 454, SEQ ID NO: 455, SEQ ID NO: SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the CD33 binding scFv is selected from the group consisting of SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 447, SEQ ID NO: 448, SEQ ID NO: 449, SEQ ID NO: 450, SEQ ID NO: 451, SEQ ID NO: 452, SEQ ID NO: 453, SEQ ID NO: 454, SEQ ID NO: 455, SEQ ID NO: 456, SEQ ID NO: 457, SEQ ID NO: 458, SEQ ID NO: 459, SEQ ID NO: 460, SEQ ID NO: 461, SEQ ID NO: 462, SEQ ID NO: 463, SEQ ID NO: 464, SEQ ID NO: 465, SEQ ID NO: 466, SEQ ID NO: 467, SEQ ID NO: 468, SEQ ID NO: 469, SEQ ID NO: 470, SEQ ID NO: 471, SEQ ID NO: 472, SEQ ID NO: 473, SEQ ID NO: 474, SEQ ID NO: 475, SEQ 6, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the CD33 binding scFv is selected from the group consisting of SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:4 55, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.

[0119] In certain embodiments, the transmembrane domain is selected from the transmembrane regions of the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD152, and CD 154. In certain embodiments, the CD33-binding scFv is connected to the transmembrane domain by a hinge region.

[0120] In certain embodiments, the intracellular signaling domain comprises a primary signaling domain, including a functional signaling domain of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In certain embodiments, the intracellular signaling domain further comprises a costimulatory signaling domain, including a functional signaling domain of a costimulatory receptor. In certain embodiments, the costimulatory receptor is selected from the group consisting of OX40, CD27, CD28, CD30, CD40, PD-1, CD2, CD7, CD258, NKG2C, B7-H3, a ligand that binds to CD83, ICAM-1, LFA-1 (CD11a / CD18), ICOS, and 4-1BB (CD137), or any combination thereof.

[0121] Another aspect of the present invention provides a vector comprising the nucleic acid. In certain embodiments, the vector is a viral vector (e.g., an AAV vector, a lentiviral vector, or an adenoviral vector).

[0122] Another aspect of the present invention provides immune effector cells expressing a CAR disclosed herein. In certain embodiments, the CAR is expressed on the plasma membrane of the cell. Another aspect of the present invention provides immune effector cells comprising a nucleic acid encoding a CAR disclosed herein. Also provided are immune effector cells comprising a vector comprising the nucleic acid. In certain embodiments, the immune effector cells are T cells (e.g., CD8 + T cells, CD4 + T cells, or NKT cells). In certain embodiments, the effector cells are NK cells.

[0123] Another aspect of the present invention is directed to SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO: 463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 9. A CD33 / CD3-directed bispecific T cell engager is provided, comprising a protein comprising a sequence at least 95% identical to an amino acid sequence selected from SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 9. A CD33 / CD3-directed bispecific T cell engager is provided, comprising a protein comprising a sequence at least 99% identical to an amino acid sequence selected from SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO: 458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.

[0124] Another aspect of the present invention is directed to SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:48 62, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 58, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458 , SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 57, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484. In certain embodiments, the antibody-drug conjugate further comprises a drug moiety selected from an auristatin, N-acetyl-calicheamicin gamma, a maytansinoid, a pyrrolobenzodiazepine, and SN-38.

[0125] Another aspect of the present invention is directed to a method for the preparation of a medicament for the treatment ... 7, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:460, SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:463, SEQ ID NO:464, SEQ ID NO:465, SEQ ID NO:466, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:470, SEQ ID NO:471, SEQ ID NO:472, SEQ ID NO:473, SEQ ID NO:474, SEQ ID NO:475, SEQ ID NO:476, SEQ ID NO:477, SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:482, SEQ ID NO:483, and SEQ ID NO:484.In certain embodiments, the present invention provides SEQ ID NO:188, SEQ ID NO:198, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:216, SEQ ID NO:217, SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:221, SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:449, SEQ ID NO:450, SEQ ID NO:451, SEQ ID NO:452, SEQ ID NO:453, SEQ ID NO:454, SEQ ID NO:455, SEQ ID NO:456, SEQ ID NO:457, SEQ ID NO:458, SEQ ID NO:459, SEQ ID NO:500, SEQ ID NO:501, SEQ ID NO:502, SEQ ID NO:503, SEQ ID NO:504, SEQ ID NO:505, SEQ ID NO:506, SEQ ID NO:507, SEQ ID NO:508, SEQ ID NO:509, SEQ ID NO:510, SEQ ID NO:511, SEQ ID NO:512, SEQ ID NO:513, SEQ ID NO:514, SEQ ID NO:515, SEQ ID NO:516, SEQ ID NO:517, SEQ ID NO:518, SEQ ID NO:519, SEQ ID NO:520, SEQ ID NO:521, SEQ ID NO:522 Provided is an immunocytokine comprising an amino acid sequence selected from SEQ ID NO: 456, SEQ ID NO: 457, SEQ ID NO: 458, SEQ ID NO: 459, SEQ ID NO: 460, SEQ ID NO: 461, SEQ ID NO: 462, SEQ ID NO: 463, SEQ ID NO: 464, SEQ ID NO: 465, SEQ ID NO: 466, SEQ ID NO: 467, SEQ ID NO: 468, SEQ ID NO: 469, SEQ ID NO: 470, SEQ ID NO: 471, SEQ ID NO: 472, SEQ ID NO: 473, SEQ ID NO: 474, SEQ ID NO: 475, SEQ ID NO: 476, SEQ ID NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID NO: 480, SEQ ID NO: 481, SEQ ID NO: 482, SEQ ID NO: 483, and SEQ ID NO: 484. In certain embodiments, the cytokine is selected from IL-2, IL-4, IL-10, IL-12, IL-15, TNF, and IFNα.

[0126] Another aspect of the present invention provides a method of treating a CD33-expressing cancer, the method comprising administering a therapeutically effective amount of a protein or formulation thereof disclosed herein to a subject in need thereof. In certain embodiments, the method comprises administering a therapeutically effective amount of an antibody or formulation thereof to a subject in need thereof. In certain embodiments, the method comprises administering a therapeutically effective amount of a monoclonal antibody or formulation thereof to a subject in need thereof. In certain embodiments, the method comprises administering a therapeutically effective amount of an engager or formulation thereof to a subject in need thereof.

[0127] In certain embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasm (MPN), lymphoma, non-Hodgkin's lymphoma, and classical Hodgkin's lymphoma. In certain embodiments, the AML is selected from undifferentiated acute myeloblastic leukemia, minimally differentiated acute myeloblastic leukemia, differentiated acute myeloblastic leukemia, acute promyelocytic leukemia (APL), acute myelomonocytic leukemia, acute myelomonocytic leukemia with eosinophilia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia (AMKL), acute basophilic leukemia, acute panmyelosis with fibrosis, and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In certain embodiments, the AML is characterized by expression of CLL-1 on AML leukemia stem cells (LSCs). In certain embodiments, the LSCs further express a cell membrane marker selected from CD34, CD38, CD123, TIM3, CD25, CD32, and CD96.

[0128] In certain embodiments, the AML is minimal residual disease (MRD). In certain embodiments, the MRD is characterized by the presence or absence of a mutation selected from FLT3-ITD ((Fms-like tyrosine kinase 3)-internal tandem duplication (ITD)), NPM1 (nucleophosmin 1), DNMT3A (DNA methyltransferase gene DNMT3A), and IDH (isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2)). In certain embodiments, the MDS is selected from MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with excess blasts (MDS-EB), MDS with isolated chromosomal abnormality del(5q), and unclassified MDS (MDS-U). In certain embodiments, the MDS is primary MDS or secondary MDS.

[0129] In certain embodiments, the ALL is selected from B-cell acute lymphoblastic leukemia (B-ALL) and T-cell acute lymphoblastic leukemia (T-ALL). In certain embodiments, the MPN is selected from polycythemia vera, essential thrombocythemia (ET), and myelofibrosis. In certain embodiments, the non-Hodgkin's lymphoma is selected from B-cell lymphoma and T-cell lymphoma. In certain embodiments, the lymphoma is selected from chronic lymphocytic leukemia (CLL), lymphoblastic lymphoma (LPL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), primary mediastinal large B-cell lymphoma (PMBL), follicular lymphoma, mantle cell lymphoma, hairy cell leukemia, plasma cell myeloma (PCM) or multiple myeloma (MM), mature T / NK-cell neoplasms, and histiocytic neoplasms.

[0130] These and other aspects and advantages of the present invention are illustrated by the following drawings, detailed description and claims.

[0131] The present invention can be more fully understood with reference to the following drawings. [Brief explanation of the drawings]

[0132] [Figure 1] Figure 1 shows a structural diagram of the extracellular domain of human CD33 extracellular domain (ECD). The CD33 ECD contains two prominent domains: a distal V domain and a membrane-proximal C domain. The ligand-binding interface is located in the V domain. The function of the C domain is unknown. The CD33 ECD is heavily glycosylated, with two N-linked glycosylation sites located in the V domain and three N-linked glycosylation sites located in the C domain. The ECD of human CD33 contains several SNPs, with the most prominent mutation, R69G, occurring in 42% of patients. SNP R69G is located in the V domain.

[0133] [Figure 2]

[0023] Figure 1 shows an alignment of the primary sequences of full-length human CD33 and cyno CD33 (SEQ ID NO: 598 and SEQ ID NO: 599, respectively). The V domains are underlined in blue and the C domains are underlined in green. Sequence differences are circled in red.

[0134] [Figure 3] A-K show SPR profiles of Fab fragments derived from CD33 monoclonal antibodies that bind to human CD33 ECD, measured by Biacore at 37° C. Each Fab fragment comprises a CD33-binding clone described herein. A is the Biacore profile of ADI-10159, B is the Biacore profile of ADI-10177, C is the Biacore profile of ADI-11776, D is the Biacore profile of ADI-11801, E is the Biacore profile of ADI-11807, F is the Biacore profile of ADI-11809, G is the Biacore profile of ADI-11815, H is the Biacore profile of ADI-11819, I is the Biacore profile of ADI-11830, J is the Biacore profile of ADI-11835, and K is the Biacore profile of a Fab fragment derived from lintuzumab.

[0135] [Figure 4]Figures A-H show SPR profiles of Fab fragments derived from CD33 monoclonal antibodies binding to cyno CD33 ECD measured by Biacore at 37°C. Each Fab fragment contains a CD33-binding clone described herein. A is the Biacore profile of ADI-10159, B is the Biacore profile of ADI-10177, C is the Biacore profile of ADI-11776, D is the Biacore profile of ADI-11807, E is the Biacore profile of ADI-11809, F is the Biacore profile of ADI-11819, G is the Biacore profile of ADI-11830, and H is the Biacore profile of ADI-11835.

[0136] [Figure 5] Panels A to T show SPR profiles of Fab fragments derived from CD33 monoclonal antibodies that bind to the V and C domains of human CD33, measured at 37°C. Each Fab fragment contains a CD33-binding clone described herein. Panels A to J represent binding to the V domain, and panels K to T represent binding to the C domain. A and K are Biacore profiles of ADI-10159, B and L are Biacore profiles of ADI-10177, C and M are Biacore profiles of ADI-11776, D and N are Biacore profiles of ADI-11801, E and O are Biacore profiles of ADI-11807, F and P are Biacore profiles of ADI-11809, G and Q are Biacore profiles of ADI-11815, H and R are Biacore profiles of ADI-11819, I and S are Biacore profiles of ADI-11830, and J and T are Biacore profiles of ADI-11835.

[0137] [Figure 6]A to D show SPR profiles of Fabs containing ADI-11815 binding to different domains of human CD33 and to human CD33 with the R69G point mutation. A: Fab binding to human CD33 ECD, B: Fab binding to the V domain, C: Fab binding to the C domain, D: Fab binding to human CD33 with R69G.

[0138] [Figure 7] A to D show SPR profiles of Fabs containing ADI-11801 binding to different domains of human CD33 and to human CD33 with the R69G point mutation. A: human CD33 ECD, B: V domain, C: C domain, D: human CD33 with R69G.

[0139] [Figure 8]

[0023] Figure 1 is a bar graph showing the binding of monoclonal antibodies, including CD33-binding clones, to CD33 expressed on human AML cells Molm-13. The CD33 antibody lintuzumab was also tested, and mean fluorescence intensity (MFI) was plotted. Five of the six antibodies show higher binding signals to CD33 compared to lintuzumab.

[0140] [Figure 9]

[0023] Figure 1 is a bar graph showing the internalization of CD33 antibodies on Molm-13 cells after 24 hours. All CD33 antibodies showed similar internalization after 24 hours. Lintuzumab showed slightly higher internalization compared to the other anti-CD33 antibodies.

[0141] [Figure 10A]Figures A-B show binding of CD33-targeted TriNKET to human NKG2D expressed on EL4-hNKG2D and KHYG-1 cells. Figure A shows binding of CD33-targeted TriNKET to human NKG2D recombinantly expressed on EL4 cells. Figure B shows binding of CD33-targeted TriNKET to human NKG2D expressed on KHYG-1 cells. For each TriNKET, the fold over background (FOB) was similar in both EL4-hNKG2D and KHYG-1 cells, and the binding rank order was maintained in both cell lines. [Figure 10B] Same as above.

[0142] [Figure 11] Figure 1 shows the binding of CD33-targeted TriNKET to CD33 expressed on human AML Molm-13 cells. Four different CD33-binding clones and five NKG2D-binding clones were used to generate a total of 20 different TriNKETs. The NKG2D-binding domain of TriNKET does not affect the binding of the CD33-binding clones to CD33.

[0143] [Figure 12] 1 is a graph showing that resting human NK cells are activated by CD33-targeted TriNKET in co-culture with CD33-expressing THP-1 AML cells.

[0144] [Figure 13] 1 is a bar graph showing that CD33 TriNKET induces resting NK cell-mediated killing of AML cells Molm-13.

[0145] [Figure 14] 1 is a bar graph showing that CD33 TriNKET induces activated NK cell-mediated killing of THP-1 cells.

[0146] [Figure 15](A) Line graphs showing that TriNKET mediates killing of AML Molm-13 cells by KHYG-1. (B) Line graphs showing that TriNKET mediates killing of human AML Molm-13 cells by resting human NK cells.

[0147] [Figure 16] 1 is a line graph showing that TriNKET mediates killing of AML cells EOL-1 by KHYG-1.

[0148] [Figure 17] (A) Line graph showing that TriNKET mediates killing of THP-1 cells by KHYG-1. (B) Line graph showing that TriNKET mediates killing of human AML cells, THP-1, by resting human NK cells.

[0149] [Figure 18] FIG. 1 is a diagram of a multispecific binding protein containing an NKG2D-binding domain (right arm), a CD33-binding domain (left arm), and an Fc domain or portion thereof that binds to CD16.

[0150] [Figure 19] FIG. 1 is a diagram of a multispecific binding protein comprising an NKG2D-binding domain or a CD33-binding domain, and an Fc domain or portion thereof that binds to CD16, where either domain can be in scFv format.

[0151] [Figure 20] Diagram of TriNKET, a form of triomab, which is a trifunctional bispecific antibody that maintains an IgG-like shape. This chimera consists of two half antibodies derived from two parent antibodies, each containing one light and one heavy chain.

[0152] [Figure 21]Diagram of TriNKET in the form of KiH common light chain (LC), which involves knob-into-hole (KIH) technology. KiH is a heterodimer containing two Fabs that bind to target 1 and target 2 and an Fc stabilized by heterodimerization mutations. TriNKET in KiH format can be a heterodimeric construct containing two Fabs that bind to target 1 and target 2, two different heavy chains, and a common light chain that pairs with both heavy chains.

[0153] [Figure 22] Diagram of TriNKET, a form of dual variable domain immunoglobulin (DVD-Ig™), which combines the target binding domains of two monoclonal antibodies via a flexible natural linker to give a tetravalent IgG-like molecule. DVD-Ig™ is a homodimeric construct in which the variable domain targeting antigen 2 is fused to the N-terminus of the variable domain of a Fab targeting antigen 1, and the construct contains a conventional Fc.

[0154] [Figure 23] Diagram of TriNKET in the form of an orthogonal Fab interface (ortho-Fab), which is a heterodimeric construct containing two Fabs that bind to target 1 and target 2 fused to an Fc. LC-HC pairing is ensured by the orthogonal interface. Heterodimerization is ensured by mutations in the Fc.

[0155] [Figure 24] FIG. 1 is a diagram of TrinKET in two-in-one Ig format.

[0156] [Figure 25] Diagram of the ES form of TriNKET, which is a heterodimeric construct containing two different Fabs that bind to target 1 and target 2 fused to an Fc. Heterodimerization is ensured by electrostatic steering mutations in the Fc.

[0157] [Figure 26] Diagram of Fab arm exchanged form TriNKET, which is an antibody that exchanges its Fab arms by swapping its heavy chain and attached light chain (half molecule) with a heavy-light chain pair from another molecule, thereby becoming a bispecific antibody. The Fab arm exchanged form (cFae) is a heterodimer containing two Fabs that bind to target 1 and target 2, and an Fc stabilized by a heterodimerization mutation.

[0158] [Figure 27] FIG. 1 is a diagram of TriNKET, a form of SEED body, which is a heterodimer containing two Fabs that bind to target 1 and target 2, and an Fc stabilized by a heterodimerization mutation.

[0159] [Figure 28] 1 is a diagram of the LuZ-Y form of TriNKET, which uses a leucine zipper to induce heterodimerization of two different HCs. The LuZ-Y form is a heterodimer containing two different scFabs that bind to target 1 and target 2, fused to Fc.

[0160] [Figure 29] FIG. 1 is a diagram of TriNKET, a form of Cov-X-body.

[0161] [Figure 30A] AB are diagrams of TriNKET, a form of κλ body, which is a heterodimeric construct containing two different Fabs fused to an Fc stabilized by heterodimerization mutations, where Fab1, targeting antigen 1, contains a kappa LC and the second Fab, targeting antigen 2, contains a lambda LC. A is an exemplary diagram of one form of κλ body, and B is an exemplary diagram of another κλ body. [Figure 30B] Same as above.

[0162] [Figure 31]Oasc-Fab heterodimer construct containing a Fab that binds target 1 and a scFab that binds target 2 fused to Fc. Heterodimerization is ensured by mutations in the Fc.

[0163] [Figure 32] DuetMab is a heterodimeric construct containing two different Fabs that bind to antigens 1 and 2 and an Fc stabilized by heterodimerization mutations. Fab1 and Fab2 contain unique S-S bridges that ensure correct pairing of the light chain (LC) and heavy chain (HC).

[0164] [Figure 33] CrossmAb, which is a heterodimeric construct containing two different Fabs that bind to target 1 and target 2 fused to an Fc stabilized by heterodimerization. The CL and CH1 domains and the VH and VL domains are swapped, e.g., CH1 is fused in-line to VL and CL is fused in-line to VH.

[0165] [Figure 34] Fit-Ig, which is a homodimeric construct in which a Fab that binds antigen 2 is fused to the N-terminus of the HC of a Fab that binds antigen 1. The construct contains wild-type Fc.

[0166] [Figure 35] FIG. 1 is a graph showing binding of A49-F3′-TriNKET-I07 and I07-F405L mAbs to cell surface human NKG2D expressed on EL4 cells.

[0167] [Figure 36] AB are graphs showing binding of A49-F3'-TriNKET-I07 and I07-F405L mAbs to the CD33+ human AML cell lines Mv4-11 (A) and Molm-13 (B).

[0168] [Figure 37] AB are graphs showing the internalization of A49-F3'-TriNKET-I07 and I07-F405L mAbs after incubation with EOL-1 cells (A) and Molm-13 cells (B).

[0169] [Figure 38A] 1 is a graph showing the specific lysis of human AML cells Molm-13 by resting human NK cells in the presence of A49-F3′-TriNKET-I07 and anti-CD33 monoclonal antibody. [Figure 38B] 1 is a graph showing the specific lysis of human AML cells EOL-1 by resting human NK cells in the presence of A49-F3′-TriNKET-I07 and anti-CD33 monoclonal antibody. [Figure 38C] 1 is a graph showing the specific lysis of human AML cells THP-1 by resting human NK cells in the presence of A49-F3′-TriNKET-I07 and anti-CD33 monoclonal antibody. [Figure 38D] 1 is a graph showing the specific lysis of human AML cells THP-1 by resting human NK cells in the presence of A49-F3′-TriNKET-I07 and anti-CD33 monoclonal antibody.

[0170] [Figure 39] 1 is a series of flow cytograms showing the expression levels of CD3, CD8, NKG2D, and CD16 on isolated primary CD8+ T cells.

[0171] [Figure 40](A-B) Graphs showing specific lysis of Molm-13 cells by isolated primary CD8+ T cells in the presence of A49-F3'-TriNKET-I07, A49-F3'-TriNKET-H76, non-targeting TriNKET, or I07-F405L mAb (labeled I07 in the figure). Primary CD8+ T cells in (A) were isolated from PBMCs of donor 1, and primary CD8+ T cells in (B) were isolated from PBMCs of donor 2. The dotted line indicates specific lysis of Molm-13 cells by CD8+ T cells in the absence of TriNKET or antibody.

[0172] [Figure 41] Figures A-E are histograms showing the binding of A49-F3'-TriNKET-I07 to NK cells (A), CD8+ T cells (B), CD4+ T cells (C), B cells (D), and monocytes (E) in human whole blood. The open dotted line represents the binding of A49-F3'-TriNKET-I07 to cells, and the solid line represents the binding of the human IgG1 isotype control to cells.

[0173] [Figure 42A] Graphs A-B show CD33 expression on monocytes. A shows CD33 expression on monocytes from four healthy donors (dark gray) and Molm-13 (light gray). The bottom five rows show signals from cell samples stained with anti-CD33 antibodies, and the top five rows show signals from the same samples stained with isotype antibodies. B shows CD33 expression on monocytes from the same donor before (light gray) and after (dark gray) negative selection of monocytes. [Figure 42B] Same as above.

[0174] [Figure 43](A-B) Graphs showing the long-term cytotoxicity of NK cells against AML Molm-13 cells and human primary monocytes in the presence of A49-F3'-TriNKET-I07. Target cell proliferation is plotted against time of co-culture with NK cells in the presence of A49-F3'-TriNKET-I07 or PMA plus ionomycin. (A) represents results from an experiment using NK cells from one donor, and (B) represents results from another experiment using NK cells from a different donor.

[0175] [Figure 44]

[0023] Figure 1 shows a trispecific antibody (TriNKET) containing a CD33-binding scFv, an NKG2D-targeting Fab, and a heterodimerized antibody constant domain that binds to CD16. This antibody format is referred to herein as F3'-TriNKET. DETAILED DESCRIPTION OF THE INVENTION

[0176] In one aspect, the present invention provides antigen-binding sites that bind to epitopes on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33. In one aspect, the present invention provides antigen-binding sites that recognize and bind to one or more conformational epitopes on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33. In one aspect, the present invention provides antigen-binding sites that recognize and bind to one or more conformational epitopes on the extracellular domain of human CD33, but do not recognize and / or bind to one or more conformational epitopes on the extracellular domain of cyno CD33. In one aspect, the present invention provides antigen-binding sites that bind to the R69G allele of human CD33. In one aspect, the present invention provides antigen-binding sites that bind to wild-type human CD33 but do not bind to the R69G allele of human CD33. In one aspect, the present invention provides antigen-binding sites that bind to an epitope on human CD33 that includes R69. In one aspect, the present invention provides an antigen-binding site that binds to human CD33 with the S128N allele. In one aspect, the present invention provides an antigen-binding site that binds to wild-type human CD33 but not to human CD33 with the S128N allele. In one aspect, the present invention provides an antigen-binding site that binds to an epitope of human CD33 that includes S128. In one aspect, the present invention provides an antigen-binding site comprising a heavy chain variable domain that binds to the extracellular domain of human CD33 and / or cyno CD33, regardless of the glycosylation profile of the target CD33.

[0177] In certain embodiments, the present invention provides antigen-binding sites that bind to the extracellular domain of human CD33 and / or cyno CD33 such that the epitopes are unique compared to the epitopes targeted by one or more anti-CD33 antibodies known in the art. In certain embodiments, the present invention provides antigen-binding sites that bind to the extracellular domain of human CD33 and / or cyno CD33 and exhibit cross-reactivity with human or cynomolgus / rhesus (cyno) CD33 and high-affinity binding to the target CD33.

[0178] The present invention provides antigen binding proteins that bind to CD33 on cancer cells, as well as pharmaceutical compositions comprising such proteins, and methods of treatment using such proteins and pharmaceutical compositions, including the treatment of cancer. Various aspects of the invention are described in the following sections, although aspects of the invention described in a particular section are not limited to any particular section.

[0179] To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0180] As used herein, the words "a" and "an" mean "one or more" and include the plural forms unless the context requires otherwise.

[0181] As used herein, the term "antigen-binding site" refers to the portion of an immunoglobulin molecule involved in antigen binding. In human antibodies, the antigen-binding site is formed by amino acid residues from the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly divergent stretches within the V regions of the heavy and light chains are called "hypervariable regions" and are interposed between adjacent, more conserved stretches known as "framework regions" or "FRs." The term "FR" therefore refers to the naturally occurring amino acid sequences flanking the hypervariable regions of immunoglobulins. In human antibody molecules, the three hypervariable regions of the light chain and the three hypervariable regions of the heavy chain are arranged relative to one another in three-dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of the bound antigen, and the three hypervariable regions of each of the heavy and light chains are called "complementarity-determining regions" or "CDRs." In certain animals, such as camels and cartilaginous fish, the antigen-binding site is formed by a single antibody chain, providing a "single-domain antibody." The antigen-binding site may be present in an intact antibody, in an antigen-binding fragment of an antibody that retains the antigen-binding surface, or in a recombinant polypeptide such as an scFv in which the heavy and light chain variable domains are joined into a single polypeptide using a peptide linker. All amino acid positions in the heavy or light chain variable regions disclosed herein are numbered according to Kabat numbering.

[0182] CDRs of an antigen-binding site can be determined by the methods described in Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of proteins of immunological interest (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996). CDRs determined according to these definitions typically contain overlapping or subsets of amino acid residues when compared with each other. In certain embodiments, the term "CDR" refers to the CDR defined by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, in Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" refers to the CDR defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of proteins of immunological interest. (1991). In certain embodiments, the heavy chain CDRs and light chain CDRs of an antibody are defined using different rules. For example, in certain embodiments, heavy chain CDRs are defined according to MacCallum (supra) and light chain CDRs are defined according to Kabat (supra), with CDRH1, CDRH2, and CDRH3 representing the heavy chain CDRs and CDRL1, CDRL2, and CDRL3 representing the light chain CDRs.

[0183] As used herein, the terms "subject" and "patient" refer to an organism treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), but more preferably include humans.

[0184] As used herein, the term "effective amount" refers to an amount of a compound (e.g., a compound of the present invention) sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., such as alleviating, reducing, modulating, ameliorating, or eliminating, or ameliorating the symptoms thereof.

[0185] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier, which makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0186] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0187] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to a subject, can yield a compound of the present invention or its active metabolite or residue. As known to those skilled in the art, "salts" of the compounds of the present invention can be derived from inorganic or organic acids and bases. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0188] Exemplary bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of formula NW4 + wherein W is C 1~4 alkyl).

[0189] Exemplary salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. + , NH4 + , and NW4 + (Wherein W is C 1~4 Examples of suitable cations include the anions of the compounds of the present invention combined with suitable cations such as alkyl groups.

[0190] For therapeutic uses, the salts of the compounds of the invention are contemplated as pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0191] Throughout the description, when compositions are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0192] As a general matter, compositions specifying percentages are by weight unless otherwise specified. Furthermore, if a variable is not accompanied by a definition, the previous definition of that variable takes precedence.

[0193] Various features and aspects of the invention are discussed in more detail below.

[0194] I. Antigen binding site In certain embodiments, the invention provides antigen-binding sites comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:1, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:2. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 21, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 22, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 23. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 434, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 22, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 435. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 2 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 24, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 25, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 26.

[0195] In certain embodiments, the invention provides antigen-binding sites comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:3, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:4. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:3 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:27, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:28, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:29. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:3 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:181, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:28, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:436. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 4 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 30, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 31, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 32.

[0196] In certain embodiments, the invention provides antigen-binding sites comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:5, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:6. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:5 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:33, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:34, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:35. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:5 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:183, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:34, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:184. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 6 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 36, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 37, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 38.In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:6 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:36, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:185, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:38. In certain embodiments, the antigen-binding site comprises an amino acid sequence at least 90% (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO:188. In certain embodiments, the antigen-binding site comprises an amino acid sequence at least 95% identical to SEQ ID NO:188. In certain embodiments, the antigen-binding site comprises an amino acid sequence at least 99% identical to SEQ ID NO:188. In a specific embodiment, the antigen binding site comprises the amino acid sequence of SEQ ID NO:188.

[0197] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:7, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:8. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:7 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:39, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:40, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:41. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:7 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:437, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:40, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:438. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 8 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 42, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 43, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 44.

[0198] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:9, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:10. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:9 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:45, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:46, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:47. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:9 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:181, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:46, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:182. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 10 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 48, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 49, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 50. In certain embodiments, the antigen-binding site comprises an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 198.In certain embodiments, the antigen-binding site comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 198. In certain embodiments, the antigen-binding site comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 198. In certain embodiments, the antigen-binding site comprises the amino acid sequence of SEQ ID NO: 198.

[0199] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 12. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 51, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 52, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 53. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 181, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 52, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 439. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 12 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 54, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 55, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 56.

[0200] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 14. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 57, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 58, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 59. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 440, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 58, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 441. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 14 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 60, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 61, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 62.

[0201] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 16. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 63, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 64, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 65. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 442, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 64, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 443. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 16 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 66, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 67, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 68.

[0202] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 69, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 70, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 71. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 181, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 70, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 444. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 72, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 73, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 74.

[0203] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:20. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 75, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 76, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 77. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 445, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 76, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 446. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 20 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 78, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 79, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 80.

[0204] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 304, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 305, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 306. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 528, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 305, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 529. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 307, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 308, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 309.

[0205] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:268, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:269. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 310, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 311, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 312. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 530, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 311, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 531. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 269 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 313, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 314, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 315.

[0206] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 316, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 317, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 318. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 532, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 317, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 533. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 319, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 320, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 321.

[0207] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 322, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 323, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 324. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 534, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 323, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 535. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 325, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 326, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 327.

[0208] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 328, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 329, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 330. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 536, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 329, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 537. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 331, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 332, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 333.

[0209] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 334, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 335, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 336. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 538, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 335, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 539. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 337, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 338, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 339.

[0210] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:278, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:279. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 340, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 341, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 342. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 540, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 341, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 541. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 279 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 343, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 344, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 345.

[0211] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 346, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 347, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 348. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 542, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 347, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 543. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 349, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 350, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 351.

[0212] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 352, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 353, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 354. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 544, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 353, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 545. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 355, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 356, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 357.

[0213] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 358, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 359, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 360. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 546, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 359, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 547. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 361, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 362, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 363.

[0214] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 364, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 365, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 366. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 548, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 365, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 549. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 367, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 368, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 369.

[0215] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:288, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:289. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 370, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 371, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 372. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 550, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 371, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 551. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 289 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 373, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 374, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 375.

[0216] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 291. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 376, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 377, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 378. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 552, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 377, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 553. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 291 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 379, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 380, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 381.

[0217] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 293. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 382, ​​a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 383, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 384. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 554, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 383, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 555. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 293 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 385, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 386, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 387.

[0218] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 295. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 388, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 389, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 390. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 556, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 389, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 557. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 295 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 391, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 392, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 393.

[0219] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:296, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:297. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 394, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 395, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 396. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 558, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 395, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 559. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 297 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 397, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 398, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 399.

[0220] In certain embodiments, the invention provides antigen-binding sites comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:298, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:299. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 400, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 401, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 402. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 560, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 401, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 561. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 299 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 403, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 404, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 405.

[0221] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 406, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 407, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 408. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 562, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 407, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 563. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 409, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 410, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 411.

[0222] In certain embodiments, the invention provides an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302, and an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 412, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 413, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 414. In certain embodiments, an antigen-binding site comprising an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 564, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 413, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 565. In certain embodiments, an antigen-binding site comprising an antibody light chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303 comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 415, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 416, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO: 417.

[0223] In each of the foregoing embodiments, it is contemplated herein that the immunoglobulin heavy chain variable region sequences and / or light chain variable region sequences that together bind to CD33 may contain amino acid alterations (e.g., substitutions, deletions, or additions of at least 1, 2, 3, 4, 5, or 10 amino acids) in the framework regions of the heavy and / or light chain variable regions that do not significantly affect their ability to bind to CD33.

[0224] Table 1 lists peptide sequences of heavy and light chain variable domains that, in combination (as either Fab fragments or single-chain variable fragments (scFv)), can bind to CD33. Unless otherwise indicated, the CDR sequences listed in Table 1 are determined according to Kabat. CD33-binding domains can differ in their binding affinity to CD33. Table 1 also lists scFv forms of heavy and light chain variable domains that bind to CD33. The exemplary nucleic acid sequences listed in Table 1 are derived from the corresponding peptide sequences listed and were generated using the EMBL-EBI Protein Sequence Back-translation program. [Table 1] JPEG2024170430000003.jpg236170 JPEG2024170430000004.jpg228170 JPEG2024170430000005.jpg239170 JPEG2024170430000006.jpg222170 JPEG2024170430000007.jpg249170 JPEG2024170430000008.jpg246170 JPEG2024170430000009.jpg246170 JPEG2024170430000010.jpg240170 JPEG2024170430000011.jpg246170 JPEG2024170430000012.jpg234170 JPEG2024170430000013.jpg246170 JPEG2024170430000014.jpg228170 JPEG2024170430000015.jpg246170 JPEG2024170430000016.jpg240170 JPEG2024170430000017.jpg246170 JPEG2024170430000018.jpg234170 JPEG2024170430000019.jpg245170 JPEG2024170430000020.jpg228170 JPEG2024170430000021.jpg246170 JPEG2024170430000022.jpg245170 JPEG2024170430000023.jpg245170 JPEG2024170430000024.jpg240170 JPEG2024170430000025.jpg245170 JPEG2024170430000026.jpg234170 JPEG2024170430000027.jpg246170 JPEG2024170430000028.jpg228170 JPEG2024170430000029.jpg246170 JPEG2024170430000030.jpg234170 JPEG2024170430000031.jpg245170 JPEG2024170430000032.jpg234170 JPEG2024170430000033.jpg245170 JPEG2024170430000034.jpg234170 JPEG2024170430000035.jpg247170 JPEG2024170430000036.jpg228170 JPEG2024170430000037.jpg245170 JPEG2024170430000038.jpg240170 JPEG2024170430000039.jpg246170 JPEG2024170430000040.jpg228170 JPEG2024170430000041.jpg246170 JPEG2024170430000042.jpg240170 JPEG2024170430000043.jpg247170 JPEG2024170430000044.jpg240170 JPEG2024170430000045.jpg246170 JPEG2024170430000046.jpg240170 JPEG2024170430000047.jpg246170 JPEG2024170430000048.jpg234170 JPEG2024170430000049.jpg246170 JPEG2024170430000050.jpg234170 JPEG2024170430000051.jpg246170 JPEG2024170430000052.jpg234170 JPEG2024170430000053.jpg246170 JPEG2024170430000054.jpg240170 JPEG2024170430000055.jpg246170 JPEG2024170430000056.jpg234170 JPEG2024170430000057.jpg246170 JPEG2024170430000058.jpg240170 JPEG2024170430000059.jpg246170 JPEG2024170430000060.jpg211170 JPEG2024170430000061.jpg228170

[0225] Antigen-binding sites that bind epitopes on the extracellular domains of human CD33 and / or cynomolgus / rhesus (cyno) CD33 In one aspect, the present invention provides an antigen-binding site comprising a heavy chain variable domain that binds to an epitope on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33.

[0226] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 1]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 1. In some embodiments, the heavy chain variable domain comprises the amino acid sequence FTFSSYGMS [SEQ ID NO:21] of SEQ ID NO:1 as the first complementarity determining region 1 ("CDR1"), NIKQDGSEKYYVDSVKG [SEQ ID NO:22] as the second CDR ("CDR2"), and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO:23] as the third CDR ("CDR3"). In some embodiments, the heavy chain variable domain comprises the amino acid sequence SYGMS [SEQ ID NO:434] of SEQ ID NO:1 as the first complementarity determining region 1 ("CDR1"), NIKQDGSEKYYVDSVKG [SEQ ID NO:22] as the second CDR ("CDR2"), and EGGPYYDSSGYFVYYGMDV [SEQ ID NO:435] as the third CDR ("CDR3"). In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYESFPTFGGGTKVEIK [SEQ ID NO: 2]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 1 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 2 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 24] of SEQ ID NO: 2 as CDR1, DASSLES [SEQ ID NO: 25] as CDR2, and QQYESFPT [SEQ ID NO: 26] as CDR3 of SEQ ID NO: 2.

[0227] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 3]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 3, FTFSSYWMS [SEQ ID NO: 27] as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 28] as CDR2, and ARPLNAGELDV [SEQ ID NO: 29] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 3, SYWMS [SEQ ID NO: 181] as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 28] as CDR2, and PLNAGELDV [SEQ ID NO: 436] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQLESYPLTFGGGTKVEIK [SEQ ID NO: 4]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 4 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 30] as CDR1, EASSLES [SEQ ID NO: 31] as CDR2, and QQLESYPLT [SEQ ID NO: 32] as CDR3 of SEQ ID NO: 4.

[0228] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGFTFSKYTMSWVRQAPGKGLEWVSAIVGSGESTYFADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 5]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 5. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:5 FTFSKYTMS [SEQ ID NO:33] as CDR1, AIVGSGESTYFADSVKG [SEQ ID NO:34] as CDR2, and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO:35] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:5 KYTMS [SEQ ID NO:183] as CDR1, AIVGSGESTYFADSVKG [SEQ ID NO:34] as CDR2, and EGGPYYDSSGYFVYYGMDV [SEQ ID NO:184] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDDLPTFGGGTKVEIK [SEQ ID NO: 6]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 5 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 6 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 36] of SEQ ID NO: 6 as CDR1, KASSLES [SEQ ID NO: 37] or KASSLE [SEQ ID NO: 185] as CDR2, and QQYDDLPT [SEQ ID NO: 38] as CDR3.

[0229] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFSDYYMHWVRQAPGQGLEWMGMINPSWGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREAADGFVGERYFDLWGRGTLVTVSS [SEQ ID NO: 7]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 7. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:7 YTFSDYYMH [SEQ ID NO:39] as CDR1, MINPSWGSTSYAQKFQG [SEQ ID NO:40] as CDR2, and AREAADGFVGERYFDL [SEQ ID NO:41] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:7 DYYMH [SEQ ID NO:437] as CDR1, AIVGSGESTYFADSVKG [SEQ ID NO:34] as CDR2, and EAADGFVGERYFDL [SEQ ID NO:438] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:7, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 7 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIVMTQSPLSLPVTPGEPASISCRSSQSLLYSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQDVALPITFGGGTKVEIK [SEQ ID NO: 8]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 7 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 8 and comprises the amino acid sequence RSSQSLLYSNGYNYLD [SEQ ID NO: 42] of SEQ ID NO: 8 as CDR1, LGSNRAS [SEQ ID NO: 43] as CDR2, and MQDVALPIT [SEQ ID NO: 44] as CDR3 of SEQ ID NO: 8.

[0230] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFGSYWMSWVRQAPGKGLEWVATIKQDGSEKSYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 9]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 9. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:9 FTFGSYWMS [SEQ ID NO:45] as CDR1, TIKQDGSEKSYVDSVKG [SEQ ID NO:46] as CDR2, and ARPLNAGELDV [SEQ ID NO:47] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO:9 SYWMS [SEQ ID NO:181] as CDR1, TIKQDGSEKSYVDSVKG [SEQ ID NO:46] as CDR2, and RPLNAGELDV [SEQ ID NO:182] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:9, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSQSYPPITFGGGTKVEIK [SEQ ID NO: 10]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 9 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 10 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 48] of SEQ ID NO: 10 as CDR1, EASSLES [SEQ ID NO: 49] as CDR2, and QQSQSYPPIT [SEQ ID NO: 50] as CDR3.

[0231] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFPSYWMSWVRQAPGKGLEWVATIKRDGSEKGYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 11]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 11. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 11, FTFPSYWMS [SEQ ID NO: 51], as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52], as CDR2, and ARPLNAGELDV [SEQ ID NO: 53], as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 11, SYWMS [SEQ ID NO: 181], as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52], as CDR2, and PLNAGELDV [SEQ ID NO: 439], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSQSYPPITFGGGTKVEIK [SEQ ID NO: 12]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 12 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 54] of SEQ ID NO: 12 as CDR1, EASSLES [SEQ ID NO: 55] as CDR2, and QQSQSYPPIT [SEQ ID NO: 56] as CDR3.

[0232] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFGTYYMHWVRQAPGQGLEWMGIINPSRGSTVYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGAGYDDEDMDVWGKGTTVTVSS [SEQ ID NO: 13]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 13. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 13, YTFGTYYMH [SEQ ID NO: 57] as CDR1, IINPSRGSTVYAQKFQG [SEQ ID NO: 58] as CDR2, and ARGAGYDDEDMDV [SEQ ID NO: 59] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 13, TYYMH [SEQ ID NO: 440] as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52] as CDR2, and GAGYDDEDMDV [SEQ ID NO: 441] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGIDSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHSYPLTFGGGTKVEIK [SEQ ID NO: 14]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 13 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 14 and comprises the amino acid sequence RASQGIDSWLA [SEQ ID NO: 60] as CDR1, AASSLQS [SEQ ID NO: 61] as CDR2, and QQAHSYPLT [SEQ ID NO: 62] as CDR3 of SEQ ID NO: 14.

[0233] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSISSSSEGIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 15]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 15. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence FTFSSAMS [SEQ ID NO: 63] of SEQ ID NO: 15 as CDR1, SISSSSEGIYYADSVKG [SEQ ID NO: 64] as CDR2, and AREGGPYYDSSGYFVYYGMDV [SEQ ID NO: 65] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence SYAMS [SEQ ID NO: 442] of SEQ ID NO: 15 as CDR1, SISSSSEGIYYADSVKG [SEQ ID NO: 64] as CDR2, and EGGPYYDSSGYFVYYGMDV [SEQ ID NO: 443] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASNSISSWLAWYQQKPGKAPKLLIYEASSTKSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYDDLPTFGGGTKVEIK [SEQ ID NO: 16]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 15 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 16 and comprises the amino acid sequence RASNSISSWLA [SEQ ID NO: 66] of SEQ ID NO: 16 as CDR1, EASSTKS [SEQ ID NO: 67] as CDR2, and QQYDDLPT [SEQ ID NO: 68] as CDR3.

[0234] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANINTDGSEVYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDVGPGIAYQGHFDYWGQGTLVTVSS [SEQ ID NO: 17]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 17. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 17 FTFSSYWMS [SEQ ID NO: 69] as CDR1, NINTDGSEVYYVDSVKG [SEQ ID NO: 70] as CDR2, and ARDVGPGIAYQGHFDY [SEQ ID NO: 71] as CDR3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 17 SYWMS [SEQ ID NO: 181] as CDR1, NINTDGSEVYYVDSVKG [SEQ ID NO: 70] as CDR2, and DVGPGIAYQGHFDY [SEQ ID NO: 444] as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQVIYSYLNWYQQKPGKAPKLLIYAASSLKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYDTPLTFGGGTKVEIK [SEQ ID NO: 18]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 17 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 18 and comprises the amino acid sequence RASQVIYSYLN [SEQ ID NO: 72] as CDR1, AASSLKS [SEQ ID NO: 73] as CDR2, and QQVYDTPLT [SEQ ID NO: 74] as CDR3 of SEQ ID NO: 18.

[0235] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of QLQLQESGPGLVKPSETLSLTCTVSGGSISSTDYYWGWIRQPPGKGLEWIGSIGYSGTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARETAHDVHGMDVWGQGTTVTVSS [SEQ ID NO: 19]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 19. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence GSISSTDYYWG [SEQ ID NO:75] of SEQ ID NO: 19 as CDR1, SIGYSGTYYNPSLKS [SEQ ID NO:76] as CDR2, and ARETAHDVHGMDV [SEQ ID NO:77] as CDR3 of SEQ ID NO: 19. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence STDYYWG [SEQ ID NO:445] of SEQ ID NO: 19 as CDR1, SIGYSGTYYNPSLKS [SEQ ID NO:76] as CDR2, and ETAHDVHGMDV [SEQ ID NO:446] as CDR3 of SEQ ID NO: 19. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33.For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence EIVLTQSPATLSLSPGERATLSCRASHSVYSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYDNLPTFGGGTKVEIK [SEQ ID NO: 20]. In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 19 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 20 and comprises the amino acid sequence RASHSVYSYLA [SEQ ID NO: 78] as CDR1, DASNRAT [SEQ ID NO: 79] as CDR2, and QQYDNLPT [SEQ ID NO: 80] as CDR3 of SEQ ID NO: 20.

[0236] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:266. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:266. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:304 as CDR1, SEQ ID NO:305 as CDR2, and SEQ ID NO:306 as CDR3 of the amino acid sequence of SEQ ID NO:266. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:528 as CDR1, SEQ ID NO:305 as CDR2, and SEQ ID NO:529 as CDR3 of the amino acid sequence of SEQ ID NO:266. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 266 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 267 and comprises SEQ ID NO: 307 as CDR1, SEQ ID NO: 308 as CDR2, and SEQ ID NO: 309 as CDR3 of the amino acid sequence of SEQ ID NO: 267.

[0237] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:268. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:268. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:310 as CDR1, SEQ ID NO:311 as CDR2, and SEQ ID NO:312 as CDR3 of the amino acid sequence of SEQ ID NO:268. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:530 as CDR1, SEQ ID NO:311 as CDR2, and SEQ ID NO:531 as CDR3 of the amino acid sequence of SEQ ID NO:268. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 269.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 268 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 269 and comprises SEQ ID NO: 313 as CDR1, SEQ ID NO: 314 as CDR2, and SEQ ID NO: 315 as CDR3 of the amino acid sequence of SEQ ID NO: 269.

[0238] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:270. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:270. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:316 as CDR1, SEQ ID NO:317 as CDR2, and SEQ ID NO:318 as CDR3 of the amino acid sequence of SEQ ID NO:270. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:532 as CDR1, SEQ ID NO:317 as CDR2, and SEQ ID NO:533 as CDR3 of the amino acid sequence of SEQ ID NO:270. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 270 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 271 and comprises SEQ ID NO: 319 as CDR1, SEQ ID NO: 320 as CDR2, and SEQ ID NO: 321 as CDR3 of the amino acid sequence of SEQ ID NO: 271.

[0239] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:272. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:272. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:322 as CDR1, SEQ ID NO:323 as CDR2, and SEQ ID NO:324 as CDR3 of the amino acid sequence of SEQ ID NO:272. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:534 as CDR1, SEQ ID NO:323 as CDR2, and SEQ ID NO:535 as CDR3 of the amino acid sequence of SEQ ID NO:272. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 272 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 273 and comprises SEQ ID NO: 325 as CDR1, SEQ ID NO: 326 as CDR2, and SEQ ID NO: 327 as CDR3 of the amino acid sequence of SEQ ID NO: 273.

[0240] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:274. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:274. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:328 as CDR1, SEQ ID NO:329 as CDR2, and SEQ ID NO:330 as CDR3 of the amino acid sequence of SEQ ID NO:274. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:536 as CDR1, SEQ ID NO:329 as CDR2, and SEQ ID NO:537 as CDR3 of the amino acid sequence of SEQ ID NO:274. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 274 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 275 and comprises SEQ ID NO: 331 as CDR1, SEQ ID NO: 332 as CDR2, and SEQ ID NO: 333 as CDR3 of the amino acid sequence of SEQ ID NO: 275.

[0241] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:276. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:276. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:334 as CDR1, SEQ ID NO:335 as CDR2, and SEQ ID NO:336 as CDR3 of the amino acid sequence of SEQ ID NO:276. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:538 as CDR1, SEQ ID NO:335 as CDR2, and SEQ ID NO:539 as CDR3 of the amino acid sequence of SEQ ID NO:276. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 276 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 277 and comprises SEQ ID NO: 337 as CDR1, SEQ ID NO: 338 as CDR2, and SEQ ID NO: 339 as CDR3 of the amino acid sequence of SEQ ID NO: 277.

[0242] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:278. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:278. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:340 as CDR1, SEQ ID NO:341 as CDR2, and SEQ ID NO:342 as CDR3 of the amino acid sequence of SEQ ID NO:278. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:540 as CDR1, SEQ ID NO:341 as CDR2, and SEQ ID NO:541 as CDR3 of the amino acid sequence of SEQ ID NO:278. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 279.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 278 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 279 and comprises SEQ ID NO: 343 as CDR1, SEQ ID NO: 344 as CDR2, and SEQ ID NO: 345 as CDR3 of the amino acid sequence of SEQ ID NO: 279.

[0243] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:280. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:280. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:346 as CDR1, SEQ ID NO:347 as CDR2, and SEQ ID NO:348 as CDR3 of the amino acid sequence of SEQ ID NO:280. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:542 as CDR1, SEQ ID NO:347 as CDR2, and SEQ ID NO:543 as CDR3 of the amino acid sequence of SEQ ID NO:280. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 280 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 281 and comprises SEQ ID NO: 349 as CDR1, SEQ ID NO: 350 as CDR2, and SEQ ID NO: 351 as CDR3 of the amino acid sequence of SEQ ID NO: 281.

[0244] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:282. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:282. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:352 as CDR1, SEQ ID NO:353 as CDR2, and SEQ ID NO:354 as CDR3 of the amino acid sequence of SEQ ID NO:282. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:544 as CDR1, SEQ ID NO:353 as CDR2, and SEQ ID NO:545 as CDR3 of the amino acid sequence of SEQ ID NO:282. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 282 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 283 and comprises SEQ ID NO: 355 as CDR1, SEQ ID NO: 356 as CDR2, and SEQ ID NO: 357 as CDR3 of the amino acid sequence of SEQ ID NO: 283.

[0245] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:284. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:284. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:358 as CDR1, SEQ ID NO:359 as CDR2, and SEQ ID NO:360 as CDR3 of the amino acid sequence of SEQ ID NO:284. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:546 as CDR1, SEQ ID NO:359 as CDR2, and SEQ ID NO:360 as CDR3 of the amino acid sequence of SEQ ID NO:547. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 284 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 285 and comprises SEQ ID NO: 361 as CDR1, SEQ ID NO: 362 as CDR2, and SEQ ID NO: 363 as CDR3 of the amino acid sequence of SEQ ID NO: 285.

[0246] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:286. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:286. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:364 as CDR1, SEQ ID NO:365 as CDR2, and SEQ ID NO:366 as CDR3 of the amino acid sequence of SEQ ID NO:286. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:548 as CDR1, SEQ ID NO:365 as CDR2, and SEQ ID NO:549 as CDR3 of the amino acid sequence of SEQ ID NO:286. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 286 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 287 and comprises SEQ ID NO: 367 as CDR1, SEQ ID NO: 368 as CDR2, and SEQ ID NO: 369 as CDR3 of the amino acid sequence of SEQ ID NO: 287.

[0247] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:288. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:288. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:370 as CDR1, SEQ ID NO:371 as CDR2, and SEQ ID NO:372 as CDR3 of the amino acid sequence of SEQ ID NO:288. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:550 as CDR1, SEQ ID NO:371 as CDR2, and SEQ ID NO:551 as CDR3 of the amino acid sequence of SEQ ID NO:288. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 289.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 288 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 289 and comprises SEQ ID NO: 373 as CDR1, SEQ ID NO: 374 as CDR2, and SEQ ID NO: 375 as CDR3 of the amino acid sequence of SEQ ID NO: 289.

[0248] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:290. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:290. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:376 as CDR1, SEQ ID NO:377 as CDR2, and SEQ ID NO:378 as CDR3 of the amino acid sequence of SEQ ID NO:290. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:552 as CDR1, SEQ ID NO:377 as CDR2, and SEQ ID NO:553 as CDR3 of the amino acid sequence of SEQ ID NO:290. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 291.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 290 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 291 and comprises SEQ ID NO: 379 as CDR1, SEQ ID NO: 380 as CDR2, and SEQ ID NO: 381 as CDR3 of the amino acid sequence of SEQ ID NO: 291.

[0249] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:292. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:292. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:382 as CDR1, SEQ ID NO:383 as CDR2, and SEQ ID NO:384 as CDR3 of the amino acid sequence of SEQ ID NO:292. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:554 as CDR1, SEQ ID NO:383 as CDR2, and SEQ ID NO:555 as CDR3 of the amino acid sequence of SEQ ID NO:292. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 293.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 292 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 293 and comprises SEQ ID NO: 385 as CDR1, SEQ ID NO: 386 as CDR2, and SEQ ID NO: 387 as CDR3 of the amino acid sequence of SEQ ID NO: 293.

[0250] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:294. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:294. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:388 as CDR1, SEQ ID NO:389 as CDR2, and SEQ ID NO:390 as CDR3 of the amino acid sequence of SEQ ID NO:294. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:556 as CDR1, SEQ ID NO:389 as CDR2, and SEQ ID NO:557 as CDR3 of the amino acid sequence of SEQ ID NO:294. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 295.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 294 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 295 and comprises SEQ ID NO: 391 as CDR1, SEQ ID NO: 392 as CDR2, and SEQ ID NO: 393 as CDR3 of the amino acid sequence of SEQ ID NO: 295.

[0251] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:296. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:296. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:394 as CDR1, SEQ ID NO:395 as CDR2, and SEQ ID NO:396 as CDR3 of the amino acid sequence of SEQ ID NO:296. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:558 as CDR1, SEQ ID NO:395 as CDR2, and SEQ ID NO:559 as CDR3 of the amino acid sequence of SEQ ID NO:296. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 297.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 296 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 297 and comprises SEQ ID NO: 397 as CDR1, SEQ ID NO: 398 as CDR2, and SEQ ID NO: 399 as CDR3 of the amino acid sequence of SEQ ID NO: 297.

[0252] In certain embodiments, the invention provides antigen-binding sites that bind to epitopes on the extracellular domains of human CD33 and cynomolgus / rhesus (cyno) CD33, wherein the antigen-binding sites comprise a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO:298. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO:298. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:400 as CDR1, SEQ ID NO:401 as CDR2, and SEQ ID NO:402 as CDR3 of the amino acid sequence of SEQ ID NO:298. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO:560 as CDR1, SEQ ID NO:401 as CDR2, and SEQ ID NO:561 as CDR3 of the amino acid sequence of SEQ ID NO:298. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 299.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 298 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 299 and comprises SEQ ID NO: 403 as CDR1, SEQ ID NO: 404 as CDR2, and SEQ ID NO: 405 as CDR3 of the amino acid sequence of SEQ ID NO: 299.

[0253] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 300. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO: 406 as CDR1, SEQ ID NO: 407 as CDR2, and SEQ ID NO: 408 as CDR3 of the amino acid sequence of SEQ ID NO: 300. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO: 562 as CDR1, SEQ ID NO: 407 as CDR2, and SEQ ID NO: 563 as CDR3 of the amino acid sequence of SEQ ID NO: 300. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 300 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 301 and comprises SEQ ID NO: 409 as CDR1, SEQ ID NO: 410 as CDR2, and SEQ ID NO: 411 as CDR3 of the amino acid sequence of SEQ ID NO: 301.

[0254] In certain embodiments, the invention provides an antigen-binding site that binds to an epitope on the extracellular domain of human CD33, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 302. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO: 412 as CDR1, SEQ ID NO: 413 as CDR2, and SEQ ID NO: 414 as CDR3 of the amino acid sequence of SEQ ID NO: 302. In some embodiments, the heavy chain variable domain incorporates SEQ ID NO: 564 as CDR1, SEQ ID NO: 413 as CDR2, and SEQ ID NO: 565 as CDR3 of the amino acid sequence of SEQ ID NO: 302. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302, in combination with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 can be paired with an antibody light chain variable domain at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303.In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 302 can be paired with an antibody light chain variable domain that is at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 303 and comprises SEQ ID NO: 415 as CDR1, SEQ ID NO: 416 as CDR2, and SEQ ID NO: 417 as CDR3 of the amino acid sequence of SEQ ID NO: 303.

[0255] Antigen-binding sites that recognize and bind conformational epitopes on the extracellular domains of human CD33 and / or cynomolgus / rhesus (cyno) CD33. In one aspect, the present invention provides antigen-binding sites comprising a heavy chain variable domain that recognizes and binds one or more conformational epitopes on the extracellular domain of human CD33 and / or cynomolgus / rhesus (cyno) CD33.

[0256] In certain embodiments, the invention provides antigen-binding sites that recognize and bind to a conformational epitope located in part in the V domain of the human CD33 extracellular domain, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 3]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 3. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 3, FTFSSYWMS [SEQ ID NO: 27], as CDR1, NIKQDGSEKYYVDSVKG [SEQ ID NO: 28], as CDR2, and ARPLNAGELDV [SEQ ID NO: 29], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQLESYPLTFGGGTKVEIK [SEQ ID NO: 4].In certain embodiments, an antibody heavy chain variable domain that is 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 3 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 4 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 30] as CDR1, EASSLES [SEQ ID NO: 31] as CDR2, and QQLESYPLT [SEQ ID NO: 32] as CDR3 of SEQ ID NO: 4.

[0257] In certain embodiments, the invention provides antigen-binding sites that recognize and bind to a conformational epitope located in part in the V domain of the human CD33 extracellular domain, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFPSYWMSWVRQAPGKGLEWVATIKRDGSEKGYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARPLNAGELDVWGQGTMVTVSS [SEQ ID NO: 11]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to SEQ ID NO: 11. In some embodiments, the heavy chain variable domain incorporates the amino acid sequence of SEQ ID NO: 11, FTFPSYWMS [SEQ ID NO: 51], as CDR1, TIKRDGSEKGYVDSVKG [SEQ ID NO: 52], as CDR2, and ARPLNAGELDV [SEQ ID NO: 53], as CDR3. In certain embodiments, an antibody heavy chain variable domain comprising an amino acid sequence at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11, together with a light chain variable domain, forms an antigen-binding site capable of binding to CD33. For example, an antibody heavy chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSQSYPPITFGGGTKVEIK [SEQ ID NO: 12].In certain embodiments, an antibody heavy chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 11 can be paired with an antibody light chain variable domain that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of SEQ ID NO: 12 and comprises the amino acid sequence RASQSISSWLA [SEQ ID NO: 54] of SEQ ID NO: 12 as CDR1, EASSLES [SEQ ID NO: 55] as CDR2, and QQSQSYPPIT [SEQ ID NO: 56] as CDR3.

[0258] In certain embodiments, the invention provides antigen-binding sites that recognize and bind to a conformational epitope located in part in the V domain of the human CD33 extracellular domain, wherein the antigen-binding site comprises a heavy chain variable domain comprising an amino acid sequence that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to the amino acid sequence of EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSISSSSEGIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGPYYDSSGYFVYYGMDVWGQGTTVTVSS [SEQ ID NO: 15]. In some embodiments, the antibody heavy chain variable domain is at least 95% identical to S...

Claims

1. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

9.

2. 2. The antibody heavy chain variable domain of claim 1, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 45, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 46, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

47.

3. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

1.

4. 4. The antibody heavy chain variable domain of claim 3, wherein the amino acid sequence comprises a complementarity determining region 1 (CDR1) sequence represented by the amino acid sequence of SEQ ID NO: 21, a complementarity determining region 2 (CDR2) sequence represented by the amino acid sequence of SEQ ID NO: 22, and a complementarity determining region 3 (CDR3) sequence represented by the amino acid sequence of SEQ ID NO:

23.

5. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

3.

6. 6. The antibody heavy chain variable domain of claim 5, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:27, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:28, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

29.

7. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

5.

8. 8. The antibody heavy chain variable domain of claim 7, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 33, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 34, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

35.

9. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

7.

10. 10. The antibody heavy chain variable domain of claim 9, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 39, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 40, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

41.

11. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

11.

12. 12. The antibody heavy chain variable domain of claim 11 , wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:51, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:52, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

53.

13. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

13.

14. 14. The antibody heavy chain variable domain of claim 13, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:57, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:58, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

59.

15. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

15.

16. 16. The antibody heavy chain variable domain of claim 15, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:63, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:64, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

65.

17. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

17.

18. 18. The antibody heavy chain variable domain of claim 17, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:69, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:70, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

71.

19. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

19.

20. 20. The antibody heavy chain variable domain of claim 19, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO: 75, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO: 76, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

77.

21. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

266.

22. 22. The antibody heavy chain variable domain of claim 21 , wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:528, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:305, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

529.

23. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

268.

24. 24. The antibody heavy chain variable domain of claim 23, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:530, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:311, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

531.

25. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

270.

26. 26. The antibody heavy chain variable domain of claim 25, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:532, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:317, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

533.

27. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

272.

28. 28. The antibody heavy chain variable domain of claim 27, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:534, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:323, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

535.

29. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

274.

30. 30. The antibody heavy chain variable domain of claim 29, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:536, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:329, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

537.

31. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

276.

32. 32. The antibody heavy chain variable domain of claim 31 , wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:538, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:335, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

539.

33. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

278.

34. 34. The antibody heavy chain variable domain of claim 33, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:540, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:341, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

541.

35. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

280.

36. 36. The antibody heavy chain variable domain of claim 35, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:542, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:347, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

543.

37. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

282.

38. 38. The antibody heavy chain variable domain of claim 37, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:544, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:353, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

545.

39. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

284.

40. 40. The antibody heavy chain variable domain of claim 39, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:546, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:359, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

547.

41. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

286.

42. 42. The antibody heavy chain variable domain of claim 41 , wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:548, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:365, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

549.

43. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

288.

44. 44. The antibody heavy chain variable domain of claim 43, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:550, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:371, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

551.

45. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

290.

46. 46. ​​The antibody heavy chain variable domain of claim 45, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:552, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:377, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

553.

47. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

292.

48. 48. The antibody heavy chain variable domain of claim 47, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:554, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:383, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

555.

49. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

294.

50. 50. The antibody heavy chain variable domain of claim 49, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:556, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:389, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

557.

51. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

296.

52. 52. The antibody heavy chain variable domain of claim 51 , wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:558, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:395, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

559.

53. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

298.

54. 54. The antibody heavy chain variable domain of claim 53, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:560, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:401, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

561.

55. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

300.

56. 56. The antibody heavy chain variable domain of claim 55, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:562, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:407, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

563.

57. An antibody heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

302.

58. 58. The antibody heavy chain variable domain of claim 57, wherein the amino acid sequence comprises a CDR1 sequence represented by the amino acid sequence of SEQ ID NO:564, a CDR2 sequence represented by the amino acid sequence of SEQ ID NO:413, and a CDR3 sequence represented by the amino acid sequence of SEQ ID NO:

565.

59. An antibody heavy chain comprising an antibody heavy chain variable domain according to any one of claims 1 to 58 and an amino acid sequence which is at least 90% identical to an antibody constant region.

60. 60. The antibody heavy chain of claim 59, wherein the antibody constant region is a human IgG constant region comprising hinge, CH2, and CH3 domains.

61. The antibody heavy chain of claim 60, wherein the antibody constant region is a human IgG constant region further comprising a CH1 domain.

62. The antibody heavy chain of any one of claims 59 to 61, wherein the antibody constant region is an IgG1 constant region.

63. 63. The antibody heavy chain of claim 62, wherein the amino acid sequence that is at least 90% identical to an antibody constant region differs from the amino acid sequence of an IgG1 constant region at one or more positions selected from the group consisting of Q347, Y349, L351, S354, E356, E357, K360, Q362, S364, T366, L368, K370, N390, K392, T394, D399, S400, D401, F405, Y407, K409, T411, and K439.

64. The amino acid sequence having at least 90% identity to an antibody constant region is selected from the group consisting of Q347E, Q347R, Y349S, Y349K, Y349T, Y349D, Y349E, Y349C, L351K, L351D, L351Y, S354C, E356K, E357Q, E357L, E357W, K360E, K360W, Q362E, S364K, S364E, S364H, S364D, T366V, T366I, T366L, T366M, T366K, T366W, T366S, L368E, L368A, L368C, L368D, L368E, L368F, L368G, L368H, L368I, L368H ...

64. The antibody heavy chain of claim 63, which differs from the amino acid sequence of the IgG1 constant region by one or more substitutions selected from the group consisting of: 8D, K370S, N390D, N390E, K392L, K392M, K392V, K392F, K392D, K392E, T394F, D399R, D399K, D399V, S400K, S400R, D401K, F405A, F405T, Y407A, Y407I, Y407V, K409F, K409W, K409D, T411D, T411E, K439D, and K439E.

65. 3. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 1 or 2 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

10.

66. 66. An antigen-binding site according to claim 65, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 48, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 49, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

50.

67. 5. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 3 or 4 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

2.

68. 68. An antigen-binding site according to claim 67, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 24, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 25, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

26.

69. 7. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 5 or 6 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

4.

70. 70. An antigen-binding site according to claim 69, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 30, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 31, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

32.

71. 9. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 7 or 8 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

6.

72. 72. An antigen-binding site according to claim 71 , wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 36, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 37, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

38.

73. 11. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 9 or 10 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

8.

74. 74. An antigen-binding site according to claim 73, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 42, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 43, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

44.

75. 13. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 11 or 12 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

12.

76. 76. An antigen-binding site according to claim 75, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO:54, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO:55, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

56.

77. 15. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 13 or 14 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

14.

78. 78. An antigen-binding site according to claim 77, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 60, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 61, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

62.

79. 17. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 15 or 16 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

16.

80. 80. An antigen-binding site according to claim 79, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 66, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 67, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

68.

81. 19. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 17 or 18 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

18.

82. 82. An antigen-binding site according to claim 81 , wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 72, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 73, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

74.

83. 21. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 19 or 20 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

20.

84. 84. An antigen-binding site according to claim 83, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 78, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 79, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

80.

85. 23. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 21 or 22 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

267.

86. 86. An antigen-binding site according to claim 85, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 307, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 308, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

309.

87. 25. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 23 or 24 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

269.

88. 88. An antigen-binding site according to claim 87, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 313, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 314, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

315.

89. 27. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 25 or 26 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

271.

90. 90. An antigen-binding site according to claim 89, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 319, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 320, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

321.

91. 29. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 27 or 28 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

273.

92. 92. An antigen-binding site according to claim 91 , wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 325, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 326, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

327.

93. 31. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 29 or 30 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

275.

94. 94. An antigen-binding site according to claim 93, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 331, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 332, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

333.

95. 33. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 31 or 32 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

277.

96. 96. An antigen-binding site according to claim 95, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 337, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 338, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

339.

97. 35. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 33 or 34 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

279.

98. 98. An antigen-binding site according to claim 97, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 343, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 344, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

345.

99. 37. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 35 or 36 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

281.

100. 100. An antigen-binding site according to claim 99, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 349, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 350, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

351.

101. 39. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 37 or 38 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

283.

102. 102. An antigen-binding site according to claim 101, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 355, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 356, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

357.

103. 41. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 39 or 40 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

285.

104. 104. An antigen-binding site according to claim 103, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 361, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 362, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

363.

105. 43. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 41 or 42 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

287.

106. 106. An antigen-binding site according to claim 105, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 367, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 368, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

369.

107. 45. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 43 or 44 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

289.

108. 108. An antigen-binding site according to claim 107, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 373, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 374, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

375.

109. 47. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 45 or 46 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

291.

110. 110. An antigen-binding site according to claim 109, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 379, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 380, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

381.

111. 49. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 47 or 48 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

293.

112. 112. An antigen-binding site according to claim 111, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 385, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 386, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

387.

113. 51. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 49 or 50 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

295.

114. 114. An antigen-binding site according to claim 113, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 391, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 392, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

393.

115. 53. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 51 or 52 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

297.

116. 116. An antigen-binding site according to claim 115, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 397, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 398, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

399.

117. 55. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 53 or 54 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

299.

118. 118. An antigen-binding site according to claim 117, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 403, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 404, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

405.

119. 57. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 55 or 56 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

301.

120. 120. An antigen-binding site according to claim 119, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 409, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 410, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

411.

121. 60. An antigen-binding site comprising an antibody heavy chain variable domain according to claim 57 or 58 and an antibody light chain variable domain comprising an amino acid sequence which is at least 90% identical to SEQ ID NO:

303.

122. 122. An antigen-binding site according to claim 121, wherein the light chain variable domain comprises a CDR1 sequence identical to the amino acid sequence of SEQ ID NO: 415, a CDR2 sequence identical to the amino acid sequence of SEQ ID NO: 416, and a CDR3 sequence identical to the amino acid sequence of SEQ ID NO:

417.

123. A protein comprising an antigen-binding site according to any one of claims 65 to 122, wherein the antigen-binding site binds to human CD33.

124. The protein of claim 123, wherein the protein further comprises a second antigen binding site that is the same as or different from the antigen binding site that binds to human CD33.

125. 125. The protein of claim 123 or 124, further comprising an antibody constant region.

126. The protein of claim 125, wherein the antibody constant region is capable of binding to CD16 and comprises two polypeptide chains, each of which comprises a hinge, a CH2 and a CH3 domain.

127. 127. The protein of claim 125 or 126, wherein each of the two polypeptide chains of the antibody constant region comprises an amino acid sequence that is at least 90% identical to a human IgG1 constant region.

128. the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region at one or more positions selected from the group consisting of Q347, Y349, L351, S354, E356, E357, K360, Q362, S364, T366, L368, K370, K392, T394, D399, S400, D401, F405, Y407, K409, T411 and K439, 128. The protein of claim 127, wherein the amino acid sequence of the other polypeptide chain of the IgG1 constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Q347, Y349, L351, S354, E356, E357, S364, T366, L368, K370, N390, K392, T394, D399, D401, F405, Y407, K409, T411 and K439.

129. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at position T366 and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of T366, L368 and Y407.

130. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region at one or more positions selected from the group consisting of T366, L368 and Y407, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region at position T366.

131. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of E357, K360, Q362, S364, L368, K370, T394, D401, F405, and T411, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Y349, E357, S364, L368, K370, T394, D401, F405, and T411.

132. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Y349, E357, S364, L368, K370, T394, D401, F405 and T411, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of E357, K360, Q362, S364, L368, K370, T394, D401, F405 and T411.

133. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of L351, D399, S400 and Y407, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of T366, N390, K392, K409 and T411.

134. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of T366, N390, K392, K409 and T411, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of L351, D399, S400 and Y407.

135. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Q347, Y349, K360, and K409, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Q347, E357, D399, and F405.

136. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Q347, E357, D399 and F405, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Y349, K360, Q347 and K409.

137. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of K370, K392, K409 and K439, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of D356, E357 and D399.

138. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of D356, E357, and D399, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of K370, K392, K409, and K439.

139. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of L351, E356, T366 and D399, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Y349, L351, L368, K392 and K409.

140. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of Y349, L351, L368, K392 and K409, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region at one or more positions selected from the group consisting of L351, E356, T366 and D399.

141. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in an S354C substitution and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in an Y349C substitution.

142. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in a Y349C substitution and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in a S354C substitution.

143. 128. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region by K360E and K409W substitutions, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region by O347R, D399V and F405T substitutions.

144. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region by O347R, D399V and F405T substitutions, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region by K360E and K409W substitutions.

145. 128. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in a T366W substitution and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in a T366S, T368A, and Y407V substitution.

146. 128. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in the following substitutions: T366S, T368A, and Y407V, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of the IgG1 constant region in the following substitution: T366W.

147. 128. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region in the following substitutions: T350V, L351Y, F405A, and Y407V, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region in the following substitutions: T350V, T366L, K392L, and T394W.

148. 128. The protein of claim 127, wherein the amino acid sequence of one polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region in the following substitutions: T350V, T366L, K392L, and T394W, and the amino acid sequence of the other polypeptide chain of the antibody constant region differs from the amino acid sequence of an IgG1 constant region in the following substitutions: T350V, L351Y, F405A, and Y407V.

149. For binding to human and cynomolgus monkey CD33, SEQ ID NOs: 1 and 2, 3 and 4, 5 and 6, 7 and 8, 9 and 10, 11 and 12, 13 and 14, 15 and 16, 17 and 18, 19 and 20, 266 and 267, 268 and 269, 270 and 271, 272 and 273, 274 and 275, 276 and 277, 278 and 279, 280 and 281, 282 and 283, 2 and 283, 284 and 285, 286 and 287, 288 and 289, 290 and 291, 292 and 293, 294 and 295, 296 and 297, 298 and 299, 300 and 301, or 302 and 303, respectively.

150. A formulation comprising a protein according to any one of claims 123 to 149 and a pharma- ceutically acceptable carrier.

151. 1. An isolated nucleic acid encoding a chimeric antigen receptor (CAR), comprising: a nucleic acid sequence encoding a CD33-binding scFv comprising a sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484; a nucleic acid sequence encoding a transmembrane domain; and a nucleic acid sequence encoding an intracellular signaling domain.

152. 1. An isolated nucleic acid encoding a chimeric antigen receptor (CAR), comprising: a nucleic acid sequence encoding a CD33-binding scFv comprising a sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484; a nucleic acid sequence encoding a transmembrane domain; and a nucleic acid sequence encoding an intracellular signaling domain.

153. 1. An isolated nucleic acid encoding a chimeric antigen receptor (CAR), comprising: a nucleic acid sequence encoding a CD33-binding scFv comprising a sequence that is at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484; a nucleic acid sequence encoding a transmembrane domain; and a nucleic acid sequence encoding an intracellular signaling domain.

154. 154. The isolated nucleic acid sequence of any one of claims 151 to 153, wherein said transmembrane domain is selected from the transmembrane regions of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD152, and CD154.

155. 155. The isolated nucleic acid of any one of claims 151 to 154, wherein the CD33 binding scFv is connected to the transmembrane domain by a hinge region.

156. 156. The isolated nucleic acid of any one of claims 151-155, wherein the intracellular signaling domain comprises a primary signaling domain comprising the functional signaling domains of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12.

157. 157. The isolated nucleic acid of any one of claims 151-156, wherein the intracellular signaling domain further comprises a costimulatory signaling domain, comprising a functional signaling domain of a costimulatory receptor.

158. 158. The isolated nucleic acid of claim 157, wherein the costimulatory receptor is selected from the group consisting of OX40, CD27, CD28, CD30, CD40, PD-1, CD2, CD7, CD258, NKG2C, B7-H3, a ligand that binds to CD83, ICAM-1, LFA-1 (CD11a / CD18), ICOS and 4-1BB (CD137), or any combination thereof.

159. An expression vector comprising the isolated nucleic acid of any one of claims 111 to 118.

160. A chimeric antigen receptor (CAR), comprising: a CD33-binding scFv comprising an amino acid sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484; a transmembrane domain; and an intracellular signaling domain.

161. The CAR of claim 160, wherein the transmembrane domain is selected from the transmembrane regions of the alpha, beta or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD152, and CD154.

162. The CAR of claim 160 or 161, wherein the CD33 binding scFv is connected to the transmembrane domain by a hinge region.

163. The CAR of any one of claims 160 to 162, wherein the intracellular signaling domain comprises a primary signaling domain comprising a functional signaling domain of CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD79a, CD79b, DAP10, and DAP12.

164. The CAR of any one of claims 160 to 163, wherein the intracellular signaling domain further comprises a costimulatory signaling domain comprising a functional signaling domain of a costimulatory receptor.

165. The CAR of claim 164, wherein the costimulatory receptor is selected from the group consisting of OX40, CD27, CD28, CD30, CD40, PD-1, CD2, CD7, CD258, NKG2C, B7-H3, a ligand that binds to CD83, ICAM-1, LFA-1 (CD11a / CD18), ICOS, and 4-1BB (CD137), or any combination thereof.

166. An immune effector cell comprising a nucleic acid according to any one of claims 151 to 158.

167. An immune effector cell comprising the vector described in claim 159.

168. An immune effector cell expressing the CAR of any one of claims 160 to 165.

169. The immune effector cell of any one of claims 166 to 168, wherein the immune effector cell is a T cell.

170. The T cell is CD8 ＋ T cells, CD4 ＋ The immune effector cell of claim 169, which is a T cell or a NKT cell.

171. The immune effector cell of any one of claims 166 to 168, wherein the immune effector cell is a NK cell.

172. A CD33 / CD3-directed bispecific T cell engager comprising a protein comprising a sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

173. A CD33 / CD3-directed bispecific T cell engager comprising a protein comprising a sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

174. A CD33 / CD3-directed bispecific T cell engager comprising a protein comprising a sequence that is at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

175. 175. An isolated nucleic acid encoding a CD33 / CD3-directed bispecific T cell engager according to any one of claims 172 to 174.

176. An antibody-drug conjugate comprising a protein comprising a sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

177. An antibody-drug conjugate comprising a protein comprising a sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

178. An antibody-drug conjugate comprising a protein comprising a sequence that is at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484.

179. 179. The antibody-drug conjugate of any one of claims 176 to 178, further comprising a drug moiety selected from an auristatin, an N-acetyl-calicheamicin gamma, a maytansinoid, a pyrrolobenzodiazepine, and SN-38.

180. An immunocytokine comprising a sequence that is at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484 connected to the cytokine.

181. An immunocytokine comprising a sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484 connected to the cytokine.

182. An immunocytokine comprising a sequence that is at least 99% identical to an amino acid sequence selected from SEQ ID NOs: 188, 198, 206-223, and 447-484 connected to the cytokine.

183. The immunocytokine of any one of claims 170 to 172, wherein the cytokine is selected from IL-2, IL-4, IL-10, IL-12, IL-15, TNF, and IFNα.

184. An isolated nucleic acid encoding an immunocytokine according to any one of claims 170 to 173.

185. 174. A method of treating a CD33 expressing cancer comprising administering to a subject in need thereof an effective amount of a protein according to any one of claims 123-149, a formulation according to claim 150, an immune effector cell according to any one of claims 166-171, a CD33 / CD3-directed bispecific T cell engager according to any one of claims 172-174, an antibody-drug conjugate according to any one of claims 176-179, or an immunocytokine according to any one of claims 180-183.

186. The method of claim 185, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CML), myeloid blast crisis of CML, acute lymphoblastic leukemia (ALL), acute lymphoblastic lymphoma, myeloproliferative neoplasms (MPN), lymphoma, non-Hodgkin's lymphoma, and classical Hodgkin's lymphoma.

187. The method of claim 186, wherein the AML is selected from undifferentiated acute myeloblastic leukemia, minimally differentiated acute myeloblastic leukemia, differentiated acute myeloblastic leukemia, acute promyelocytic leukemia (APL), acute myelomonocytic leukemia, acute myelomonocytic leukemia with eosinophilia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia (AMKL), acute basophilic leukemia, acute panmyelosis with fibrosis, and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

188. The method of claim 186 or 187, wherein the AML is characterized by expression of CLL-1 on AML leukemic stem cells (LSCs).

189. The method of claim 188, wherein the LSCs further express a cell membrane marker selected from CD34, CD38, CD123, TIM3, CD25, CD32, and CD96.

190. The method of any one of claims 186 to 189, wherein the AML is minimal residual disease (MRD).

191. 191. The method of claim 190, wherein the MRD is characterized by the presence or absence of a mutation selected from FLT3-ITD ((Fms-like tyrosine kinase 3)-internal tandem duplication (ITD)), NPM1 (nucleophosmin 1), DNMT3A (DNA methyltransferase gene DNMT3A), and IDH (isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2)).

192. 187. The method of claim 186, wherein the MDS is selected from MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with ringed sideroblasts (MDS-RS), MDS with excess blasts (MDS-EB), MDS with isolated chromosomal abnormality del(5q), and unclassified MDS (MDS-U).

193. The method of claim 186 or 192, wherein the MDS is primary MDS or secondary MDS.

194. 187. The method of claim 186, wherein the ALL is selected from B-cell acute lymphoblastic leukemia (B-ALL) and T-cell acute lymphoblastic leukemia (T-ALL).

195. 187. The method of claim 186, wherein the MPN is selected from polycythemia vera, essential thrombocythemia (ET), and myelofibrosis.

196. 187. The method of claim 186, wherein the non-Hodgkin's lymphoma is selected from B cell lymphoma and T cell lymphoma.

197. The method of claim 186, wherein the lymphoma is selected from chronic lymphocytic leukemia (CLL), lymphoblastic lymphoma (LPL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), primary mediastinal large B-cell lymphoma (PMBL), follicular lymphoma, mantle cell lymphoma, hairy cell leukemia, plasma cell myeloma (PCM) or multiple myeloma (MM), mature T / NK cell neoplasms, and histiocytic neoplasms.

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