Human Anti-CD45 antibodies and uses thereof

Abstract

Human anti-CD45 antibodies are described. The anti-CD45 antibodies can be engineered into numerous formats, such as antibody-radioisotope conjugates, antibody-immunotoxin conjugates, antibody-drug conjugates (ADCs), antibody-detectable label conjugates, antibody-nanoparticle conjugates, antibody-bead conjugates, multi-domain binding molecules, single chain variable fragments (scFv), and recombinant receptors and can be used as research, diagnostic, or therapeutic tools against CD45-related disorders. Examples of CD45 related disorders include cancers (solid tumors and hematologic malignancies such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)), infections, autoimmune disorders, and metabolic disorders, among other disorders described herein.

Description

HUMAN ANTI-CD45 ANTIBODIES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 661 ,394 filed June 18, 2024, which is incorporated herein by reference in its entirety as if fully set forth herein.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under CA078902 awarded by the National Institutes of Health. The government has certain rights in the invention.REFERENCE TO SEQUENCE LISTING

[0003] The Sequence Listing associated with this application is provided in XML format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the file containing the Sequence Listing is 3G04732.xml. The file is 865,320 bytes, was created on June 17, 2025, and is being submitted electronically via Patent Center.FIELD OF THE DISCLOSURE

[0004] The current disclosure provides human anti-CD45 antibodies. The disclosed antibodies have a wide variety of research, diagnostic, and therapeutic uses when working with cells of hematopoietic origin. The antibodies can be used in the treatment of hematologic malignancies, as lymphodepleting agents prior to adoptive cell therapy, in autologous or allogeneic transplant to restore hematopoietic capability, to allow for the development of anti-tumor immune responses, and / or to facilitate engraftment of normal or gene edited hematopoietic stem / progenitor cells in patients with malignant or non-malignant disorders undergoing hematopoietic cell transplantation (HCT), among other uses described elsewhere herein.BACKGROUND OF THE DISCLOSURE

[0005] CD45 is a transmembrane protein that is expressed by cells of hematopoietic origin, with the exception of mature erythrocytes and platelets. It is a signaling molecule that plays a key role in T-cell and B-cell receptor signal transduction. CD45 also regulates a number of cellular processes including cell growth and differentiation.

[0006] Due to its broad expression across cells of hematopoietic origin, anti-CD45 antibodies have numerous uses in treating pathologies of the hematopoietic system, such as diseases of a particular blood cell, metabolic disorders, cancers, and autoimmune conditions, among others.

[0007] An example of a pathology of the hematopoietic system that can be treated with anti-CD45 antibodies includes acute leukemia. Acute leukemias are cancers of blood cells that originate inthe bone marrow. According to the National Institutes of Health, there were 26,000 new cases of acute leukemia in the United States in 2022. Conventional first-line treatment for acute leukemia includes (multiagent) chemotherapy and, in many cases, small molecule drugs or immunotherapeutics. In many patients, hematopoietic cell transplantation (HCT) plays an important role, either as part of an initial curative-intent treatment strategy or as part of a therapeutic strategy to treat relapsed or refractory disease. However, current HCT regimens can cause significant toxicity and adverse events, including graft-versus-host disease and multiorgan dysfunction, limiting benefits.

[0008] Due to well characterized cell surface marker expression in leukemia (and other hematological malignancies), targeted immunotherapies using antibodies against cell surface markers of cancer cells are of particular interest. For instance, 85% to 90% of acute leukemias express CD45. This expression pattern, as well as the stability of expression on the surface of cancer cells renders CD45 a promising target for immunotherapy.

[0009] While anti-CD45 antibodies have been identified, a significant concern for antibody-based therapies is the inherent immunogenicity of antibodies derived from rodents. For example, the murine anti-CD45 antibody, BC8, recognizes all human isoforms of CD45. However, although BC8 is a promising clinical therapeutic, many patients experience significant infusion toxicities because of the murine nature of BC8. Moreover, human anti-mouse antibody (HAMA) immunization can occur, even after just a single BC8 infusion for dosimetry purposes, which precludes future use of any murine monoclonal antibody (mAb) in the patient that experienced the HAMA. There is a need for human anti-CD45 antibodies to mitigate immune activation from murine antibody-based therapies.SUMMARY OF THE DISCLOSURE

[0010] The current disclosure provides human antibodies that bind CD45. The antibodies disclosed herein can be used for diagnostic, research, and therapeutic purposes. For example, the antibodies disclosed herein can be used for CD45-targeted immunotherapy including CD45- directed radioimmunotherapy, therapy with antibody-drug conjugates, and immunotoxin therapy. The antibodies can be used to treat hematologic malignancies, as lymphodepleting agents prior to adoptive cell therapy, in autologous or allogeneic transplant to restore hematopoietic capability, to allow for the development of anti-tumor immune responses, and / or to facilitate engraftment of normal or gene edited hematopoietic stem / progenitor cells in patients with malignant or non- malignant disorders undergoing hematopoietic cell transplantation (HCT), among other uses described elsewhere herein.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0011] FIG. 1. CD45 immunogens used to generate anti-human anti-CD45 antibodies. Native protein structures include a transmembrane domain and intracellular domains. Immunogens used for antibody generation include the human CD45 extracellular domain (ECD) fused with the Fc domain of mouse IgG 1 .

[0012] FIG. 2. Immunization strategy for generation of fully human anti-CD45 antibodies. ATX- Gx™ platform (Alloy Therapeutics, Waltham, MA): transgenic mice with fully human heavy chain repertoire, separate animals for human kappa light chain (GK) and human lambda light chain (GL) were inoculated 3-4 times with CD45-mmFc fusion proteins.

[0013] FIG. 3. SDS-PAGE of 14 fully human anti-CD45 antibodies. 1 or 5 pg of purified recombinant human lgG4 antibodies were run on SDS-PAGE and stained with Coomassie blue to visualize antibodies as intact immunoglobulins under non-reducing conditions (NR) or heavy and light chains under reducing (R) conditions. A reduced control antibody, 2D5 (Ctrl), is shown. ATXCD45 clone designations are as indicated. A molecular weight ladder is included, kD of standards are indicated.

[0014] FIG. 4. Binding characteristics of 14 fully human recombinant anti-CD45 antibodies. Antibodies were bound to either parental RS4;11 cells, which express CD45, or RS4;11 cells that lack CD45 expression due to deletion of CD45 with CRISPR / Cas9 targeting human CD45 alleles. 1 pg / ml anti-human anti-CD45 lgG4 antibody binding was visualized with a phycoerythrin (PE)- conjugated anti-human Ig kappa secondary antibody. 1 pg / ml 13R4 lgG4 or ChiBC8 lgG4 are shown as controls.

[0015] FIG. 5. Binding characteristics of 14 fully human recombinant anti-CD45 antibodies. Antibodies were bound to either parental NALM6 cells, which lack CD45 expression, or NALM6 re-expressing CD45 splice variants CD45ROor CD45RABC. 1 pg / ml anti-human anti-CD45 lgG4 antibody binding was visualized with a PE-conjugated anti-human Ig Kappa secondary antibody. 1 pg / ml 13R4 lgG4 or ChiBC8 lgG4 are shown as controls. 6 antibodies are specific for CD45RO, and 8 are designated anti-CD45PANantibodies because they bind to both CD45ROand CD45RABC.

[0016] FIG. 6. Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) of 10 fully human anti-CD45 antibodies. 5 pg of purified recombinant human lgG1 (1 B5 and 1 B6) or lgG4 (all others) antibodies were run on SDS-PAGE and stained with Coomassie blue to visualize antibodies as intact immunoglobulins under non-reducing conditions (NR) or heavy and light chains under reducing (R) conditions. ATXCD45 clone designations are indicated. A molecular weight ladder is included, kD of standards are indicated.

[0017] FIG. 7. Binding characteristics of supernatants containing anti-human anti-CD45antibodies from 10 unique monoclonal hybridomas derived from ATX-GK mice (having human heavy and kappa light chain repertoires). Supernatants containing anti-CD45 antibodies were bound to either parental RS4;11 cells, which express CD45, or RS4;11 cells that lack CD45 expression due to deletion of CD45 with CRISPR / Cas9 targeting human CD45 alleles. Binding of anti-human anti-CD45 ATX-GK-derived antibodies contained in hybridoma supernatants was visualized with a PE-conjugated pan-anti-mouse secondary antibody. Murine BC8 (mBC8), a mouse lgG1 / K antibody, is included as a positive control for binding to human CD45. BHV-1 , a mouse lgG1 / K antibody that binds bovine herpes virus, is shown as a negative control, and secondary antibody alone (i.e., without primary antibody) is included, to demonstrate level of background antibody staining.

[0018] FIG. 8. Binding characteristics of 9 fully human recombinant anti-CD45 antibodies. Antibodies were bound to either parental RS4;11 cells, which express CD45, or RS4;11 cells that lack CD45 expression due to deletion of CD45 with CRISPR / Cas9 targeting human CD45 alleles. All antibodies are human lgG4 / K isotype and are used at 1 pg / ml unless otherwise indicated. Primary antibody binding was visualized with a PE-conjugated anti-human IgG secondary antibody. Anti-CD45 antibody clones 1C3, 1G7 were shown previously (FIG. 4) and are included here for cross-comparison. ChiBC8 is included as positive control for human CD45 binding. 13R4, an antibody that binds bacterial beta-galactosidase, is shown as negative control, and secondary antibody alone (No 1°) is included to demonstrate level of background antibody staining.

[0019] FIG. 9. Binding characteristics of 9 fully human recombinant anti-CD45 antibodies. Antibodies were bound to either parental NALM6 cells, which lack CD45 expression, or NALM6 re-expressing CD45 splice variants CD45ROor CD45RABC. All antibodies are human lgG4 / K isotype and are used at 1 pg / ml unless otherwise indicated. Primary antibody binding was visualized with a PE-conjugated anti-human IgG secondary antibody. Anti-CD45 antibody clones 1C3, 1G7 were shown previously (FIG. 5) and are included here for cross-comparison. ChiBC8 is included as positive control for human CD45 binding. 13R4, an antibody that binds bacterial beta-galactosidase, is shown as negative control, and secondary antibody alone (No 1°) is included to demonstrate level of background antibody staining. All 9 antibodies are designated anti-CD45PANantibodies because they bind to both CD45ROand CD45RABC.

[0020] FIG. 10. Binding characteristics of 14 fully human recombinant pan-anti-CD45 antibodies. Antibodies were bound to CD45-positive human cell lines. All antibodies are human lgG4 / K isotype and are used at 1 pg / ml unless otherwise indicated. Primary antibody binding was visualized with a PE-conjugated anti-human IgG secondary antibody. ChiBC8 is included as positive control for human CD45 binding. 13R4, an antibody that binds bacterial beta-galactosidase, is shown as negative control, and secondary antibody alone (No 1°) is included to demonstrate level of background antibody staining. All 14 of the CD45PANantibodies bind to all 5 of the CD45-positive cell lines.

[0021] FIG. 11. The fully human recombinant pan-anti-CD45 antibody clone 1 E1 induces cell death in selected human cell lines. Anti-CD45 antibody-induced cytotoxicity is shown. Anti-CD45 antibodies (1 E1 , BC8) or controls (13R4, no primary antibody), all as lgG4 / K isotype, were combined with human cancer target cells for 24 hours. Experiments were performed without addition of immune effector cells. Human CD45-positive cancer target cells were either myeloid cells (THP-1, OCI-AML3) or T cells (Jurkat and MOLT-4). Jurkat cells were generated that lack CD45 expression due to deletion of CD45 with CRISPR / Cas9 targeting human CD45 alleles and used as an antigen-negative control cell line. Viable cell counts, cytotoxicity and change in dead cells (percentage change in DAPI-positive cells compared to no antibody control) are shown. All antibodies are used at 5 pg / ml. 1 E1 and BC8 are potent inducers of cell death in THP-1 and Jurkat cell lines, but not in OCI-AML3 or MOLT-4 cells. Removal of CD45 expression renders Jurkat cells resistant to 1 E1 and BC8 killing, indicating CD45-dependent Jurkat cytotoxicity.

[0022] FIG. 12. Time course of 1E1 induced cell death in Jurkat and THP-1 cell lines. Anti-CD45 antibody-induced cytotoxicity is shown. Anti-CD45 antibodies (1 E1 , BC8) or controls (13R4, no primary antibody), all as lgG4 / K isotype, were combined with human cancer target cells for 24 / 48 / 72 hours. Experiments were performed without addition of immune effector cells. Viable cell counts, cytotoxicity and change in dead cells (percentage change in DAPI-positive cells compared to no antibody control) are shown. All antibodies are used at 5 pg / ml. 1 E1 and BC8 induce death of THP-1 and Jurkat cell lines at 24 and 48 hours, but not at 72 hours, with the most pronounced cytotoxicity at 24 hours.

[0023] FIG. 13. 15 fully human anti-CD45 antibodies elicit diverse cell death responses in Jurkat and THP-1 cell lines. Anti-CD45 antibody-induced cytotoxicity is shown. 15 fully human anti-CD45 antibodies were tested, with BC8 as positive control, or 13R4 as negative control, all as lgG4 / K isotype. Antibodies were combined with human cancer target cells for 24 hours. Experiments were performed without addition of immune effector cells. Viable cell counts, cytotoxicity and change in dead cells are shown. Jurkat cells were generated that lack CD45 expression due to deletion of CD45 with CRISPR / Cas9 targeting human CD45 alleles and used as an antigennegative control cell line. All antibodies are used at 5 pg / ml. Anti-CD45 antibody clones induced similar responses in both THP-1 and Jurkat cell lines. Jurkat cells that were CD45-negative were resistant to anti-CD45 antibody-induced killing.

[0024] FIG. 14. In vivo characteristics of211At-labeled anti-CD45 antibodies. For assessment ofin vivo efficacy of211At-CD45 RIT, 1 x 105Luciferase-transduced MOLM-13 (M0LM-13Luc) cells were injected into the tail vein of NRG mice to generate a disseminated tumor model. 2 days later, animals (8 / group) were treated with 50 g of radiolabeled antibody as indicated. One group did not receive any antibody and served as the no treatment control (No mAb). BC8 is included as a positive control. Shown are Kaplan-Meier survival estimates.

[0025] FIG. 15. In vivo characteristics of211At-labeled anti-CD45 antibodies. For assessment of in vivo efficacy of211At-CD45 RIT, 1 x 105Luciferase-transduced MOLM-13 (MOLM-13Luc) cells were injected into the tail vein of NRG mice to generate a disseminated tumor model. 2 days later, animals (8 / group) were treated with 50 pg of radiolabeled antibody as indicated. One group did not receive any antibody and served as the no treatment control (No mAb). BC8 is included as a positive control, 13R4 is included as negative control. Shown are Kaplan-Meier survival estimates.

[0026] FIG. 16. In vivo characteristics of211At-labeled anti-CD45 antibodies. For assessment of in vivo efficacy of211At-CD45 RIT, 1 x 105Luciferase-transduced ML-1 (ML-1Luc) cells were injected via the tail vein of Nod Rag2 yc (NRG) mice to generate a disseminated tumor model. 2 days later, animals (8 / group) were treated with 50 pg of radiolabeled antibody as indicated. One group did not receive any mAb and served as the no treatment control (No mAb). BC8 is included as a positive control. Shown are Kaplan-Meier survival estimates.

[0027] FIG. 17. Binding affinities of anti-CD45 antibodies. Measurements were performed with a Sartorius Octet Red96 biolayer interferometry (BLI-Octet) instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1 % BSA, 0.02% Tween-20) at 30°C to assess affinities. Affinities are shown as KD (nM), and fitting views included for samples with R-values above 0.98.

[0028] FIG. 18. Binding affinities of anti-CD45 antibodies, 1A2 and 1A4. Measurements were performed with a BLI-Octet instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1% BSA, 0.02% Tween-20) at 30°C to assess affinities.

[0029] FIG. 19. Binding affinities of anti-CD45 antibodies, 1A7 and 1 B5. Measurements were performed with a BLI-Octet instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1% BSA, 0.02% Tween-20) at 30°C to assess affinities.

[0030] FIG. 20. Binding affinities of anti-CD45 antibodies, 1C3 and 1C4. Measurements wereperformed with a BLI-Octet instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1% BSA, 0.02% Tween-20) at 30°C to assess affinities.

[0031] FIG. 21. Binding affinities of anti-CD45 antibodies, 1 E1 and 1 E2. Measurements were performed with a BLI-Octet instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1% BSA, 0.02% Tween-20) at 30°C to assess affinities.

[0032] FIG. 22. Binding affinities of anti-CD45 antibodies, 1G6 and 1 H1. Measurements were performed with a BLI-Octet instrument using anti-human IgG Fc Capture (AHC) biosensors and immobilized antibody (1 pg / ml). For these experiments, a peptide encoding the complete extracellular portion of human CD45RO was used in binding buffer (PBS, 0.1% BSA, 0.02% Tween-20) at 30°C to assess affinities.

[0033] FIG. 23. Binding of human anti-CD45 antibodies to cynomologus macaque CD45-positive lymphocytes. Antibodies were screened against cynomolgous monkey (Macaca fascicularis) whole blood to assess binding to CD45-positive lymphocytes. 0.4 x 106cells were stained with 1 pg / ml of primary anti-CD45 antibody. BC8 (CHiBC8 and HuBC8 versions), an anti-human CD45 antibody with established cross-reactivity against nonhuman primate (NHP) CD45, was used as positive control, 13R4 as negative control, and no primary antibody control, followed by PE- conjugated anti-human Fc secondary antibody. ChiBC8, HuBC8, 1 B6, 1 D6 and 1 B5 show crossreactivity with cynomolgus monkey lymphocytes.

[0034] FIG. 24. Binding of human anti-CD45 antibodies to pigtail macaque CD45-positive lymphocytes. Antibodies were screened against pigtail monkey (Macaca nemestrina) whole blood to assess binding to CD45-positive lymphocytes. 1.0 x 106cells were stained with 1 pg / ml of primary anti-CD45 antibody. BC8 (CHiBC8 and HuBC8 versions), an anti-human anti-CD45 antibody with established cross-reactivity against NHP CD45, was used as positive control, 13R4 as negative control, and no primary antibody control, followed by PE-conjugated anti-human Fc secondary antibody. ChiBC8, HuBC8, 1B6, 1 D6 and 1B5 show cross-reactivity with pigtail monkey lymphocytes.

[0035] FIG. 25. Binding of human anti-CD45 antibodies to rhesus macaque CD45-positive lymphocytes. Antibodies were screened against rhesus monkey (Macaca mulatta) whole blood to assess binding to CD45-positive lymphocytes. 1.0 x 106cells were stained with 1 pg / ml of primary anti-CD45 antibody. BC8 (CHiBC8 and HuBC8 versions), an anti-human anti-CD45 antibody withestablished cross-reactivity against NHP CD45, was used as positive control, 13R4 as negative control, and no primary antibody control, followed by PE-conjugated anti-human Fc secondary antibody. ChiBC8, HuBC8, 1 B6, 1 D6 and 1 B5 show cross-reactivity with rhesus monkey lymphocytes.

[0036] FIG. 26. Sequences supporting the disclosure including Light Chain Signal Peptides (SEQ ID NOs: 12-20, 22, and 23); Heavy Chain Signal Peptides (SEQ ID NOs: 24-38, 40, and 41); Osteonectin signal peptide (SEQ ID NO: 42) and coding sequence (SEQ ID NO: 763); Human immunoglobulin kappa signal peptide (SEQ ID NO: 43) and coding sequence (SEQ ID NO: 764); Signal peptide (SEQ ID NO: 44); Antibody Light and Heavy chains without signal peptide (SEQ ID NOs: 785-856); 1 A2_Hs_lgK_light chain (LC) (SEQ ID NO: 45); 1A2_Hs_lgG1_heavy chain (HC) (SEQ ID NO: 46); 1A2_Hs_lgG4_S228P_HC (SEQ ID NO: 47); 1A4_Hs_lgK_LC (SEQ ID NO: 48); 1A4_Hs_lgG1_HC (SEQ ID NO: 49); 1A4_Hs_lgG4_S228P_HC (SEQ ID NO: 50); 1 B2_Hs_lgK_LC (SEQ ID NO: 51); 1 B2_Hs_lgG1_HC (SEQ ID NO: 52);1 B2_Hs_lgG4_S228P_HC (SEQ ID NO: 53); 1C3_Hs_lgK_LC (SEQ ID NO: 54);1C3_Hs_lgG1_HC (SEQ ID NO: 55); 1C3_Hs_lgG4_S228P_HC (SEQ ID NO: 56);1C4_Hs_lgK_LC (SEQ ID NO: 57); 1C4_Hs_lgG1_HC (SEQ ID NO: 58);1C4_Hs_lgG4_S228P_HC (SEQ ID NO: 59); 1 E1_Hs_lgK_LC (SEQ ID NO: 60);1 E1_Hs_lgG1_HC (SEQ ID NO: 61); 1 E1_Hs_lgG4_S228P_HC (SEQ ID NO: 62);1G5_Hs_lgK_LC (SEQ ID NO: 63); 1G5_Hs_lgG1_HC (SEQ ID NO: 64);1G5_Hs_lgG4_S228P_HC (SEQ ID NO: 65); 1G7_Hs_lgK_LC (SEQ ID NO: 66);1G7_Hs_lgG1_HC (SEQ ID NO: 67); 1G7_Hs_lgG4_S228P_HC (SEQ ID NO: 68);1 H6_Hs_lgK_LC (SEQ ID NO: 69); 1 H6_Hs_lgG1_HC (SEQ ID NO: 70);1 H6_Hs_lgG4_S228P_HC (SEQ ID NO: 71); 2A2_Hs_lgK_LC (SEQ ID NO: 72);2A2_Hs_lgG1_HC (SEQ ID NO: 73); 2A2_Hs_lgG4_S228P_HC (SEQ ID NO: 74);2A3_Hs_lgK_LC (SEQ ID NO: 75); 2A3_Hs_lgG1_HC (SEQ ID NO: 76);2A3_Hs_lgG4_S228P_HC (SEQ ID NO: 77); 2A10_Hs_lgK_LC (SEQ ID NO: 78);2A10_Hs_lgG1_HC (SEQ ID NO: 79); 2A10_Hs_lgG4_S228P_HC (SEQ ID NO: 80); 2D6_Hs_lgK_LC (SEQ ID NO: 81); 2D6_Hs_lgG1_HC (SEQ ID NO: 82);2D6_Hs_lgG4_S228P_HC (SEQ ID NO: 83); 3C2_Hs_lgK_LC (SEQ ID NO: 84);3C2_Hs_lgG1_HC (SEQ ID NO: 85); 3C2_Hs_lgG4_S228P_HC (SEQ ID NO: 86);1A5_Hs_lgK_LC (SEQ ID NO: 87); 1A5_Hs_lgG1_HC (SEQ ID NO: 88);1A5_Hs_lgG4_S228P_HC (SEQ ID NO: 89); 1A7_Hs_lgK_LC (SEQ ID NO: 90);1A7_Hs_lgG1_HC (SEQ ID NO: 91); 1A7_Hs_lgG4_S228P_HC (SEQ ID NO: 92);1 B4_Hs_lgK_LC (SEQ ID NO: 93); 1 B4_Hs_lgG1_HC (SEQ ID NO: 94);1 B4_Hs_lgG4_S228P_HC (SEQ ID NO: 95); 1 B5_Hs_lgK_LC (SEQ ID NO: 96); 1 B5_Hs_lgG1_HC (SEQ ID NO: 97); 1 B5_Hs_lgG4_S228P_HC (SEQ ID NO: 98); 1 B6_Hs_lgK_LC (SEQ ID NO: 99); 1 B6_Hs_lgG1_HC (SEQ ID NO: 100); 1 B6_Hs_lgG4_S228P_HC (SEQ ID NO: 101); 1 D3_Hs_lgK_LC (SEQ ID NO: 102); 1 D3_Hs_lgG1_HC (SEQ ID NO: 103); 1 D3_Hs_lgG4_S228P_HC (SEQ ID NO: 104); 1 D6_Hs_lgK_LC (SEQ ID NO: 105); 1 D6_Hs_lgG1_HC (SEQ ID NO: 106); 1 D6_Hs_lgG4_S228P_HC (SEQ ID NO: 107); 1 E2_Hs_lgK_LC (SEQ ID NO: 108); 1 E2_Hs_lgG1_HC (SEQ ID NO: 109); 1 E2_Hs_lgG4_S228P_HC (SEQ ID NO: 110); 1G6_Hs_lgK_LC (SEQ ID NO: 118); 1G6_Hs_lgG1_HC (SEQ ID NO: 119); 1G6_Hs_lgG4_S228P_HC (SEQ ID NO: 120); 1 H1_Hs_lgK_LC (SEQ ID NO: 121); 1 H1_Hs_lgG1_HC (SEQ ID NO: 122); 1H1_Hs_lgG4_S228P_HC (SEQ ID NO: 123); CD45RO- mmFc fusion protein (SEQ ID NO: 124); CD45RABC-mmFc fusion protein (SEQ ID NO: 125); 1A2_Hs_lgK_LC coding sequence (SEQ ID NO: 126); 1A2_Hs_lgG1_HC coding sequence (SEQ ID NO: 127); 1A2_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 128); 1A4_Hs_lgK_LC coding sequence (SEQ ID NO: 129); 1A4_Hs_lgG1_HC coding sequence (SEQ ID NO: 130); 1A4_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 131); 1 B2_Hs_lgK_LC coding sequence (SEQ ID NO: 132); 1 B2_Hs_lgG1_HC coding sequence (SEQ ID NO: 133); 1 B2_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 134); 1C3_Hs_lgK_LC coding sequence (SEQ ID NO: 135); 1C3_Hs_lgG1_HC coding sequence (SEQ ID NO: 136); 1C3_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 137); 1C4_Hs_lgK_LC coding sequence (SEQ ID NO: 138); 1C4_Hs_lgG1_HC coding sequence (SEQ ID NO: 139); 1C4_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 140); 1E1_Hs_lgK_LC coding sequence (SEQ ID NO: 141); 1 E1_Hs_lgG1_HC coding sequence (SEQ ID NO: 142); 1 E1_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 143); 1G5_Hs_lgK_LC coding sequence (SEQ ID NO: 144); 1G5_Hs_lgG1_HC coding sequence (SEQ ID NO: 145); 1G5_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 146); 1G7_Hs_lgK_LC coding sequence (SEQ ID NO: 147); 1G7_Hs_lgG1_HC coding sequence (SEQ ID NO: 148); 1G7_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 149); 1 H6_Hs_lgK_LC coding sequence (SEQ ID NO: 150); 1 H6_Hs_lgG1_HC coding sequence (SEQ ID NO: 151); 1 H6_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 152); 2A2_Hs_lgK_LC coding sequence (SEQ ID NO: 153); 2A2_Hs_lgG1_HC coding sequence (SEQ ID NO: 154); 2A2_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 155); 2A3_Hs_lgK_LC coding sequence (SEQ ID NO: 156); 2A3_Hs_lgG1_HC coding sequence (SEQ ID NO: 157); 2A3_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 158); 2A10_Hs_lgK_LC codingsequence (SEQ ID NO: 159); 2A10_Hs_lgG1_HC coding sequence (SEQ ID NO: 160); 2A10_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 161); 2D6_Hs_lgK_LC coding sequence (SEQ ID NO: 162); 2D6_Hs_lgG1_HC coding sequence (SEQ ID NO: 163); 2D6_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 164); 3C2_Hs_lgK_LC coding sequence (SEQ ID NO: 165); 3C2_Hs_lgG1_HC coding sequence (SEQ ID NO: 166); 3C2_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 167); 1A5_Hs_lgK_LC coding sequence (SEQ ID NO: 168); 1A5_Hs_lgG1_HC coding sequence (SEQ ID NO: 169); 1A5_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 170); 1A7_Hs_lgK_LC coding sequence (SEQ ID NO: 171); 1A7_Hs_lgG1_HC coding sequence (SEQ ID NO: 172); 1A7_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 173); 1 B4_Hs_lgK_LC coding sequence (SEQ ID NO: 174); 1 B4_Hs_lgG1_HC coding sequence (SEQ ID NO: 175); 1 B4_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 176); 1 B5_Hs_lgK_LC coding sequence (SEQ ID NO: 177); 1 B5_Hs_lgG1_HC coding sequence (SEQ ID NO: 178); 1 B5_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 179); 1 B6_Hs_lgK_LC coding sequence (SEQ ID NO: 180); 1 B6_Hs_lgG1_HC coding sequence (SEQ ID NO: 181); 1 B6_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 182); 1 D3_Hs_lgK_LC coding sequence (SEQ ID NO: 183); 1 D3_Hs_lgG1_HC coding sequence (SEQ ID NO: 184); 1 D3_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 185); 1 D6_Hs_lgK_LC coding sequence (SEQ ID NO: 186); 1 D6_Hs_lgG1_HC coding sequence (SEQ ID NO: 187); 1 D6_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 188); 1E2_Hs_lgK_LC coding sequence (SEQ ID NO: 189); 1 E2_Hs_lgG1_HC coding sequence (SEQ ID NO: 190); 1 E2_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 191); 1G6_Hs_lgK_LC coding sequence (SEQ ID NO: 199); 1G6_Hs_lgG1_HC coding sequence (SEQ ID NO: 200); 1G6_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 201); 1 H1_Hs_lgK_LC coding sequence (SEQ ID NO: 202); 1 H1_Hs_lgG1_HC coding sequence (SEQ ID NO: 203); 1 H1_Hs_lgG4_S228P_HC coding sequence (SEQ ID NO: 204); CD45RO-mmFc fusion protein coding sequence (SEQ ID NO: 205); and CD45RABC-mmFc fusion protein coding sequence (SEQ ID NO: 206).DETAILED DESCRIPTION

[0037] CD45 (leukocyte common antigen) is a transmembrane protein tyrosine phosphatase that is expressed on almost all hematopoietic cells. Exceptions are mature thrombocytes, mature erythrocytes, and some of their progenitors. Consistent with this broad expression on cells of the blood system, most hematologic malignancies express CD45. CD45 is displayed at a relativelyhigh copy number (200,000 / cell), is relatively stable on the cell surface, and the antigen is not appreciably shed after ligand binding. This expression pattern and stability on the cell surface, combined with the radiosensitivity of hematopoietic cells, renders CD45 an ideal target for radioimmunotherapy (RIT) applications. Proof-of-principle of this approach has been achieved with 0-emitters such as iodine-131 (131l) and yttrium-90 (90Y). When coupled to the murine anti- CD45 IgG 1 monoclonal antibody (mAb) BC8, 2-to-3-fold higher radiation doses were delivered to the spleen and bone marrow than any critical normal organ together with high- or reduced- intensity conditioning in patients with acute leukemias or myelodysplastic syndrome (MDS).1311- BC8 (also known as “lomab-B [apamistamab-l131]”) was recently tested in a phase 3, registrationtype multicenter trial (SIERRA; NCT02665065) for this purpose. The study, conducted at over 20 academic sites in the U.S. and Canada, completed accrual of 153 patients in September 2021 , showed improved outcomes with use of lomab-B relative to conventional care and transplantation in case of remission achievement, supporting value of CD45 as therapeutic target.

[0038] More recently, increasing interest has centered around a-emitters such as astatine-211 (211At) for RIT. Compared to 0-emitters, a-emitters deposit a higher decay energy (5-8 MeV vs. 0.66-2.3 MeV) over a much shorter distance (55-70 pm vs. 0.3-2.3 mm) for potent, precise, and efficient killing of target cells or small clusters of cells and minimized toxicity to normal, nontargeted surrounding cells. For several a-emitters, including211At, it has been shown that as few as 10 hits or less per cell kill hematopoietic neoplasms.211At is particularly useful for clinical development because of its t1 / 2 of 7.2 hours (enabling high-yield radiolabeling and easy drug delivery) and because it does not release a-emitting daughter radionuclides that could cause organ toxicity. In animal models,211At-labeled BC8 was highly efficacious against acute leukemia, in vivo, including models of measurable residual disease (MRD) burdens. A first-in-human trial testing211At-labeled BC8 (211At-B10-BC8) combined with fludarabine / 2-3 Gy total body irradiation (TBI) before HCT for adults with acute leukemia or MDS with human leukocyte antigen (HLA)- matched related or unrelated donors (NCT3128034) have been initiated. More recently, a second trial testing211At-B10-BC8 with HLA-haploidentical donors (NCT03670966) has also been initiated, as has a trial of this radioimmunotherapeutic in patients with non-malignant blood disorders. Data from these patients indicate that doses of211At up to 400-500 pCi / kg can be safely delivered with the anti-CD45 antibody together with nonmyeloablative conditioning.

[0039] Although BC8 is a promising clinical therapeutic, many patients experience significant infusion toxicities because of the murine nature of BC8. Moreover, human anti-mouse antibody (HAMA) immunization can occur, even after just a single BC8 infusion, limiting its clinical use. Development of HAMA precludes future use of any murine antibody-based therapy. Fully humananti-CD45 antibodies are expected to have minimized infusion toxicities and no risks for HAMA reaction, thereby forming the basis for improved CD45-targeted immunotherapeutics which, unlike drugs built on murine antibodies such as BC8, would allow multi-dosing with the same reagent.

[0040] The current disclosure provides a suite of fully human anti-CD45 antibodies. To accomplish this, ATX mice (Alloy Therapeutics, Waltham, MA) were used. ATX mice are transgenic animals generated to serve as an in vivo discovery platform optimized for the development of fully human antibody sequences, encompassing haplotype diversity and a full human heavy chain repertoire (40V, 23D, and 6J segments), with separate mice for human kappa (19V, 5J segments) and human lambda chain repertoires (22V, 5J segments). In order to generate anti-CD45 antibodies in these mice, immunogens that represent 2 different versions of the extracellular domain of CD45 were used: one immunogen representing the full-length version of CD45 protein, CD45RABC, and another immunogen version that is a well characterized naturally occurring splice variant of CD45 that lacks 3 exons (exons 4, 5 and 6), also known as CD45RO.

[0041] A total of 10 ATX mice were immunized. After 3-4 rounds of immunogen administrations, splenocytes were obtained from immunized mice and electrofusions performed to generate hybridoma cells. Using a 384-well plate approach, hybridoma cells were then plated. Supernatants were screened using human CD45+ cell lines Jurkat (T-cell derivative) and RS4;11 (B-cell derivative) as well as a CD45-negative clonal subline of RS4;11 that was generated with CRISPR / Cas9 targeted knock-out of the CD45 allele. More than 200 polyclonal populations of hybridoma cells with high antibody binding activity to human CD45+ target cells compared to CD45- control cells were identified.

[0042] The current disclosure thus provides human antibodies that bind different isoforms of CD45. The disclosed antibodies can be used as research, diagnostic, and / or therapeutic tools against hematologic disorders including, for example, malignancies such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The disclosed anti-CD45 antibodies can be used within immune targeting reagents (e.g., bispecific antibodies or multimerized antibodies), within antibody drug conjugates (e.g., for chemotherapy and / or radioimmunotherapy (e.g., with the a and p emitters noted above), and within recombinant receptors such as chimeric antigen receptors (CAR) or engineered T cell receptors (eTCR) among other uses described elsewhere herein. As is understood by one of ordinary skill in the art, when anti-CD45 antibodies are used for treatment of a subject (e.g., within a CAR), strategies should be employed (e.g., CD45 knockout or epitope shielding) to avoid fratricide of immune effector cells which are normallyCD45+.

[0043] Aspects of the current disclosure are now described with additional details and options as follows: (i) Antibodies; (ii) Antibody Variants; (iii) Multi-Domain Binding Molecules; (iv) Expression of Recombinant Proteins; (v) Anti-CD45 Antibody Conjugates; (vi) Recombinant Receptors; (vii) Immune Cells; (viii) Cell Sample Collection and Cell Enrichment; (ix) Genetic Engineering Techniques; (x) Nanoparticles; (xi) Compositions and Formulations; (xii) Methods of Use; (xiii) Kits; (xiv) Exemplary Embodiments; and (xv) Closing Paragraphs. These headings are provided for organizational purposes only and do not limit the scope or interpretation of the disclosure.

[0044] (i) Antibodies. Conventional naturally occurring antibody structural units include a tetramer structure with a pair of polypeptide chains, each pair having one light chain and one heavy chain. The amino-terminal portion of each chain includes a variable region that is responsible for antigen recognition and epitope binding. The variable regions exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called complementarity determining regions (CDRs). The CDRs from the two chains of each pair are aligned by the framework regions, which enables binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chain variable regions include the domains FR1 , CDR1 , FR2, CDR2, FR3, CDR3 and FR4. In particular embodiments, an antibody, as referred to herein, is a binding domain. Unless otherwise indicated, the term “antibody” includes (in addition to antibodies having two full-length heavy chains and two full-length light chains as described above) variants, derivatives, and fragments thereof, examples of which are described below. Furthermore, unless explicitly excluded, antibodies can include monoclonal antibodies (mAbs), single chain variable fragments (scFvs), bispecific antibodies, trispecific antibodies, tetraspecific antibodies, multispecific antibodies, polyclonal antibodies, linear antibodies, minibodies, domain antibodies, synthetic antibodies, chimeric antibodies, antibody fusions, and fragments thereof, respectively. In particular embodiments, antibodies can include oligomers or multiplexed versions of the antibodies disclosed herein.

[0045] The assignment of amino acids to each domain can be in accordance with Kabat numbering (Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme)); Chothia (Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme)), Martin (Abinandan et al., Mol Immunol. 45:3832-3839 (2008), “Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains”), Gelfand, Contact (MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (Contact numbering scheme)), IMGT (Lefranc M Pet al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 January; 27(1):55-77 (“IMGT” numbering scheme)), AHo (Honegger A and Pluckthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun. 8; 309(3):657-70, (AHo numbering scheme)), North (North et al., J Mol Biol. 406(2) :228-256 (2011), “A new clustering of antibody CDR loop conformations”), or other numbering schemes.

[0046] Definitive delineation of a CDR and identification of residues including the binding site of an antibody can be accomplished by solving the structure of the antibody and / or solving the structure of the antibody-epitope complex. In particular embodiments, this can be accomplished by methods such as X-ray crystallography and cryoelectron microscopy. Alternatively, CDRs are determined by comparison to known antibodies (linear sequence) and without resorting to solving a crystal structure. To determine residues involved in binding, a co-crystal structure of the Fab (antibody fragment) bound to the target can optionally be determined. Software programs and bioinformatical tools, such as ABodyBuilder2 and Paratome, can also be used to determine CDR sequences.

[0047] The carboxy-terminal portion of each chain defines a constant region, which can be responsible for effector function particularly in the heavy chain (the Fc). Examples of effector functions include: C1q binding and complement dependent cytotoxicity (CDC); antibodydependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptors); and B-cell activation.

[0048] Human light chains are classified as kappa (K) and lambda (A) light chains. In particular embodiments, a human IgK Fc region includes the sequence: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 1). In particular embodiments, a human IgA Fc region includes the sequence: GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 2).

[0049] Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, lgG1 , lgG2, lgG3, and lgG4. IgM has subclasses including lgM1 and lgM2. IgA is similarly subdivided into subclasses including lgA1 and lgA2.

[0050] In particular embodiments, a human lgG1 Fc region includes the sequence: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK (SEQ ID NO: 3).

[0051] In particular embodiments, a human lgG1 Fc region includes the sequence: THTCPPCPAPEFFGGPSVFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVETVFHQDWENGKEYKCKVSNKAFPVPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGPFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[0052] In particular embodiments, a human lgG2 Fc region includes the amino acid sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKP KDTLMISRTPEVTCWVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVH QDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK (SEQ ID NO: 5)

[0053] In particular embodiments, a human lgG2 Fc region includes the amino acid sequence: PAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 6)

[0054] In particular embodiments, a human lgG3 Fc region includes the amino acid sequence: ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTPLGDTTHTCPRCPEPKSCDTPPPC PRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESS GQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPG K (SEQ ID NO: 7)

[0055] In particular embodiments, a human lgG3 Fc region includes the amino acid sequence: PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPR EEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 8).

[0056] In particular embodiments, a human lgG4 Fc region includes the amino acid sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK (SEQ ID NO: 9).

[0057] In particular embodiments, a human lgG4 Fc region includes the amino acid sequence: PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 10).

[0058] In particular embodiments, a human lgG4_S228P Fc region includes the sequence: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK (SEQ ID NO: 11).

[0059] The choice of constant region can depend, in part, whether antibody-dependent cell- mediated cytotoxicity, antibody dependent cellular phagocytosis and / or complement dependent cytotoxicity are desired. For example, human isotopes lgG1 and lgG3 have strong complementdependent cytotoxicity, human isotype lgG2 has weak complement-dependent cytotoxicity and human lgG4 lacks complement-dependent cytotoxicity. Human lgG1 and lgG3 also induce stronger cell mediated effector functions than human lgG2 and lgG4.

[0060] In particular embodiments, a light chain constant region includes a human IgK Fc region or a human IgA Fc region.

[0061] In particular embodiments, a heavy chain constant region includes a human lgG1 Fc region or a human lgG4 Fc region.

[0062] Within full-length light and heavy chains, the variable and constant regions are joined by a “J” region of amino acids, with the heavy chain also including a “D” region of amino acids. See, e.g., Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).

[0063] Antibodies bind epitopes on antigens. The term antigen refers to a molecule or a portion of a molecule capable of being bound by an antibody. An epitope is a region of an antigen that isbound by the variable region of an antibody. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three-dimensional structural characteristics, and / or specific charge characteristics. When the antigen is a protein or peptide, the epitope includes specific amino acids within that protein or peptide that contact the variable region of an antibody.

[0064] In particular embodiments, “bind” means that the variable region associates with its target epitope with a dissociation constant (Kd or KD) of 10-8M or less, in particular embodiments of from 10-5M to 10'13M, in particular embodiments of from 10'5M to 10'10M, in particular embodiments of from 10'5M to 10’7M, in particular embodiments of from 10'8M to 10'13M, or in particular embodiments of from 10'9M to 10’13M. The term can be further used to indicate that the variable region does not bind to other biomolecules present (e.g., it binds to other biomolecules with a dissociation constant (Kd) of 10'4M or more, in particular embodiments of from 10’4M to 1 M).

[0065] In particular embodiments, Kd can be characterized using BIAcore. For example, in particular embodiments, Kd can be measured using surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25°C with immobilized antigen CM5 chips at 10 response units (RU).

[0066] A monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies including the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies can be made by a variety of techniques, including the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

[0067] A “human antibody” is one which includes an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source (e.g., ATX mice) that utilizes human antibody repertoires or other human antibody-encoding sequences.

[0068] A “human consensus framework” is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VLor VHframework sequences. Generally, the selection of human immunoglobulin VLor VHsequences is from a subgroup of variable domain sequences. The subgroup of sequences can be a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91- 3242, Bethesda Md. (1991), vols. 1-3. In particular embodiments, for the VL, the subgroup is subgroup kappa I as in Kabat et al. (supra). In particular embodiments, for the VH, the subgroup is subgroup III as in Kabat et al. (supra).

[0069] Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype bind to a non-polymorphic region of one or more other isotypes.

[0070] Referring to the antibodies provided herein, the following CDR sets are provided. A CDR set refers to 3 light chain CDRs and 3 heavy chain CDRs that together result in binding to CD45.

[0071] Table 1: Antibody CDR Sequences according to North.

[0072] Table 2: Antibody CDR Sequences according to IMGT.

[0073] Table 3: Antibody CDR Sequences according to Kabat.

[0074] Table 4. Antibody CDR Sequences according to Chothia.

[0075] Table 5: Antibody CDR Sequences according to Contact.

[0076] CDR predictions were generated using the program SAbPred http: / / opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / ). ABodyBuilder2 within SAbPred (Dunbar, et al., Nucleic Acids Res. 44:W474-W478, 2016) was used.

[0077] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1A2 (1A2). In particular embodiments, 1A2 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQSVRTNLAWFQQKPGQAPRLLFYGASTRATGIPARFS GSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPLTFGGGAKVEIK (SEQ ID NO: 207) and a variable heavy chain including the sequence:QVYLVESGGGLVKPGGSLRLSCAVSGFTFSGYYMSWIRQAPGKGLDWISYISTSGSFIQYGDS VKGRFTISRDNAKNSMYLQMNSLRAEDTAVYYCARRAGGATTFDIWGQGTMVTVSS (SEQ ID NO: 208).

[0078] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1A4 (1A4). In particular embodiments, 1A4 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQSVRSNLAWYQQKPGQAPSLLIYDTSTRATDIPARFSG SGSGTEFTLTISGLQSEDFAVYYCQQYNNWPLTFGGGTKVEIK (SEQ ID NO: 209) and a variable heavy chain including the sequence:QVQLVESGGGLVKPGGSLRLSCAASGFSFSDYYMNWIRQAPGKGLEWVSYISTSVTFIKYADS VKGRFTISRDNAKKSLYLQMNSLRVEDTAVYYCARRAVGAPAFDIWGQGTMVTVSS (SEQ ID NO: 210).

[0079] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 B2 (1 B2). In particular embodiments, 1 B2 includes a variable light chain including the sequence:EIVLTQSPATLSVSPGERATLSCRASQSVTSNFAWYQQKPGQAPRLLIHGASTRATGIPARFSG SESGTEFTLTISSLQSEDFAVYYCQQYKNWPLTFGGGTKVEIE (SEQ ID NO: 211) and a variable heavy chain including the sequence:QVHLVESGGGLVKPGGSLRLSCAASGFTFSNYYMSWIRQAPGKGLEWISYINLSGSFIHYADS VKGRFTISRDNARNSVYLQM NSLRAEDTAVYYCARRGGGATI FDN WGQGI LVTVSA (SEQ ID NO: 212).

[0080] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1C3 (1C3). In particular embodiments, 1C3 includes a variable light chain including the sequence:EIVMTQSPDTLSVSPGERATLSCRASQSVRSNLAWYQQKPGQAPRLLFYSASTRATGIPARFS GSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPLTFGGGAKVEIK (SEQ ID NO: 213) and a variable heavy chain including the sequence:QVHLVESGGGLVKPGGSLRLSCAVSGFTFSGYYMSWIRQAPGKGLDWISYINTSGSFIHYADS VKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRAAGTTTFDIWGQGTMVTVSS (SEQ ID NO: 214).

[0081] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1C4 (1C4). In particular embodiments, 1C4 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQNVRNNLAWYQQRPGQAPRLLIFGASTRATGIPARFS GSGSGTEFTLNISSLQSEDSAVYYCQQCNDWPLTFGPGTKVDFK (SEQ ID NO: 215) and a variable heavy chain including the sequence:QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYYMNWIRQAPGKGLEWVSYINLSGSFIRYGD SMKGRFTISRDNARNSLFLQMNSLRVEDTAVYYCARRGGGNTIFDYWGQGTLVTVSS (SEQ ID NO: 216).

[0082] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 E1 (1 E1). In particular embodiments, 1 E1 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQSVRSNLAWYQQKPGQAPRLLFYGASTRATGIPARFS GSGSGTEFTLTISSLQSEDFAVYYCQQFNNWPLTFGGGAKVEIK (SEQ ID NO: 217) and a variable heavy chain including the sequence:QVHLVESGGGLVKPGGSLRLSCAVSGFTFSGYYMSWIRQAPGKGLDWIAYINTSGSFIQYADS VKGRFTISRDNAKNSMYLQMDSLRAEDTAVYYCARRAGGSTTFDIWGQGTMVTVSS (SEQ ID NO: 218).

[0083] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1G5 (1G5). In particular embodiments, 1G5 includes a variable light chain including the sequence:DVVLTQSPLSLSVTLGQPASISCRSSQSLVYGDGNTYLNWFQQRPGQSPRRLIYRASDRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTYWPPYTFGPGTKLELK (SEQ ID NO: 219) and a variable heavy chain including the sequence:EVQLVESGGGLVQPGGSLRLSCVGSGFTFRNYWMTWVRQAPGRGLEWVANIKFDGSETYYV DSVKGRFTTSRDSAKNSLFLQMNSLRGEDTGVYYCARMKQMDVWGKGTTVTVSS (SEQ ID NO: 220).

[0084] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1G7 (1G7). In particular embodiments, 1G7 includes a variable light chain including the sequence:EIVMTQSPATLSLSPGERATLSCRASQSVSSNLVWYQQKPGQAPRLLIYGAFTRATGIPARFSG SGSGTDFTLTISSLQSEDFAVYYCQQYNNWLYTFGQGTKLEIK (SEQ ID NO: 221) and a variable heavy chain including the sequence:EVQVVESGGGLVQPGGSLRLSCAASGFTFNTYAMSWVRQAPGKGLEWVSTISGSGNSRYYP DSVKGRFTISRDNSKNTLNLQMNSLRAEDTALYFCARGKDWGVFDYWGQGTLVTVSS (SEQ ID NO: 222).

[0085] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1H6 (1 H6). In particular embodiments, 1 H6 includes a variable light chain including the sequence:EIVLTQSPGTLSLSPGERATLSCRASQSVRSGSLAWYQQKPGQAPRLLVYGASRRATGIPDRF SGSGSGTDFTLTISRLEPEDSAVYYCQQYGRLYTFGQGTNLEIK (SEQ ID NO: 223) and a variable heavy chain including the sequence:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGKINFAQ KFQGRVTMTTDTFTSTAYMELRSLRSDDTAVYYCVREDNGSYYGWFDPWGQGTLVTVSS (SEQ ID NO: 224).

[0086] In particular embodiments, a human anti-CD45 antibody includes 45-ATX2A2 (2A2). In particular embodiments, 2A2 includes a variable light chain including the sequence:DIVMTQSPDSLAVSLGERATINCKSSQSVLYISNNKNYLAWYQQKPGQPPKLLIYWASTRESGV PDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIK (SEQ ID NO: 225) and a variable heavy chain including the sequence:QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWNWIRQPPGKGLEWIGYIYYSGNTNYNPSL KSRVTISVDTSKNQLSLKLSSVTAADTAVYYCAREYCTNGVCYNGWFDPWGRGTLVTVSS (SEQ ID NO: 226).

[0087] In particular embodiments, a human anti-CD45 antibody includes 45-ATX2A3 (2A3). In particular embodiments, 2A3 includes a variable light chain including the sequence:DIVMTQSPDSLTVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESG VPDRFSGSGSGTDFTLTISSLQAEDVSVYYCQQYYSVPRTFGQGTKVEIK (SEQ ID NO: 227) and a variable heavy chain including the sequence:QVQLQESGPGLVKPSETLSLTCTVSSGSISSYYWNWIRQAPGKGLEWIGYIYYSGSTNYNPSL KSRVTISVETSKNQLSLKLSSVTAADTAVYYCAREYCTNGVCYNGWFAPWGQGILVTVSS (SEQ ID NO: 228).

[0088] In particular embodiments, a human anti-CD45 antibody includes 45-ATX2A10 (2A10). In particular embodiments, 2A10 includes a variable light chain including the sequence:DIVMTQSPDSLTLSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESG VPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIK (SEQ ID NO: 229)and a variable heavy chain including the sequence: QVQLQESGPGLVKPSETLSLTCTVSGVSISTYYWNWIRQPPGKGLEWIGYIYYSGSTNYNPSLK SRVTISVDTSKNQLSLKLSSVTAADTAVYYCAREYCTNGVCYNGWFDPWGQGTLVTVSS (SEQ ID NO: 230).

[0089] In particular embodiments, a human anti-CD45 antibody includes 45-ATX2D6 (2D6). In particular embodiments, 2D6 includes a variable light chain including the sequence:DIVLTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIK (SEQ ID NO: 231) and a variable heavy chain including the sequence:QVQLQESGPGLVKPSETLSLTCTVSGGSITSYYWNWIRQPPGKGLEWIGYIYYSGNTNYNPSL KSRVTISVDTSKNQLSLKLSSVTAADTAVYYCAREFCTNGVCYNGWFDPWGQGTLVTVSS (SEQ ID NO: 232).

[0090] In particular embodiments, a human anti-CD45 antibody includes 45-ATX3C2 (3C2). In particular embodiments, 3C2 includes a variable light chain including the sequence:EIVLTQSPGTLSLSPGERATLSCRASQSVSDNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGSDFTLTISGLEPEDFAVYYCQQYGSSPMYTFGQGTKLVIR (SEQ ID NO: 233) and a variable heavy chain including the sequence:EVQLVESGGGLIQPGGSLRLSCAASGFTFSTYDMHWVRQATGKGLEWVSVIGTAGDRYYPGSVKGRFTISRDNAKNSLYLQMNSLRAGDTAVYYCAREGITSGGVITFAFDIWGQGTMVTVSS (SEQ ID NO: 234).

[0091] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1A5 (1A5). In particular embodiments, 1A5 includes a variable light chain including the sequence:DIVMTQTPLSLSVTLGQPASISCRSSQSLLQSDGNTFLTWLHQRPGQPPRLLIYKISYRFSGVPD RFSGSGAGTDFTLQIRRVEAQDVGVYYCMQATQFPITFGQGTRLEIQ (SEQ ID NO: 235) and a variable heavy chain including the sequence:QVHLVQSGTEVKKPGASVKVSCKASGFSFTSYGISWVRQAPGQGLEWMGWINPDSGHTDSA QKVQGRVTMSADTSTTAAYMELRSLRSDDTAVYFCARGVHWFDPWGQGTLVIVSS (SEQ ID NO: 236).

[0092] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1A7 (1A7). In particular embodiments, 1A7 includes a variable light chain including the sequence:EVLLTQSPATLSLSPGERATLSCRASQSVGNYLAWYQQKPGQAPRLLIYDASNRATGIPARFT GRGSGTDFTLTISSLEPEDFAIYYCQQRSNWPPTFGQGTKVEIK (SEQ ID NO: 237) and a variable heavy chain including the sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFAMSWVRQAPGKGLEWVSVITGSGYSTNYADSVKGRFTISRDNSRNTLFLEMNSLRAEDTAIYNCAKTLLYTNYLDYWGQGILVTVSS (SEQ ID NO: 238).

[0093] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 B4 (1 B4). In particular embodiments, 1 B4 includes a variable light chain including the sequence:EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGRSYTFGQGTKLEIK (SEQ ID NO: 239) and a variable heavy chain including the sequence:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGKINYA QKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCVREDNGSYYGWFDPWGQGTLVTVSS (SEQ ID NO: 240).

[0094] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 B5 (1 B5). In particular embodiments, 1 B5 includes a variable light chain including the sequence:EIVVTQSPATLSVSPGERATLSCRASQTISNNLAWYQQKPGQAPRLLISGASTRATGIPARFSG AGSGTEFTLTINSLQSEDFAVYYCQQYNHWMYTFGQGTKLEIK (SEQ ID NO: 241) and a variable heavy chain including the sequence:EVQLVESGGGLVQPGGSLRLSCEATGFTFTNYPMTWVRQAPGKGLEWVSSISVSGRSTYYPD SVKGRFTIFRDNSKNILYLQMNSLRAGDSAAYYCAKNWEAFDYWGQGILVTVSS (SEQ ID NO: 242).

[0095] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 B6 (1 B6). In particular embodiments, 1 B6 includes a variable light chain including the sequence:DVVMTQSPLSLPVTLGQPASISCRSSQSLVYTDGNTYLNWFQQRPGQSPRRLIYRVSNRVSGV PDRFSGSGSGTNFTLKISSVEAGDVGLYYCMQDTHWPLTFGGGTKVEIK (SEQ ID NO: 243) and a variable heavy chain including the sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYAMNVWRQAPGKGLEWVSSISGRGGSTYYP DSVKGRFTISRDNSKNTLHLQMNSLRAEDTAIYYCAKEEGVGPIFGIEYWGQGTLVTVSS (SEQ ID NO: 244).

[0096] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1D3 (1 D3). In particular embodiments, 1 D3 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQNIRSNLAWYQQKPGQASRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSGDFAVYYCQQYNNWPLTFGGGTKVEIK (SEQ ID NO: 245) and a variable heavy chain including the sequence:QVLLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISISGSFIYYADSV KGRFTISRDNAKNSLYLQMNSLTAEDTAVYYCARRAVGATAFDIWGQGTMVTVSS (SEQ ID NO: 246).

[0097] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1D6 (1 D6). In particular embodiments, 1 D6 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASARATGIPARFS GTGSGTEFILTISSLQSEDSAVYYCHQYNIWLYSFGQGTNLEIK (SEQ ID NO: 247) and a variable heavy chain including the sequence:EVQLVESGGALVPPGGSLTLYCAASGFTFNSSVMNWVRQAPGKGLDWVSSISYTGGSVYYPD SVKGRFTISRDNSKNMLHLQMNSLRAEDTAVYYCAKGRDWGVFENWGQGTLVTVSS (SEQ ID NO: 248).

[0098] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1 E2 (1 E2). In particular embodiments, 1 E2 includes a variable light chain including the sequence:EIVLTQSPGTLSLSPGERTTLSCRTSQSLSSSSLAWYQQKPGQAPRLLIYGASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGRSYTFGRGTKLEIK (SEQ ID NO: 249) and a variable heavy chain including the sequence:QVHLVQSGAEVKKPGASVKVSCKASGYNFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYA QNLQGRVTMTTDTSTSTVYMELRSLRSDDTAVYFCAREDNRSYYGWFDPWGQGTLVTVSS (SEQ ID NO: 250).

[0099] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1G6 (1G6). In particular embodiments, 1G6 includes a variable light chain including the sequence:AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWFQQKPGKAPKLLIYAASSLHSGVPSRFSG SGSDTDFTLTISSLQPEDFATYYCLQDYNYPFTFGPGTKVDIK (SEQ ID NO: 256) and a variable heavy chain including the sequence:EVQLVESGGGVVRPGGSLRLSCTASGFIFDDYGMTWVRQAPGKGLEWVSGIHWNGGSTGYA DSVKGRFTLSRDNAKNSLYLQMDSLRAEDTAFYYCTRDLGIGARGVFWGQGTLVTVSS (SEQ ID NO: 257).

[0100] In particular embodiments, a human anti-CD45 antibody includes 45-ATX1H1 (1 H1). In particular embodiments, 1 H1 includes a variable light chain including the sequence:EIVMTQSPATLSVSPGERATLSCRASQNIRSNLAWYQQKPGQASRLLIYGASTRATGIPARFSG SGSGTEFTLTISSLQSGDFAVYYCQQYNNWPLTFGGGTKVEIK (SEQ ID NO: 245) and a variable heavy chain including the sequence:QVHLVESGGGLVKPGGSLRLSCAASGFTFSNYYMSWIRQAPGKGLEWVSYISLSGGFIQYADS VKGRFIISRDNAKNSLYLQMNSLRAEDTAVYYCVRRGGGATIFDYWGQGILVTVSA (SEQ ID NO: 258).

[0101] In particular embodiments, an anti-CD45 antibody includes a human light chain variable region and a human heavy chain variable region. In particular embodiments, an anti-CD45antibody includes a light chain including an IgK light chain constant region; and a heavy chain including an IgG 1 heavy chain constant region. In particular embodiments, an anti-CD45 antibody includes a light chain including an IgK light chain constant region; and a heavy chain including an lgG4 heavy chain constant region. In particular embodiments, the lgG4 heavy chain constant region includes an S228P modification.

[0102] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1A2 (i.e., 1A2 light chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 12. In some embodiments, the 1A2 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1A2 light chain includes SEQ ID NO: 785. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A2 light chain includes the sequence of SEQ ID NO: 45. In particular embodiments, the 1A2 light chain is encoded by the sequence of SEQ ID NO: 126.

[0103] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A2 (i.e., 1A2 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1A2 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1A2 heavy chain includes SEQ ID NO: 786. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1A2 heavy chain includes the sequence of SEQ ID NO: 46. In particular embodiments, the 1A2 heavy chain is encoded by the sequence of SEQ ID NO: 127.

[0104] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A2 (i.e., 1A2 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1A2 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1A2 heavy chain includes SEQ ID NO: 787. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1A2 heavy chain includes the sequence of SEQ ID NO: 47. In particular embodiments, the 1A2 heavy chain is encoded by the sequence of SEQ ID NO: 128.

[0105] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1A4 (i.e., 1A4 light chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1A4 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1A4 light chain includes SEQ ID NO: 788. In some embodiments, the signal peptide includes thesequence of SEQ ID NO: 42. In particular embodiments, the 1A4 light chain includes the sequence of SEQ ID NO: 48. In particular embodiments, the 1A4 light chain is encoded by the sequence of SEQ ID NO: 129.

[0106] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A4 (i.e. , 1A4 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 25. In some embodiments, the 1A4 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1A4 heavy chain includes SEQ ID NO: 789. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1A4 heavy chain includes the sequence of SEQ ID NO: 49. In particular embodiments, the 1A4 heavy chain is encoded by the sequence of SEQ ID NO: 130.

[0107] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A4 (i.e., 1A4 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 25. In some embodiments, the 1A4 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1A4 heavy chain includes SEQ ID NO: 790. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1A4 heavy chain includes the sequence of SEQ ID NO: 50. In particular embodiments, the 1A4 heavy chain is encoded by the sequence of SEQ ID NO: 131.

[0108] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 B2 (i.e., 1 B2 light chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1 B2 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 B2 light chain includes SEQ ID NO: 791. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B2 light chain includes the sequence of SEQ ID NO: 51. In particular embodiments, the 1B2 light chain is encoded by the sequence of SEQ ID NO: 132.

[0109] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B2 (i.e., 1 B2 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 26. In some embodiments, the 1 B2 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 B2 heavy chain includes SEQ ID NO: 792. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1 B2 heavy chain includes the sequence of SEQ ID NO: 52. In particular embodiments, the 1B2 heavy chain isencoded by the sequence of SEQ ID NO: 133.

[0110] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B2 (i.e., 1 B2 heavy chain) and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 26. In some embodiments, the 1 B2 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 B2 heavy chain includes SEQ ID NO: 793. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1 B2 heavy chain includes the sequence of SEQ ID NO: 53. In particular embodiments, the 1B2 heavy chain is encoded by the sequence of SEQ ID NO: 134.

[0111] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1C3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1C3 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1C3 light chain includes SEQ ID NO: 794. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1C3 light chain includes the sequence of SEQ ID NO: 54. In particular embodiments, the 1C3 light chain is encoded by the sequence of SEQ ID NO: 135.

[0112] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1C3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 27. In some embodiments, the 1C3 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1C3 heavy chain includes SEQ ID NO: 795. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1C3 heavy chain includes the sequence of SEQ ID NO: 55. In particular embodiments, the 1C3 heavy chain is encoded by the sequence of SEQ ID NO: 136.

[0113] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1C3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 27. In some embodiments, the 1C3 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 103 heavy chain includes SEQ ID NO: 796. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1C3 heavy chain includes the sequence of SEQ ID NO: 56. In particular embodiments, the 1C3 heavy chain is encoded by the sequence of SEQ ID NO: 137.

[0114] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain ofclone 1C4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 14. In some embodiments, the 1C4 light chain includes a human lgt< light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1C4 light chain includes SEQ ID NO: 797. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1C4 light chain includes the sequence of SEQ ID NO: 57. In particular embodiments, the 1C4 light chain is encoded by the sequence of SEQ ID NO: 138.

[0115] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1C4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 28. In some embodiments, the 1C4 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1C4 heavy chain includes SEQ ID NO: 798. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1C4 heavy chain includes the sequence of SEQ ID NO: 58. In particular embodiments, the 1C4 heavy chain is encoded by the sequence of SEQ ID NO: 139.

[0116] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1C4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 28. In some embodiments, the 1C4 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1C4 heavy chain includes SEQ ID NO: 799. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1C4 heavy chain includes the sequence of SEQ ID NO: 59. In particular embodiments, the 1C4 heavy chain is encoded by the sequence of SEQ ID NO: 140.

[0117] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 E1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1E1 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 E1 light chain includes SEQ ID NO: 800. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 E1 light chain includes the sequence of SEQ ID NO: 60. In particular embodiments, the 1 E1 light chain is encoded by the sequence of SEQ ID NO: 141.

[0118] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 E1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1 E1 heavy chain includes a human I gG 1 heavy chain constantregion having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 E1 heavy chain includes SEQ ID NO: 801. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1 E1 heavy chain includes the sequence of SEQ ID NO: 61. In particular embodiments, the 1E1 heavy chain is encoded by the sequence of SEQ ID NO: 142.

[0119] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 E1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1 E1 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 E1 heavy chain includes SEQ ID NO: 802. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1 E1 heavy chain includes the sequence of SEQ ID NO: 62. In particular embodiments, the 1 E1 heavy chain is encoded by the sequence of SEQ ID NO: 143.

[0120] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1G5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 15. In some embodiments, the 1G5 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1G5 light chain includes SEQ ID NO: 803. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1G5 light chain includes the sequence of SEQ ID NO: 63. In particular embodiments, the 1G5 light chain is encoded by the sequence of SEQ ID NO: 144.

[0121] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 29. In some embodiments, the 1G5 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1G5 heavy chain includes SEQ ID NO: 804. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1G5 heavy chain includes the sequence of SEQ ID NO: 64. In particular embodiments, the 1G5 heavy chain is encoded by the sequence of SEQ ID NO: 145.

[0122] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 29. In some embodiments, the 1G5 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1G5 heavy chain includes SEQ ID NO: 805. In some embodiments, the signal peptide includes thesequence of SEQ ID NO: 43. In particular embodiments, the 1G5 heavy chain includes the sequence of SEQ ID NO: 65. In particular embodiments, the 1G5 heavy chain is encoded by the sequence of SEQ ID NO: 146.

[0123] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1G7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1G7 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1G7 light chain includes SEQ ID NO: 806. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1G7 light chain includes the sequence of SEQ ID NO: 66. In particular embodiments, the 1G7 light chain is encoded by the sequence of SEQ ID NO: 147.

[0124] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 30. In some embodiments, the 1G7 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1G7 heavy chain includes SEQ ID NO: 807. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1G7 heavy chain includes the sequence of SEQ ID NO: 67. In particular embodiments, the 1G7 heavy chain is encoded by the sequence of SEQ ID NO: 148.

[0125] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 30. In some embodiments, the 1G7 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1G7 heavy chain includes SEQ ID NO: 808. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1G7 heavy chain includes the sequence of SEQ ID NO: 68. In particular embodiments, the 1G7 heavy chain is encoded by the sequence of SEQ ID NO: 149.

[0126] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 H6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 18. In some embodiments, the 1H6 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 H6 light chain includes SEQ ID NO: 809. In some embodiments, the a signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 H6 light chain includes the sequence of SEQ ID NO: 69. In particular embodiments, the 1 H6 light chain is encoded by the sequence of SEQ IDNO: 150.

[0127] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1H6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 31. In some embodiments, the 1 H6 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 H6 heavy chain includes SEQ ID NO: 810. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1H6 heavy chain includes the sequence of SEQ ID NO: 70. In particular embodiments, the 1H6 heavy chain is encoded by the sequence of SEQ ID NO: 151.

[0128] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1H6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 31 . In some embodiments, the 1 H6 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 H6 heavy chain includes SEQ ID NO: 811. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 1 H6 heavy chain includes the sequence of SEQ ID NO: 71 . In particular embodiments, the 1 H6 heavy chain is encoded by the sequence of SEQ ID NO: 152.

[0129] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 2A2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 22. In some embodiments, the 2A2 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 2A2 light chain includes SEQ ID NO: 812. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 2A2 light chain includes the sequence of SEQ ID NO: 72. In particular embodiments, the 2A2 light chain is encoded by the sequence of SEQ ID NO: 153.

[0130] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2A2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A2 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 2A2 heavy chain includes SEQ ID NO: 813. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A2 heavy chain includes the sequence of SEQ ID NO: 73. In particular embodiments, the 2A2 heavy chain is encoded by the sequence of SEQ ID NO: 154.

[0131] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chainof clone 2A2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A2 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 2A2 heavy chain includes SEQ ID NO: 814. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A2 heavy chain includes the sequence of SEQ ID NO: 74. In particular embodiments, the 2A2 heavy chain is encoded by the sequence of SEQ ID NO: 155.

[0132] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 2A3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 22. In some embodiments, the 2A3 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 2A3 light chain includes SEQ ID NO: 815. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 2A3 light chain includes the sequence of SEQ ID NO: 75. In particular embodiments, the 2A3 light chain is encoded by the sequence of SEQ ID NO: 156.

[0133] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2A3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A3 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 2A3 heavy chain includes SEQ ID NO: 816. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A3 heavy chain includes the sequence of SEQ ID NO: 76. In particular embodiments, the 2A3 heavy chain is encoded by the sequence of SEQ ID NO: 157.

[0134] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2A3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A3 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 2A3 heavy chain includes SEQ ID NO: 817. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A3 heavy chain includes the sequence of SEQ ID NO: 77. In particular embodiments, the 2A3 heavy chain is encoded by the sequence of SEQ ID NO: 158.

[0135] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 2A10 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 16. In some embodiments, the 2A10 light chain includes a human IgK light chain constantregion having the sequence of SEQ ID NO: 1. In particular embodiments, the 2A10 light chain includes SEQ ID NO: 818. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 2A10 light chain includes the sequence of SEQ ID NO: 78. In particular embodiments, the 2A10 light chain is encoded by the sequence of SEQ ID NO: 159.

[0136] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2A10 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A10 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 2A10 heavy chain includes SEQ ID NO: 819. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A10 heavy chain includes the sequence of SEQ ID NO: 79. In particular embodiments, the 2A10 heavy chain is encoded by the sequence of SEQ ID NO: 160.

[0137] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2A10 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2A10 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 2A10 heavy chain includes SEQ ID NO: 820. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2A10 heavy chain includes the sequence of SEQ ID NO: 80. In particular embodiments, the 2A10 heavy chain is encoded by the sequence of SEQ ID NO: 161.

[0138] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 2D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 17. In some embodiments, the 2D6 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 2D6 light chain includes SEQ ID NO: 821. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 2D6 light chain includes the sequence of SEQ ID NO: 81. In particular embodiments, the 2D6 light chain is encoded by the sequence of SEQ ID NO: 162.

[0139] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2D6 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 2D6 heavy chain includes SEQ ID NO: 822. In some embodiments, the signal peptide includes the sequence ofSEQ ID NO: 43. In particular embodiments, the 2D6 heavy chain includes the sequence of SEQ ID NO: 82. In particular embodiments, the 2D6 heavy chain is encoded by the sequence of SEQ ID NO: 163.

[0140] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 2D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 32. In some embodiments, the 2D6 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 2D6 heavy chain includes SEQ ID NO: 823. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 2D6 heavy chain includes the sequence of SEQ ID NO: 83. In particular embodiments, the 2D6 heavy chain is encoded by the sequence of SEQ ID NO: 164.

[0141] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 3C2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 18. In some embodiments, the 3C2 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 3C2 light chain includes SEQ ID NO: 824. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 3C2 light chain includes the sequence of SEQ ID NO: 84. In particular embodiments, the 3C2 light chain is encoded by the sequence of SEQ ID NO: 165.

[0142] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 3C2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 33. In some embodiments, the 3C2 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 3C2 heavy chain includes SEQ ID NO: 825. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 3C2 heavy chain includes the sequence of SEQ ID NO: 85. In particular embodiments, the 3C2 heavy chain is encoded by the sequence of SEQ ID NO: 166.

[0143] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 3C2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 33. In some embodiments, the 3C2 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 3C2 heavy chain includes SEQ ID NO: 826. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 43. In particular embodiments, the 3C2 heavy chain includes the sequence of SEQ ID NO: 86. In particular embodiments, the 3C2 heavy chain is encoded by thesequence of SEQ ID NO: 167.

[0144] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1A5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 19. In some embodiments, the 1A5 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1A5 light chain includes SEQ ID NO: 827. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A5 light chain includes the sequence of SEQ ID NO: 87. In particular embodiments, the 1A5 light chain is encoded by the sequence of SEQ ID NO: 168.

[0145] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 34. In some embodiments, the 1A5 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1A5 heavy chain includes SEQ ID NO: 828. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A5 heavy chain includes the sequence of SEQ ID NO: 88. In particular embodiments, the 1A5 heavy chain is encoded by the sequence of SEQ ID NO: 169.

[0146] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 34. In some embodiments, the 1A5 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1A5 heavy chain includes SEQ ID NO: 829. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A5 heavy chain includes the sequence of SEQ ID NO: 89. In particular embodiments, the 1A5 heavy chain is encoded by the sequence of SEQ ID NO: 170.

[0147] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1A7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1A7 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1A7 light chain includes SEQ ID NO: 830. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A7 light chain includes the sequence of SEQ ID NO: 90. In particular embodiments, the 1A7 light chain is encoded by the sequence of SEQ ID NO: 171.

[0148] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chainof clone 1A7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 35. In some embodiments, the 1A7 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1A7 heavy chain includes SEQ ID NO: 831. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A7 heavy chain includes the sequence of SEQ ID NO: 91 . In particular embodiments, the 1A7 heavy chain is encoded by the sequence of SEQ ID NO: 172.

[0149] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1A7 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 35. In some embodiments, the 1A7 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1A7 heavy chain includes SEQ ID NO: 832. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1A7 heavy chain includes the sequence of SEQ ID NO: 92. In particular embodiments, the 1A7 heavy chain is encoded by the sequence of SEQ ID NO: 173.

[0150] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 B4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 18. In some embodiments, the 1B4 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 B4 light chain includes SEQ ID NO: 833. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1B4 light chain includes the sequence of SEQ ID NO: 93. In particular embodiments, the 1 B4 light chain is encoded by the sequence of SEQ ID NO: 174.

[0151] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 31. In some embodiments, the 1 B4 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 B4 heavy chain includes SEQ ID NO: 834. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B4 heavy chain includes the sequence of SEQ ID NO: 94. In particular embodiments, the 1B4 heavy chain is encoded by the sequence of SEQ ID NO: 175.

[0152] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B4 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 31 . In some embodiments, the 1 B4 heavy chain includes a human lgG4_S228P heavy chainconstant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 B4 heavy chain includes SEQ ID NO: 835. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B4 heavy chain includes the sequence of SEQ ID NO: 95. In particular embodiments, the 1 B4 heavy chain is encoded by the sequence of SEQ ID NO: 176.

[0153] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 B5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1B5 light chain includes a human lgt< light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 B5 light chain includes SEQ ID NO: 836. In some embodiments, the 1 signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1B5 light chain includes the sequence of SEQ ID NO: 96. In particular embodiments, the 1 B5 light chain is encoded by the sequence of SEQ ID NO: 177.

[0154] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 30. In some embodiments, the 1 B5 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 B5 heavy chain includes SEQ ID NO: 837. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B5 heavy chain includes the sequence of SEQ ID NO: 97. In particular embodiments, the 1B5 heavy chain is encoded by the sequence of SEQ ID NO: 178.

[0155] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B5 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 30. In some embodiments, the 1 B5 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 B5 heavy chain includes SEQ ID NO: 838. In some embodiments, the 1 B5 heavy chain includes a signal peptide having the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B5 heavy chain includes the sequence of SEQ ID NO: 98. In particular embodiments, the 1 B5 heavy chain is encoded by the sequence of SEQ ID NO: 179.

[0156] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 B6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 15. In some embodiments, the 1B6 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 B6 light chain includes SEQ ID NO: 839. In some embodiments, the signal peptide includes the sequence ofSEQ ID NO: 42. In particular embodiments, the 1B6 light chain includes the sequence of SEQ ID NO: 99. In particular embodiments, the 1 B6 light chain is encoded by the sequence of SEQ ID NO: 180.

[0157] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 36. In some embodiments, the 1 B6 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 B6 heavy chain includes SEQ ID NO: 840. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B6 heavy chain includes the sequence of SEQ ID NO: 100. In particular embodiments, the 1 B6 heavy chain is encoded by the sequence of SEQ ID NO: 181.

[0158] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 B6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 36. In some embodiments, the 1 B6 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 B6 heavy chain includes SEQ ID NO: 841. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 B6 heavy chain includes the sequence of SEQ ID NO: 101. In particular embodiments, the 1 B6 heavy chain is encoded by the sequence of SEQ ID NO: 182.

[0159] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 D3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1D3 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 D3 light chain includes SEQ ID NO: 842. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 D3 light chain includes the sequence of SEQ ID NO: 102. In particular embodiments, the 1 D3 light chain is encoded by the sequence of SEQ ID NO: 183.

[0160] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1D3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1 D3 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 D3 heavy chain includes SEQ ID NO: 843. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1D3 heavy chain includes the sequence of SEQ ID NO: 103. In particular embodiments, the 1 D3 heavy chain is encoded by the sequence of SEQID NO: 184.

[0161] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1D3 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 24. In some embodiments, the 1 D3 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 D3 heavy chain includes SEQ ID NO: 844. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 D3 heavy chain includes the sequence of SEQ ID NO: 104 In particular embodiments, the 1 D3 heavy chain is encoded by the sequence of SEQ ID NO: 185.

[0162] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 20. In some embodiments, the 1D6 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 D6 light chain includes SEQ ID NO: 845. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 D6 light chain includes the sequence of SEQ ID NO: 105. In particular embodiments, the 1 D6 light chain is encoded by the sequence of SEQ ID NO: 186.

[0163] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 37. In some embodiments, the 1 D6 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 D6 heavy chain includes SEQ ID NO: 846. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1D6 heavy chain includes the sequence of SEQ ID NO: 106. In particular embodiments, the 1 D6 heavy chain is encoded by the sequence of SEQ ID NO: 187.

[0164] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1D6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 37. In some embodiments, the 1 D6 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 D6 heavy chain includes SEQ ID NO: 847. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 D6 heavy chain includes the sequence of SEQ ID NO: 107. In particular embodiments, the 1 D6 heavy chain is encoded by the sequence of SEQ ID NO: 188.

[0165] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain ofclone 1 E2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 18. In some embodiments, the 1E2 light chain includes a human lgt< light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 E2 light chain includes SEQ ID NO: 848. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1E2 light chain includes the sequence of SEQ ID NO: 108. In particular embodiments, the 1 E2 light chain is encoded by the sequence of SEQ ID NO: 189.

[0166] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 E2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 38. In some embodiments, the 1 E2 heavy chain includes a human I gG 1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 E2 heavy chain includes SEQ ID NO: 849. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 E2 heavy chain includes the sequence of SEQ ID NO: 109. In particular embodiments, the 1 E2 heavy chain is encoded by the sequence of SEQ ID NO: 190.

[0167] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1 E2 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 38. In some embodiments, the 1 E2 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 E2 heavy chain includes SEQ ID NO: 850. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 E2 heavy chain includes the sequence of SEQ ID NO: 110. In particular embodiments, the 1 E2 heavy chain is encoded by the sequence of SEQ ID NO: 191.

[0168] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1G6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 23. In some embodiments, the 1G6 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1G6 light chain includes SEQ ID NO: 851. In some embodiments, the peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1G6 light chain includes the sequence of SEQ ID NO: 118. In particular embodiments, the 1G6 light chain is encoded by the sequence of SEQ ID NO: 199.

[0169] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 40. In some embodiments, the 1G6 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1G6 heavy chainincludes SEQ ID NO: 852. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1G6 heavy chain includes the sequence of SEQ ID NO: 119. In particular embodiments, the 1G6 heavy chain is encoded by the sequence of SEQ ID NO: 200.

[0170] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1G6 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 40. In some embodiments, the 1G6 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1G6 heavy chain includes SEQ ID NO: 853. In some embodiments, the a signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1G6 heavy chain includes the sequence of SEQ ID NO: 120. In particular embodiments, the 1G6 heavy chain is encoded by the sequence of SEQ ID NO: 201.

[0171] In particular embodiments, a light chain of an anti-CD45 antibody includes a light chain of clone 1 H1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 13. In some embodiments, the 1H1 light chain includes a human IgK light chain constant region having the sequence of SEQ ID NO: 1. In particular embodiments, the 1 H1 light chain includes SEQ ID NO: 854. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 H1 light chain includes the sequence of SEQ ID NO: 121. In particular embodiments, the 1 H1 light chain is encoded by the sequence of SEQ ID NO: 202.

[0172] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1H1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 41. In some embodiments, the 1 H1 heavy chain includes a human lgG1 heavy chain constant region having the sequence of SEQ ID NO: 3. In particular embodiments, the 1 H1 heavy chain includes SEQ ID NO: 855. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1H1 heavy chain includes the sequence of SEQ ID NO: 122. In particular embodiments, the 1 H1 heavy chain is encoded by the sequence of SEQ ID NO: 203.

[0173] In particular embodiments, a heavy chain of an anti-CD45 antibody includes a heavy chain of clone 1H1 and a signal peptide. In particular embodiments, the signal peptide includes SEQ ID NO: 41 . In some embodiments, the 1 H1 heavy chain includes a human lgG4_S228P heavy chain constant region having the sequence of SEQ ID NO: 11. In particular embodiments, the 1 H1 heavy chain includes SEQ ID NO: 856. In some embodiments, the signal peptide includes the sequence of SEQ ID NO: 42. In particular embodiments, the 1 H1 heavy chain includes thesequence of SEQ ID NO: 123. In particular embodiments, the 1 H1 heavy chain is encoded by the sequence of SEQ ID NO: 204.

[0174] In particular embodiments, the light and / or heavy chains described in any of SEQ ID NOs: 785-856 can also include a signal peptide. In particular embodiments, the signal peptide includes an immunoglobulin kappa signal peptide or osteonectin signal peptide. In particular embodiments, the immunoglobulin kappa signal peptide includes SEQ ID NO: 43. In particular embodiments, the osteonectin signal peptide includes SEQ ID NO: 42.

[0175] (ii) Antibody Variants. Antibodies disclosed herein can be utilized to prepare various forms of relevant binding domain molecules. For example, particular embodiments can include binding fragments of an antibody, e.g., Fv, Fab, Fab', F(ab')2, and single chain Fv fragments (scFvs) or any biologically effective fragments of an immunoglobulin that bind specifically to an epitope described herein.

[0176] In particular embodiments, an antibody fragment is used. An “antibody fragment” denotes a portion of a full-length antibody that retains the ability to bind to an epitope. Antibody fragments can be made by various techniques, including proteolytic digestion of an intact antibody as well as production by recombinant host-cells (e.g., mammalian suspension cell lines, E. coli or phage), as described herein. Antibody fragments can be screened for their binding properties in the same manner as intact antibodies. Examples of antibody fragments include Fv, scFv, Fab, Fab', Fab'- SH, F(ab')2j diabodies; and linear antibodies.

[0177] A single chain variable fragment (scFv) is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins connected with a short linker peptide. Fv fragments include the V and VHdomains of a single arm of an antibody but lack the constant regions. Although the two domains of the Fv fragment, V and VH, are coded by separate genes, they can be joined, using, for example, recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VLand VHregions pair to form monovalent molecules (single chain Fv (scFv)). For additional information regarding Fv and scFv, see e.g., Bird, et al., Science 242:423-426, 1988; Huston, et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988; Plueckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore (eds.), Springer-Verlag, New York), (1994) 269-315; WO 1993 / 16185; U.S. Pat. No. 5,571 ,894; and U.S. Pat. No. 5,587,458.

[0178] Linker sequences that are used to connect the VL and VH of an scFv are generally five to 35 amino acids in length. In particular embodiments, a VL-VH linker includes from five to 35, ten to 30 amino acids or from 15 to 25 amino acids. Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies. Linker sequences of scFv arecommonly Gly-Ser linkers.

[0179] In particular embodiments, the linker sequence includes sets of glycine and serine repeats such as from one to ten repeats of (GlyxSery)n, wherein x and y are independently an integer from 0 to 10 provided that x and y are not both 0 and wherein n is an integer of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10). Particular examples include (Gly4Ser)n(SEQ ID NO: 259), (Gly3Ser)n(Gly4Ser)n(SEQ ID NO: 260), (Gly3Ser)n(Gly2Ser)n (SEQ ID NO: 261), and (Gly3Ser)n(Gly4Ser)i (SEQ ID NO: 262). In particular embodiments, the linker is (Gly4Ser)4(SEQ ID NO: 263), (Gly4Ser)3(SEQ ID NO: 264), (Gly4Ser)2(SEQ ID NO: 265), (Gly4Ser)i (SEQ ID NO: 266), (Gly3Ser)2(SEQ ID NO: 267), (Gly3Ser)i (SEQ ID NO: 268), (Gly2Ser)2(SEQ ID NO: 269) or (Gly2Ser)i, GGSGGGSGGSG (SEQ ID NO: 270), GGSGGGSGSG (SEQ ID NO: 271), or GGSGGGSG (SEQ ID NO: 272).

[0180] In particular embodiments, a linker region is (GGGGS)n(SEQ ID NO: 259) wherein n is an integer including, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more. In particular embodiments, the linker includes the Whitlow linker: GSTSGSGKPGSGEGSTKG (SEQ ID NO: 766; Whitlow et al., Protein Eng 6(8):989-95, 1993). In particular embodiments, the spacer is (EAAAK)n(SEQ ID NO: 765) wherein n is an integer including 1 , 2, 3, 4, 5, 6, 7, 8, 9, or more.

[0181] Additional examples of antibody-based binding domain formats include scFv-based grababodies and soluble VH domain antibodies. These antibodies form binding regions using only heavy chain variable regions. See, for example, Jespers et al., Nat. Biotechnol. 22:1161 , 2004; Cortez-Retamozo et al., Cancer Res. 64:2853, 2004; Baral et al., Nature Med. 12:580, 2006; and Barthelemy et al., J. Biol. Chem. 283:3639, 2008.

[0182] A Fab fragment is a monovalent antibody fragment including VL, VH, CL and CH1 domains. A F(ab')2fragment is a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region. For discussion of Fab and F(ab')2fragments having increased in vivo half-life, see U.S. Patent 5,869,046. Diabodies include two epitope-binding sites that may be bivalent. See, for example, EP 0404097; WQ1993 / 01161 ; and Holliger, et al., Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993. Dual affinity retargeting antibodies (DART™; based on the diabody format but featuring a C-terminal disulfide bridge for additional stabilization (Moore et al., Blood 117:4542-51 , 2011)) can also be used. Antibody fragments can also include isolated CDRs. For a review of antibody fragments, see Hudson, et al., Nat. Med. 9:129-134, 2003.

[0183] In particular embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody, thereby generating an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., a human I gG 1 , lgG2, lgG3 or lgG4 Fc region) including an amino acid modification (e.g., a substitution) at one or more amino acid positions. Numerous Fc modifications are known in the art, and a representative sampling of such possiblemodifications are described herein.

[0184] In particular embodiments, variants (including Fc variants) have been modified from a reference sequence to produce an administration benefit. Exemplary administration benefits can include (1) reduced susceptibility to proteolysis, (2) reduced susceptibility to oxidation, (3) altered binding affinity for forming protein complexes, (4) altered binding affinities, (5) reduced immunogenicity; and / or (6) extended half-life. While the disclosure below describes these modifications in terms of their application to antibodies, when applicable to another particular anti- CD45 binding domain format (e.g., bispecific antibodies), the modifications can also be applied to these other formats.

[0185] In particular embodiments, an lgG4 Fc region is mutated to form the lgG4_S228P Fc region. lgG4 antibodies can undergo a process called Fab arm exchange which results in functionally monovalent, bispecific antibodies with unknown specificity and thus potentially reduced therapeutic efficacy. Mutating the wildtype lgG4 serine at position 228 within the corehinge region to a proline creates the lgG4_S228P mutant. In particular embodiments, the lgG4_S228P mutant prevents Fab arm exchange. In particular embodiments, the S228P mutation is located at residue 108 of SEQ ID NO: 11.

[0186] In particular embodiments the antibodies can be mutated to increase their affinity for Fc receptors. Exemplary mutations that increase the affinity for Fc receptors include: G236A / S239D / A330L / I332E (GASDALIE). Smith et al., Proceedings of the National Academy of Sciences of the United States of America, 109(16), 6181-6186, 2012. In particular embodiments, an antibody variant includes an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues). In particular embodiments, alterations are made in the Fc region that result in altered C1q binding and / or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551 , WO 99 / 51642, and Idusogie et al., J. Immunol. 164: 4178-4184, 2000.

[0187] In particular embodiments, it may be desirable to create cysteine engineered antibodies, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further below. In particular embodiments, residue 5400 (EU numbering) of the heavy chain Fc region is selected. Cysteine engineered antibodies may be generated as described, e.g., in U.S. Pat. No. 7,521 ,541.

[0188] Antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1 % to 80%, from 1 % to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., W02000 / 61739; WO 2001 / 29246; W02002 / 031140; US2002 / 0164328;W02003 / 085119; W02003 / 084570; US2003 / 0115614; US2003 / 0157108; US2004 / 0093621 ; US2004 / 0110704; US2004 / 0132140; US2004 / 0110282; US2004 / 0109865; W02005 / 035586; W02005 / 035778; W02005 / 053742; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); and Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545, 1986, and knockout cell lines, such as alpha- 1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki etal., Biotech. Bioeng. 87: 614, 2004; Kanda et al., Biotechnol. Bioeng., 94(4):680-688, 2006; and W02003 / 085107).

[0189] In particular embodiments, modified antibodies include those wherein one or more amino acids have been replaced with a non-amino acid component, or where the amino acid has been conjugated to a functional group or a functional group has been otherwise associated with an amino acid. The modified amino acid may be, e.g., a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, or an amino acid conjugated to an organic derivatizing agent. Amino acid(s) can be modified, for example, co-translationally or post-translationally during recombinant production (e.g., N-linked glycosylation at N-X-S / T motifs during expression in mammalian cells) or modified by synthetic means. The modified amino acid can be within the sequence or at the terminal end of a sequence. Modifications also include nitrited constructs.

[0190] In particular embodiments, variants include glycosylation variants wherein the number and / or type of glycosylation site has been altered compared to the amino acid sequences of a reference sequence. In particular embodiments, glycosylation variants include a greater or a lesser number of N-linked glycosylation sites than the reference sequence. An N-linkedglycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X can be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (e.g., those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the reference sequence. These cysteine variants can be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. These cysteine variants generally have fewer cysteine residues than the reference sequence, and typically have an even number to minimize interactions resulting from unpaired cysteines.

[0191] PEGylation particularly is a process by which polyethylene glycol (PEG) polymer chains are covalently conjugated to other molecules such as proteins. Several methods of PEGylating proteins have been reported in the literature. For example, N-hydroxy succinimide (NHS)-PEG was used to PEGylate the free amine groups of lysine residues and N-terminus of proteins; PEGs bearing aldehyde groups have been used to PEGylate the amino-termini of proteins in the presence of a reducing reagent; PEGs with maleimide functional groups have been used for selectively PEGylating the free thiol groups of cysteine residues in proteins; and site-specific PEGylation of acetyl-phenylalanine residues can be performed.

[0192] Covalent attachment of proteins to PEG has proven to be a useful method to increase the half-lives of proteins in the body (Abuchowski, A. et al., Cancer Biochem. Biophys., 1984, 7:175- 186; Hershfield, M. S. etal., N. Engl. J. Medicine, 1987, 316:589-596; and Meyers, F. J. et al., Clin. Pharmacol. Then, 49:307-313, 1991). The attachment of PEG to proteins not only protects the molecules against enzymatic degradation, but also reduces their clearance rate from the body. The size of PEG attached to a protein has significant impact on the half-life of the protein. The ability of PEGylation to decrease clearance is generally not a function of how many PEG groups are attached to the protein, but the overall molecular weight of the altered protein. Usually the larger the PEG is, the longer the in vivo half-life of the attached protein. In addition, PEGylation can also decrease protein aggregation (Suzuki et al., Biochem. Bioph. Acta 788:248, 1984), alter protein immunogenicity (Abuchowski et al., J. Biol. Chem. 252: 3582, 1977), and increase protein solubility as described, for example, in PCT Publication No. WO 92 / 16221).

[0193] Several sizes of PEGs are commercially available (Nektar Advanced PEGylation Catalog2005-2006; and NOF DDS Catalogue Ver 7.1), which are suitable for producing proteins with targeted circulating half-lives. A variety of active PEGs have been used including mPEG succinimidyl succinate, mPEG succinimidyl carbonate, and PEG aldehydes, such as mPEG- propionaldehyde.

[0194] In particular embodiments, the antibody can be fused or coupled to an Fc polypeptide that includes amino acid alterations that extend the in vivo half-life of an antibody that contains the altered Fc polypeptide as compared to the half-life of a similar antibody containing the same Fc polypeptide without the amino acid alterations. In particular embodiments, Fc polypeptide amino acid alterations can include M252Y, S254T, T256E, M428L, and / or N434S and can be used together, separately or in any combination. For example, M428L / N434S is a pair of mutations that increase the half-life of antibodies in serum, as described in Zalevsky et al., Nature Biotechnology 28, 157-159, 2010. Other alterations that can be helpful are described in US Patent No. 7,083,784, US Patent No. 7,670,600, US Publication No. 2010 / 0234575, PCT / US2012 / 070146, and Zwolak, Scientific Reports 7: 15521 , 2017. In particular embodiments, any substitution at one of the following amino acid positions in an Fc polypeptide can be considered an Fc alteration that extends half-life: 250, 251, 252, 259, 307, 308, 332, 378, 380, 428, 430, 434, 436. Each of these alterations or combinations of these alterations can be used to extend the half-life of a bispecific antibody as described herein.

[0195] In particular embodiments, Fc modifications include hulgG4 ProAlaAla, hulgG2m4, and / or hulgG2sigma mutations. In particular embodiments, one or several amino acids at the amino or carboxy terminus of the light and / or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. Substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No. 5,624,821 ; Tso et al., US Patent No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004). For additional information regarding Fc mutations that create administration benefits, see Saunders, Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life, Frontiers in Immunology (2019) Vol. 10, Article 1296.

[0196] (iii) Multi-Domain Binding Molecules. Multi-domain binding molecules include at least two binding domains, wherein at least one binding domain includes an anti-CD45 antibody disclosed herein. In particular embodiments, a multi-domain binding molecule includes at least one, at least two, at least, three, at least four binding domains that bind an epitope on CD45. In particular embodiments, all of the binding domains of a multi-domain binding molecule bind CD45.

[0197] Multi-domain binding molecules include bispecific antibodies which bind at least two epitopes wherein at least one of the epitopes is located on CD45. Multi-domain binding molecules include trispecific antibodies which binds at least 3 epitopes, wherein at least one of the epitopes is located on CD45, and so on.

[0198] Bispecific antibodies can be prepared utilizing antibody fragments (for example, F(ab')2bispecific antibodies). For example, WO 1996 / 016673 describes a bispecific anti-ErbB2 / anti-Fc gamma Rill antibody; US Pat. No. 5,837,234 describes a bispecific anti-ErbB2 / anti-Fc gamma Rl antibody; WO 1998 / 002463 describes a bispecific anti-ErbB2 / Fc alpha antibody; and US 5,821 ,337 describes a bispecific anti-ErbB2 / anti-CD3 antibody.

[0199] Some additional exemplary bispecific antibodies have two heavy chains (each having three heavy chain CDRs, followed by (N-terminal to C-terminal) a CH1 domain, a hinge, a CH2 domain, and a CH3 domain), and two immunoglobulin light chains that confer antigen-binding specificity through association with each heavy chain. However, as indicated, additional architectures are envisioned, including bi-specific antibodies in which the light chain(s) associate with each heavy chain but do not (or minimally) contribute to antigen-binding specificity, or that can bind one or more of the epitopes bound by the heavy chain antigen-binding regions, or that can associate with each heavy chain and enable binding of one or both of the heavy chains to one or both epitopes.

[0200] Two antibodies or fragments thereof can be linked through a linker to form a bispecific antibody. In particular embodiments, the two antibodies or fragments thereof can bind the same epitope or different epitopes. Examples of linkers can be found in Chen et al., Adv Drug Deliv Rev. 2013 Oct 15; 65(10): 1357-1369. Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target.

[0201] Commonly used flexible linkers include linker sequence with the amino acids glycine and serine (Gly-Ser linkers) which are described elsewhere herein.

[0202] Linkers that include one or more antibody hinge regions and / or immunoglobulin heavy chain constant regions, such as CH3 alone or a CH2CH3 sequence can also be used. Additional examples of linkers can be found in Chen et al., Adv Drug Deliv Rev. 2013 Oct 15; 65(10): 1357- 1369. Linkers can be flexible, rigid, or semi-rigid, depending on the desired functional domain presentation to a target.

[0203] In some situations, flexible linkers may be incapable of maintaining a distance or positioning of binding domains needed for a particular use. In these instances, rigid or semi-rigid linkers may be useful. Examples of rigid or semi-rigid linkers include proline-rich linkers. In particular embodiments, a proline-rich linker is a peptide sequence having more proline residuesthan would be expected based on chance alone. In particular embodiments, a proline-rich linker is one having at least 30%, at least 35%, at least 36%, at least 39%, at least 40%, at least 48%, at least 50%, or at least 51 % proline residues. Particular examples of proline-rich linkers include fragments of proline-rich salivary proteins (PRPs).

[0204] In particular embodiments, binding domains disclosed herein can be used to create bi-, tri, (or more) specific immune cell engaging molecules. Immune cell engaging molecules have at least one binding domain that binds a receptor on an immune cell and alters the activation state of the immune cell. Examples of multi-domain immune cell engaging molecules include those which bind both an immune cell (e.g., T-cell or NK-cells) activating epitope and CD45, with the goal of bringing immune cells to CD45-expressing cells to destroy them. See, for example, US 2008 / 0145362. Such molecules are referred to herein as immune-activating multi-specifics or I- AMS). BiTEs® (Amgen, Thousand Oaks, CA) are one form of l-AMS. Immune cells that can be targeted for localized activation by l-AMS within the current disclosure include, for example, B- cells, T-cells, natural killer (NK) cells, and macrophages which are discussed in more detail herein.

[0205] l-AMS disclosed herein can target any T-cell activating epitope that upon binding induces T-cell activation. Examples of such T-cell activating epitopes are on T-cell markers including CD2, CD3, CD7, CD27, CD28, CD30, CD40, CD83, 4-1 BB (CD137), 0X40, lymphocyte function- associated antigen-1 (LFA-1), LIGHT, NKG2C, and B7-H3.

[0206] In particular embodiments, the CD3 binding domain (e.g., scFv) is derived from the OKT3 antibody (the same as the one utilized in blinatumomab), otelixizumab, teplizumab, visilizumab, 20G6-F3, 4B4-D7, 4E7-C9, 18F5-H10, or TR66. The OKT3 antibody is described in detail in U.S. Patent No. 5,929,212.

[0207] In particular embodiments, the OKT3 binding domain includes a light chain variable region of QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFR GSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (SEQ ID NO: 273) and a heavy chain variable region of QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYN QKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSAKTTA PSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSV TVTSS (SEQ ID NO: 274).

[0208] In particular embodiments, the binding domain includes a light chain variable region including a CDRL1 sequence including SASSSVSYMN (SEQ ID NO: 275), a CDRL2 sequence including DTSKLAS (SEQ ID NO: 276), a CDRL3 sequence including QQWSSNPFTF (SEQ IDNO: 277), a CDRH1 sequence including RYTMH (SEQ ID NO: 278), a CDRH2 sequence including YINPSRGYTNYNQKFKD (SEQ ID NO: 279), and a CDRH3 sequence including YYDDHYCL (SEQ ID NO: 280). In particular embodiments, the binding domain is human. For more information regarding binding domains that bind CD3, see U.S. Pat. No. 8785604, PCT / US 17 / 42264, and / or W002051871.

[0209] In particular embodiments, a binding domain is “derived from” a reference antibody when the binding domain includes the CDRs of the reference antibody, according to a known numbering scheme (e.g., Kabat, Chothia, Martin, or others).

[0210] CD28 binds to B7-1 (CD80) and B7-2 (CD86) and is the most potent of the known costimulatory molecules (June et al., Immunol. Today 15:321 , 1994; Linsley et al., Ann. Rev. Immunol. 11 :191 , 1993). In particular embodiments, the CD28 binding domain is derived from TGN1412, CD80, CD86 or the 9D7 antibody. Additional antibodies that bind CD28 include 9.3, KOLT-2, 15E8, 248.23.2, and EX5.3D10.

[0211] In particular embodiments, the binding domain that binds CD28 is derived from TGN-1412 and / or theralizumab. In particular embodiments, the binding domain includes a light chain variable region of DIQMTQSPSSLSASVGDRVTITCKTNENIYSNLAWYQQKDGKSPQLLIYAATHLVEGVPSRFSG SGSGTQYSLTISSLQPEDFGNYYCQHFWGTPXTFGGGTKLEI KR, wherein X=C, A, or N. (SEQ ID NO: 281) and a heavy chain variable region of VQLQQSGAELKKPGASVKVSCKASGYTFTEYIIHWIKLRSGQGLEWIGWFYPGSNDIQYNAQF KGKATLTADKSSSTVYMELTGLTPEDSAVYFCARRDDFSGYDALPYWGQGTLVTVSA (SEQ ID NO: 282).

[0212] In particular embodiments, the binding domain includes a light chain variable region including a CDRL1 sequence including HASQNIYVWLN (SEQ ID NO: 283), a CDRL2 sequence including KASNLHT (SEQ ID NO: 284), a CDRL3 sequence including QQGQTYPYT (SEQ ID NO: 285), a CDRH1 sequence including SYYIH (SEQ ID NO: 286), a CDRH2 sequence including CIYPGNVNTNYNEKFKD (SEQ ID NO: 287), and a CDRH3 sequence including SHYGLDWNFDV (SEQ ID NO: 288). In particular embodiments, the binding domain is human. For more information regarding binding domains that bind CD28, see U.S. Pat. No. US8785604 and / or W002051871.

[0213] Activated T-cells express 4-1 BB (CD137). In particular embodiments, the 4-1 BB binding domain includes a light chain variable region including a CDRL1 sequence including RASQSVS (SEQ ID NO: 289), a CDRL2 sequence including ASNRAT (SEQ ID NO: 290), and a CDRL3 sequence including QRSNWPPALT (SEQ ID NO: 291) and a heavy chain variable regionincluding a CDRH1 sequence including YYWS (SEQ ID NO: 292), a CDRH2 sequence including INH, and a CDRH3 sequence including YGPGNYDWYFDL (SEQ ID NO: 293).

[0214] Particular embodiments disclosed herein including binding domains that bind epitopes on CD8. In particular embodiments, the CD8 binding domain (e.g., scFv) is derived from the OKT8 antibody.

[0215] In particular embodiments natural killer cells (also known as NK-cells, K-cells, and killer cells) are targeted for localized activation by l-AMS. NK cells can induce apoptosis or cell lysis by releasing granules that disrupt cellular membranes and can secrete cytokines to recruit other immune cells.

[0216] Examples of commercially available antibodies that bind to an NK cell receptor and induce and / or enhance activation of NK cells include: 5C6 and 1D11 , which bind and activate NKG2D (available from BioLegend® San Diego, CA); mAb 33, which binds and activates KIR2DL4 (available from BioLegend®); P44-8, which binds and activates NKp44 (available from BioLegend®); SK1 , which binds and activates CD8; and 3G8 which binds and activates CD16.

[0217] Binding domains of l-AMS and other engineered formats described herein may be joined through a linker. As indicated previously, a linker is an amino acid sequence which can provide flexibility and room for conformational movement between the binding domains of a l-AM. Any appropriate linker may be used.

[0218] Other forms of bispecific binding molecules include the single chain “Janusins” described in Traunecker et al. (Embo Journal, 10, 3655-3659, 1991).

[0219] Bispecific binding molecules with extended half-lives are described in, for example, US Patent No. 8,921,528 and US Patent Publication No. 2014 / 0308285.

[0220] Because albumin has an extended serum half-life, it can be of use in improving the pharmacokinetics of administered anti-CD45 antibodies. In particular embodiments, anti-CD45 antibodies can be linked to albumin. In other particular embodiments, anti-CD45 antibodies can be linked to albumin-binding domains (ABDs). ABDs include, for example, albumin-binding peptides, antibodies, antibody fragments, and designed ankyrin repeat proteins (DARPins).

[0221] In particular embodiments, multi-domain binding molecules with extended half-lives include multi-domain binding molecules wherein at least one binding domain binds albumin. In particular embodiments, the multi-domain binding molecule that binds albumin includes a binding domain that binds CD45 linked to a binding domain that binds albumin.

[0222] In particular embodiments, an albumin-binding domain has the sequence: DITGAALLEAKEAAINELKQYGISDYYVTLINKAKTVEGVNALKAEILSALP (SEQ ID NO: 294). In particular embodiments, an albumin-binding domain includes a variant of the sequence of SEQID NO: 294, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: E12D, T29H-K35D, and A45D.

[0223] In particular embodiments, an albumin-binding domain includes the sequence: LKEAKEKAIEELKKAGITSDYYFDLINKAKTVEGVNALKDEILKA (SEQ ID NO: 295). In particular embodiments, an albumin-binding domain includes a variant of the sequence of SEQ ID NO: 295, wherein the variant sequence is modified by at least one amino acid substitution selected from the group including: Y21 , Y22, L25, K30, T31 , E33, G34, A37, L38, E41 , I42 and A45.

[0224] Additional binding domains that bind albumin include CA645 as described in Adams et al., 2016 MAbs 8(7): 1336-1346 (see, e.g., Protein Data Bank accession codes 5FUZ and 5FUO); anti-HSA Nanobody™ (Ablynx, Ghent, Belgium), AlbudAb™ (GlaxoSmithKline, Brentford, United Kingdom), and other high-affinity albumin nanobody sequences as described in Shen et al., 2020 bioRxivdov. https: / / doi.org / 10.1101 / 2020.08.19.257725; Mester, et al., 2021 mAbs. 13:1 ; Tijink et al., 2008 Mol Cancer Ther (7) (8) 2288-2297; and Roovers et al., Cancer Immunol Immunother 2007; 56: 303-317.

[0225] In particular embodiments, multi-domain binding molecules are multimers of an antibody disclosed herein. Multimerization strategies include formation of a fusion protein using protein linkers or use of IgA or IgM constant regions as a multimerization scaffold. In certain aspects, multimerization is achieved by linking antibodies or binding domains of antibodies in a fusion protein with protein linkers. Fusion proteins include different protein domains linked to each other directly or through intervening linker segments such that the function of each included domain is retained.

[0226] Certain examples include fusion protein with two or three copies of an antibody or binding domain disclosed herein (e.g., an anti-CD45 antibody), each linked with the Gly-Ser linker (Gly4Ser)n(SEQ ID NO: 259) wherein n is an integer of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10. In particular embodiments, n is 3.

[0227] A “multimerization domain” is a domain that causes two or more proteins (monomers) to interact with each other through covalent and / or non-covalent association(s). Multimerization domains are highly conserved protein sequences that can include different types of sequence motifs such as leucine zipper, helix loop-helix, ankyrin and PAS (Feuerstein et al, Proc. Natl. Acad. Sci. USA, 91:10655-10659, 1994). Multimerization domains present in proteins can bind to form dimers, trimers, tetramers, pentamers, hexamers, heptamers, etc., depending on the number of units / monomers incorporated into the multimer, and / or homomultimers or heteromultimers, depending on whether the binding monomers are the same type or a different type (US Patent No. 10030065).

[0228] Dimerization domains can include protein sequence motifs such as coiled coils, acid patches, zinc fingers, calcium hands, a CH1-CL pair, an "interface" with an engineered "knob" and / or "protruberance" (US 5821333), leucine zippers (US 5932448), SH2 and SH3 (Vidal et al., Biochemistry, 43:7336- 44, 2004), PTB (Zhou et al., Nature, 378:584- 592, 1995), WW (Sudol Prog Biochys MoL Bio, 65:113-132, 1996), PDZ (Kim et al., Nature, 378: 85-88, 1995; Komau et al., Science, 269:1737-1740, 1995) and WD40 (Hu et al., J Biol Chem., 273:33489- 33494, 1998). Additional examples of molecules that contain dimerization domains / motifs are receptor dimer pairs such as the interleukin-8 receptor (IL-8R), integrin heterodimers such as LFA-I and GPU Ib / ll la, dimeric ligand polypeptides such as nerve growth factor (NGF), neurotrophin-3 (NT- 3), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), VEGF-C, VEGF-D, PDGF members, and brain-derived neurotrophic factor (BDNF) (Arakawa et al., J Biol. Chem., 269:27833-27839, 1994; Radziejewski et al., Biochem, 32: 1350, 1993) and variants of some of these domains with modified affinities (PCT Publication No. WO 2012 / 001647).

[0229] In particular embodiments, the sequence corresponding to a dimerization motif / domain includes the leucine zipper domain of Jun (US5932448;RIARLEEKVKTLKAQNSELASTANMLREQVAQLKQKVMN (SEQ ID NO: 296)), the dimerization domain of Fos (US 5932448; LTDTLQAETDQLEDKKSALQTEIANLLKEKEKLEFILAA (SEQ ID NO: 297)), a consensus sequence for a WW motif (PCT Publication No. WO 1997 / 037223), the dimerization domain of the SH2B adapter protein from GenBank Accession no. AAF73912.1 (Nishi et al., Mol Cell Biol, 25: 2607-2621 , 2005;WREFCESHARAAALDFARRFRLYLASHPQYAGPGAEAAFSRRFAELFLQHFEAEVARAS (SEQ ID NO: 298)), the SH3 domain of IB1 from GenBank Accession no. AAD22543.1 (Kristensen el al., EMBO J., 25: 785-797, 2006;THRAIFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMRTGARGVFPAYYAIE (SEQ ID. NO: 388)), the PTB domain of human DOK-7 from GenBank Accession no. NP_005535.1 (Wagner et al., Cold Spring Harb Perspect Biol. 5: a008987, 2013;LGEVHRFHVTVAPGTKLESGPATLHLCNDVLVLARDIPPAVTGQWKLSDLRRYGAVPSGFIFEG GTRCGYWAGVFFLSSAEGEQISFLFDCIVRGISPTKG (SEQ ID NO: 299)), the PDZ-like domain of SATB1 from UniProt Accession No. Q01826 (Galande et al., Mol Cell Biol. Aug; 21: 5591-5604, 2001 ;DCKEEHAEFVLVRKDMLFNQLIEMALLSLGYSHSSAAQAKGLIQVGKWNPVPLSYVTDAPDAT VADMLQDVYHVVTLKIQLHSCPKLEDLPPEQWSHTTVRNALKDLLKDMNQSS (SEQ ID NO: 300)), the WD40 repeats of APAF from UniProt Accession No. 014727 (Jorgensen et al., 2009. PLOS One. 4(12):e8463;CAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRN ASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINT EDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIG NVSTPLMCLSESTNSTERNVMWGGCGSQLFSYAAFSDSNIITVVVDTALYIAKQNSPWEVWD KKTEKLCGLIDCVHFLREVMVKETKIFSFSNDFTIQKLIETRTNKESKHKMSYSGRVKTLCLQKN TALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQ KEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE (SEQ ID NO: 301)), the PAS motif of the dioxin receptor from UniProt Accession No. I6L9E7 (Pongratz et al., Mol Cell Biol, 18:4079- 4088, 1998;DQELKHLILEAADGFLFIVSCETGRVVYVSDSVTPVLNQQQSEWFGSTLYDQVHPDDVDKLRE QLSTSENALTGR (SEQ ID NO: 302)) and the EF hand motif of parvalbumin from UniProt Accession No. P20472 (Jamalian et al., Int J Proteomics, 2014: 153712, 2014;LSAKETKMLMAAGDKDGDGKIGVDEFSTLVAES (SEQ ID NO: 303)).

[0230] In particular embodiments, the dimerization domain can be a dimerization and docking domain (DDD) on one antibody and an anchoring domain (AD) on another antibody to facilitate a stably tethered structure. In particular embodiments, the DDD (DDD1 and DDD2) are derived from the regulatory subunits of a cAMP-dependent protein kinase (PKA), and the AD (AD1 and AD2) are derived from a specific region found in various A-kinase anchoring proteins (AKAPs) that mediates association with the R subunits of PKA. In particular embodiments, DDD1 includes the amino acid sequence: SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 304). In particular embodiments, DDD2 includes the amino acid sequence: CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA (SEQ ID NO: 305). In particular embodiments, AD1 includes the amino acid sequence: QIEYLAKQIVDNAIQQA (SEQ ID NO: 306). In particular embodiments, AD2 includes the amino acid sequence: CGQIEYLAKQIVDNAIQQAGC (SEQ ID NO: 307). However, one skilled in the art will realize that other DDDs and ADs are known and can be used such as: the 4-helix bundle type DDD domains may be obtained from p53, DCoH (pterin 4 alpha carbinolamine dehydratase / dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)) and HNF-1 (hepatocyte nuclear factor 1). Other AD sequences of potential use may be found in Patent Publication No. US2003 / 0232420A1.

[0231] The X-type four-helix bundle dimerization motif that is a structural characteristic of the DDD (Newlon, et al. EMBO J. 2001 ; 20: 1651-1662; Newlon, et al. Nature Struct Biol. 1999; 3: 222-227) is found in other classes of proteins, such as the S100 proteins (for example, S100B and calcyclin), and the hepatocyte nuclear factor (HNF) family of transcriptional factors (for example, HNF-1 a and HNF-1 P). Over 300 proteins that are involved in either signal transductionor transcriptional activation also contain a module of 65-70 amino acids termed the sterile a motif (SAM) domain, which has a variation of the X-type four-helix bundle present on its dimerization interface. For S100B, this X-type four-helix bundle enables the binding of each dimer to two p53 peptides derived from the c-terminal regulatory domain (residues 367-388) with micromolar affinity (Rustandi, et al. Biochemistry. 1998; 37: 1951-1960). Similarly, the N-terminal dimerization domain of HNF-1a (HNF-p1) was shown to associate with a dimer of DCoH (dimerization cofactor for HNF-1) via a dimer of HNF-p1 (Rose, et al. Nature Struct Biol. 2000; 7: 744-748). In alternative embodiments, these naturally occurring systems can also be used to provide stable multimeric structures with multiple functions or binding specificities. Other binding events such as those between an enzyme and its substrate / inhibitor, for example, cutinase and phosphonates (Hodneland, et al. Proc Natl Acd Sci USA. 2002; 99: 5048-5052), may also be utilized to generate the two associating components (the “docking” step), which are subsequently stabilized covalently (the “lock” step).

[0232] In particular embodiments, dimerization of antibodies can be induced by a chemical inducer. This method of dimerization requires one antibody to contain a chemical inducer of dimerization binding domain 1 (CBD1) and the second antibody to contain the second chemical inducer of dimerization binding domain (CBD2), wherein CBD1 and CBD2 are capable of simultaneously binding to a chemical inducer of dimerization (CID). If the CID is rapamycin, CBD1 and CBD2 can be the rapamycin binding domain of FK-binding protein 12 (FKBP12) and the FKBP12-Rapamycin Binding (FRB) domain of mTOR. In particular embodiments, FKBP12 includes the sequence: MGVQVETISPGDGRTFPKRGQTCWHYTGMLEDGKKFDSSRDRNPFKFMLGKQEVIRGWEEG VAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLE (SEQ ID NO: 308).

[0233] In particular embodiments, FRB includes the sequence:MASRILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRD LMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKLES (SEQ ID NO: 309). If the CID is FK506 / cyclosporin fusion protein or a derivative thereof, CBD1 and CBD2 can be the FK506 (Tacrolimus) binding domain of FK-binding protein 12 (FKBP12) and the cyclosporin binding domain of cylcophilin A. If the CID is estrone / biotin fusion protein or a derivative thereof, CBD1 and CBD2 can be an oestrogen-binding domain (EBD) and a streptavidin binding domain. If the CID is dexamethasone / methotrexate fusion molecule or a derivative thereof, CBD1 and CBD2 can be a glucocorticoid-binding domain (GBD) and a dihydrofolate reductase (DHFR) binding domain. If the CID is O6-benzylguanine derivative / methotrexate fusion molecule or a derivative thereof, CBD1 and CBD2 can be an O6-alkylguanine-DNA alkyltransferase (AGT) binding domainand a dihydrofolate reductase (DHFR) binding domain. If the CID is RSL1 or a derivative thereof, CBD1 and CBD2 can be a retinoic acid receptor domain and an ecodysone receptor domain. If the CID is AP1903 or a derivative thereof, CBD1 and CBD2 can be the FK506 binding protein (FKBP12) binding domains including a F36V mutation. Use of the CID binding domains can also be used to alter the affinity to the CID. For instance, altering amino acids at positions 2095, 2098, and 2101 of FRB can alter binding to Rapamycin: KTW has high, KHF intermediate and PLW is low (Bayle et al, Chemistry & Biology 13, 99-107, January 2006).

[0234] In particular embodiments, antibodies can multimerize using a transmembrane polypeptide derived from a FCERI chain. In particular embodiments, an antibody can include a part of a FCERI alpha chain and another antibody can include a part of an FCERI beta chain or variant thereof such that said FCERI chains spontaneously dimerize together to form a dimeric antibody. In particular embodiments, antibodies can include a part of a FCERI alpha chain and a part of a FCERI gamma chain or variant thereof such that said FCERI chains spontaneously trimerize together to form a trimeric antibody, and in another embodiment the multi-chain antibody can include a part of FCERI alpha chain, a part of FCERI beta chain and a part of FCERI gamma chain or variants thereof such that said FCERI chains spontaneously tetramerize together to form a tetrameric antibody.

[0235] In particular embodiments, additional methods of causing dimerization can be utilized. Additional modifications to generate a dimerization domain in antibody could include: replacing the C-terminus domain with murine counterparts; generating a second interchain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both antibodies; swapping interacting residues in each of the antibodies in the C-terminus domains (“knob-in-hole”); and fusing the variable domains of the antibodies directly to CD3 (CD3 fusion) (Schmitt et al., Hum. Gene Ther. 2009. 20:1240-1248).

[0236] Particular embodiments can utilize multimerization domains, such as C4b multimerization domains or ferritin multimerization domains. Full-length native C4b includes seven a-chains linked together by a multimerization (i.e., heptamerization) domain at the C-terminus of the a-chains. Blom et al., (2004) Mol Immunol 40: 1333-1346. Ferritin is an iron storage protein found in almost all living organisms, and has been extensively studied and engineered for a number of biochemical / biomedical purposes (US 20090233377; Meldrum, et al. Science 257, 522-523 (1992); U.S. 20110038025; Yamashita, Biochim Biophys Acta 1800, 846-857 (2010), including as a multimerizing vaccine platform for displaying peptide epitopes (US 20060251679 (2006); Li, et al. Industrial Biotechnol 2, 143-147 (2006)).

[0237] Mutlimerization with encapsulin and lumazine synthase can also be performed. Both canbe linked to antibodies to create self-assembling 60mer particles (Jardine et al., 2013, Science 340, 711-716 and Kanekiyo et al., 2015, Cell 162, 1090-1100).

[0238] Multimerized antibodies and antibody-like molecules such as IgA and IgM antibodies have emerged as promising drug candidates in the fields of, e.g., immuno-oncology and infectious diseases allowing for improved specificity, improved avidity, and the ability to bind to multiple binding targets. See, e.g., U.S. Patent Nos. 9,951 ,134, 10,400,038, and 9,938,347, U.S. Patent Application Publication Nos. US20190100597A1 , US20180118814A1 , US20180118816A1 , US20190185570A1 , and US20180265596A1 , and PCT Publication Nos. WO 2018 / 017888, WO 2018 / 017763, WO 2018 / 017889, WO 2018 / 017761, and WO 2019 / 165340.

[0239] Particular embodiments include using IgA and IgM constant region domains to allow the binding portion of molecules provided herein to readily multimerize into dimers, pentamers or hexamers. Basic immunoglobulin structures in vertebrate systems are described above and are well understood. (See, e.g., Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 2nd ed. 1988).

[0240] Immunoglobulin A (IgA), as the major class of antibody present in the mucosal secretions of most mammals, represents a key first line of defense against invasion by inhaled and ingested pathogens. IgA is also found at significant concentrations in the serum of many species, where it functions as a second line of defense mediating elimination of pathogens that have breached the mucosal surface. Receptors specific for the Fc region of IgA, FcaR, are key mediators of IgA effector function. Native IgA is a tetrameric protein including two identical light chains (K or A) and two identical heavy chains. IgA, similarly to IgG, contains three constant domains (CA1-CA3), with a hinge region between the CA1 and CA2 domains. The main difference between lgA1 and lgA2 resides in the hinge region that lies between the two Fab arms and the Fc region. I gA1 has an extended hinge region due to the insertion of a duplicated stretch of amino acids, which is absent in lgA2. Both forms of IgA have the capacity to form dimers, in which two monomer units, are arranged in an end-to-end configuration stabilized by disulfide bridges and incorporation of a J-chain. J-chains are also part of IgM pentamers and are discussed in more detail below.

[0241] Both IgA and IgM (discussed further below in relation to pentamers and hexamers) possess an 18-amino acid extension in the C terminus called the "tailpiece" (tp). The IgA and IgM tp is highly conserved among various animal species. The conserved penultimate cysteine residue in the IgA and IgM tp has been demonstrated to be involved in multimerization by forming a disulfide bond between heavy chains to permit formation of a multimer. Both tp contain an N- linked carbohydrate addition site, the presence of which is required for dimer formation in IgA and J-chain incorporation and pentamer formation in IgM. However, the structure and composition ofthe N-linked carbohydrates in the tp differ, suggesting differences in the accessibility of the glycans to processing by glycosyltransferases. Particularly, the IgA (atp) and IgM (ptp) tp differ at seven amino acid positions.

[0242] The human lgA1 constant region typically includes the amino acid sequence: ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDASGDL YTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPR LSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLCGCYSVSSVL PGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEELALNELVTLTCLAR GFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMV GHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 312). Referring to this SEQ ID NO: 312, the human CA1 domain extends from amino acid 6 to amino acid 98; the human lgA1 hinge region extends from amino acid 102 to amino acid 124, the human CA2 domain extends from amino acid 125 to amino acid 219, the human CA3 domain extends from amino acid 228 to amino acid 330, and the tp extends from amino acid 331 to amino acid 352.

[0243] The human lgA2 constant region typically includes the amino acid sequence ASPTSPKVFPLSLDSTPQDGNWVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDASGD LYTTSSQLTLPATQCPDGKSVTCHVKHYTNPSQDVTVPCPVPPPPPCCHPRLSLHRPALEDLL LGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGCAQPWNHG ETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLARGFSPKDVLVRW LQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDTFSCMVGHEALPLAFTQK TIDRLAGKPTHVNVSVVMAEVDGTCY (SEQ ID NO: 313). Referring to this SEQ ID NO: 313, the human CA1 domain extends from amino acid 6 to amino acid 98, the human lgA2 hinge region extends from amino acid 102 to amino acid 111 , the human CA2 domain extends from amino acid 113 to amino acid 206, the human CA3 domain extends from amino acid 215 to amino acid 317, and the tp extends from amino acid 318 to amino acid 340.

[0244] As indicated, two IgA binding units can form a complex with two additional polypeptide chains, the J chain (e.g., SEQ ID NO: 326, the mature human J chain) and the secretory component to form a bivalent secretory IgA (slgA)-derived binding molecule. An exemplary precursor secretory component includes the sequence: MLLFVLTCLLAVFPAISTKSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGC ITLISSEGYVSSKYAGRANLTNFPENGTFWNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVS QGPGLLNDTKVYTVDLGRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRL DIQGTGQLLFSVVINQLRLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFH CALGPEVANVAKFLCRQSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSVVITGLRKEDAGRYLCGAHSDGQLQEGSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIK YWCLWEGAQNGRCPLLVDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTN GDTLWRTTVEIKIIEGEPNLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALP SQDEGPSKAFVNCDENSRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAA GSRDVSLAKADAAPDEKVLDSGFREIENKAIQDPRLFAEEKAVADTRDQADGSRASVDSGSSE EQGGSSRALVSTLVPLGLVLAVGAVAVGVARARHRKNVDRVSIRSYRTDISMSDFENSREFGA NDNMGASSITQETSLGGKEEFVATTESTTETKEPKKAKRSSKEEAEMAYKDFLLQSSTVAAEA QDGPQEA (SEQ ID NO: 310). An exemplary mature secretory component includes KSPIFGPEEVNSVEGNSVSITCYYPPTSVNRHTRKYWCRQGARGGCITLISSEGYVSSKYAGR ANLTNFPENGTFVVNIAQLSQDDSGRYKCGLGINSRGLSFDVSLEVSQGPGLLNDTKVYTVDL GRTVTINCPFKTENAQKRKSLYKQIGLYPVLVIDSSGYVNPNYTGRIRLDIQGTGQLLFSVVINQL RLSDAGQYLCQAGDDSNSNKKNADLQVLKPEPELVYEDLRGSVTFHCALGPEVANVAKFLCR QSSGENCDVVVNTLGKRAPAFEGRILLNPQDKDGSFSWITGLRKEDAGRYLCGAHSDGQLQE GSPIQAWQLFVNEESTIPRSPTVVKGVAGGSVAVLCPYNRKESKSIKYWCLWEGAQNGRCPLL VDSEGWVKAQYEGRLSLLEEPGNGTFTVILNQLTSRDAGFYWCLTNGDTLWRTTVEIKIIEGEP NLKVPGNVTAVLGETLKVPCHFPCKFSSYEKYWCKWNNTGCQALPSQDEGPSKAFVNCDEN SRLVSLTLNLVTRADEGWYWCGVKQGHFYGETAAVYVAVEERKAAGSRDVSLAKADAAPDEK VLDSGFREIENKAIQDPR (SEQ ID NO: 311). While not wishing to be bound by theory, and as indicated above, the assembly of two IgA binding units into a dimeric IgA-derived binding molecule is thought to involve the CA3 and tp domains. See, e.g., Braathen, R., el al., J. Biol. Chem. 277:42755-42762 (2002). Accordingly, a multimerizing dimeric IgA-derived binding molecule provided in this disclosure typically includes IgA constant regions that include at least the CA3 and tp domains.

[0245] An engineered IgA heavy chain constant region can additionally include a CA2 domain or a fragment thereof, an IgA hinge region or fragment thereof, a CA1 domain or a fragment thereof, and / or other IgA (or other immunoglobulin, e.g., IgG) heavy chain domains, including, e.g., an IgG hinge region. In certain embodiments, a binding molecule as provided herein can include a complete IgA heavy chain constant region (e.g., SEQ ID NO: 312 or SEQ ID NO: 313), or a variant, derivative, or analog thereof.

[0246] In particular embodiments, the IgA heavy chain constant regions can include amino acids 125 to 353 of SEQ ID NO: 312 or amino acids 113 to 340 of SEQ ID NO: 313. In particular embodiments, the IgA heavy chain constant regions can each further include an IgA or IgG hinge region situated N-terminal to the IgA CA2 domains. For example, the IgA heavy chain constant regions can include amino acids 102 to 353 of SEQ ID NO: 312 or amino acids 102 to 340 of SEQID NO: 313. In particular embodiments, the IgA heavy chain constant regions can each further include an IgA CA1 domain situated N-terminal to the IgA hinge region.

[0247] Each of the strategies discussed above can be used to create IgA antibody-based dimers.

[0248] Particular embodiments include IgM immunoglobulin constant region domains that allow the binding portion of molecules provided herein to readily multimerize into pentamers or hexamers.

[0249] Particular embodiments include IgM constant regions (or variants thereof). These embodiments have the ability to form hexamers, or in association with a J-chain, form pentamers. Embodiments with an IgM constant region typically include at least the Cp4-tp domains of the IgM constant region but can include heavy chain constant region domains from other antibody isotypes, e.g., IgG, from the same species or from a different species. In particular embodiments, one or more constant region domains can be deleted so long as the IgM antibody is capable of forming hexamers and / or pentamers. Thus, an IgM antibody can be, e.g., a hybrid IgM / IgG antibody or can be a “multimerizing fragment” of an IgM-derived binding molecule.

[0250] The assembly of five or six IgM binding units into a pentameric or hexameric IgM antibody is thought to involve the Cp4 and tp domains. See, e.g., Braathen, R., et al., J Biol. Chem. 277:42755-42762 (2002). Accordingly, a pentameric or hexameric IgM antibody described in this disclosure typically includes at least the Cp4 and / or tp domains (also referred to herein collectively as Cp4-tp). A “multimerizing fragment” of an IgM heavy chain constant region thus includes at least the Cp4-tp domains. An IgM heavy chain constant region can additionally include a Cp3 domain or a fragment thereof, a Cp2 domain or a fragment thereof, a Cp1 domain or a fragment thereof, and / or other IgM heavy chain domains.

[0251] Five IgM monomers form a complex with a J-chain to form a native IgM molecule. The J- chain is considered to facilitate polymerization of p chains before IgM is secreted from antibodyproducing cells. Sequences for the human IGJ gene are known in the art, for example, (IGMT Accession: J00256, X86355, M25625, AJ879487). The J chain establishes the disulfide bridges between IgM antibodies to form multimeric structures such as pentamers. See, for example, Sorensen et al. International Immunology, (2000), pages 19-27. While crystallization of IgM has proved to be notoriously challenging, Czajkowsky and Shao (PNAS 106(35): 14960-14965, 2009) published a homology-based structural model of IgM, based on the structure of the IgE Fc domain and the known disulfide pairings. The authors report that the human IgM pentamer is a mushroomshaped molecule with a flexural bias. The IgM heavy (p) chain contains five N-linked glycosylation sites: Asn-171 , Asn-332, Asn-395, Asn-402 and Asn-563. In an IgM antibody where each binding unit is bivalent, the binding molecule itself can have 10 or 12 valencies.

[0252] The Kabat numbering system for the human IgM constant domain can be found in Kabat, et. al. “Tabulation and Analysis of Amino acid and nucleic acid Sequences of Precursors, V- Regions, C-Regions, J-Chain, T-Cell Receptors for Antigen, T-Cell Surface Antigens, b-2 Microglobulins, Major Histocompatibility Antigens, Thy-I, Complement, C-Reactive Protein, Thymopoietin, Integrins, Post-gamma Globulin, a-2 Macroglobulins, and Other Related Proteins,” U.S. Dept of Health and Human Services (1991). IgM constant regions can be numbered sequentially (i.e., amino acid #1 starting with the first amino acid of the constant region) or by using the Kabat numbering scheme.

[0253] A “full length IgM antibody heavy chain” is a polypeptide that includes, in N- terminal to C- terminal direction, an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CM1 or Cp1), an antibody heavy chain constant domain 2 (CM2 or Cp2), an antibody heavy chain constant domain 3 (CM3 or Cp3), and an antibody heavy chain constant domain 4 (CM4 or Cp4) that can include a tp, as indicated above.

[0254] In particular embodiments, each binding unit of a multimeric binding molecule as provided herein includes two IgM heavy chain constant regions or multimerizing fragments or variants thereof, each including at least an IgM Cp4 domain and an IgM tp domain. In certain embodiments the IgM heavy chain constant regions can each further include an IgM Cp3 domain situated N- terminal to the IgM Cp4 and IgM tp domains.

[0255] In particular embodiments, the IgM heavy chain constant regions can each further include an IgM Cp2 domain situated N-terminal to the IgM Cp3 domain. Exemplary multimeric binding molecules provided herein include human IgM constant regions that include the wild-type human Cp2, Cp3, and Cp4-tp domains as follows: VIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAE AKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSF ASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWN SGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADV FVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNR VTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 314).

[0256] In certain IgM-derived multimeric binding molecules as provided herein each IgM constant region can include, instead of, or in addition to an IgM Cp2 domain, an IgG hinge region or functional variant thereof situated N-terminal to the IgM Cp3 domain. An exemplary variant human lgG1 hinge region amino acid sequence in which the cysteine at position 6 is substituted with serine is VEPKSSDKTHTCPPCPAP (SEQ ID NO: 315). An exemplary IgM constant region of this type includes the variant human I gG 1 hinge region fused to a multimerizing fragment of the humanIgM constant region including the Cp3, Cp4, and tp domains, and includes the amino acid sequence:VEPKSSDKTHTCPPCPAPDQDTAI RVFAI PPSFASI FLTKSTKLTCLVTDLTTYDSVTISWTRQNG EAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHR PDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPG RYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY (SEQ ID NO: 316).

[0257] Human IgM constant regions, and also certain non-human primate IgM constant regions, as provided herein typically include five (5) naturally-occurring asparagine (N)-linked glycosylation motifs or sites. As used herein “an N-linked glycosylation motif” includes the amino acid sequence N-X1-S / T, wherein N is asparagine, X1 is any amino acid except proline (P), and S / T is serine (S) or threonine (T). The glycan is attached to the nitrogen atom of the asparagine residue. See, e.g., Drickamer K, Taylor ME (2006), Introduction to Glycobiology (2nd ed.). Oxford University Press, USA. N-linked glycosylation motifs occur in the human IgM heavy chain constant regions of SEQ ID NO: 317 or SEQ ID NO: 318 starting at positions 46 (“N1 ”), 209 (“N2”), 272 (“N3”), 279 (“N4”), and 440 (“N5”). These five motifs are conserved in non-human primate IgM heavy chain constant regions, and four of the five are conserved in the mouse IgM heavy chain constant region. Each of these sites in the human IgM heavy chain constant region, except for N4, can be mutated to prevent glycosylation at that site, while still allowing IgM expression and assembly into a hexamer or pentamer.

[0258] The human IgM heavy chain constant region typically includes the amino acid sequence GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP R KSKLI CQATG FSP RQ I Q VSWLR EG KQVGSGVTTDQ VQAEA KESG PTTYKVTSTLTI KES D WL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 317; identical to, e.g., GenBank Accession Nos. pir||S37768, CAA47708.1 , and CAA47714.1). Referring to this SEQ ID NO: 317, the human Cp1 region ranges from amino acid 5 to amino acid 102; the human Cp2 region ranges from amino acid 114 to amino acid 205, the human Cp3 region ranges from amino acid 224 to amino acid 319, the C 4 region ranges from amino acid 329 to amino acid 430, and the tp ranges from amino acid 431 to amino acid 453.

[0259] In particular embodiments, an IgM heavy chain constant region includes the sequence: GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL GQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDS VTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTI SRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSA PMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLV MSDTAGTCY (SEQ ID NO: 318; (UniProt ID P01871)— allele IGHM*04). This sequence differs from SEQ ID NO: 318 by one amino acid at position 191.

[0260] Other forms of the human IgM constant region with minor sequence variations exist, including GenBank Accession Nos. P01871.4, CAB37838.1 , and pir||MHHU. The amino acid substitutions, insertions, and / or deletions at positions corresponding to SEQ ID NO: 317 described herein can likewise be incorporated into alternate human IgM sequences, as well as into IgM constant region amino acid sequences of other species, e.g., those shown in FIG. 1 of PCT / US2019 / 020374.

[0261] In certain aspects, a variant human IgM constant region includes an amino acid substitution corresponding to the wild-type human IgM constant region at position P311 , P313, R344, E345, S401, E402, and / or E403 of SEQ ID NO: 317. These positions correspond to the Kabat numbering system as follows: S401 of SEQ ID NO: 317 corresponds to S524 of Kabat; E402 of SEQ ID NO: 317 corresponds to E525 of Kabat; E403 of SEQ ID NO: 317 corresponds to E526 of Kabat; R344 of SEQ ID NO: 317 corresponds to R467 of Kabat; and E345 of SEQ ID NO: 317 corresponds to E468 of Kabat.

[0262] In particular embodiments, “corresponds to” means the designated position of SEQ ID NO: 317 and the amino acid in the sequence of the IgM constant region of any species which is homologous to the specified position. See FIG. 1 of PCT / US2019 / 020374.

[0263] In particular embodiments, P311 of SEQ ID NO: 317 can be substituted, e.g., with alanine (P311A), serine (P311S), or glycine (P311G) and / or P313 of SEQ ID NO: 317 can be substituted, e.g., with alanine (P313A), serine (P313S), or glycine (P313G). P311 and P313 of SEQ ID NO: 317 can be substituted with alanine (P311A) and serine (P313S), respectively as shown in the following sequence: (mutations in bold underline) GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLASSLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 319).

[0264] In certain aspects, S401 of SEQ ID NO: 317 can be substituted with any amino acid. In certain aspects, S401 of SEQ ID NO: 317 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline):GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP R KSKLI CQATG FSP RQ I Q VSWLR EG KQVGSGVTTDQ VQAEA KESG PTTYKVTSTLTI KES D WL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVAEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 320).

[0265] In certain aspects, E402 of SEQ ID NO: 317 can be substituted with any amino acid. In certain aspects, E402 of SEQ ID NO: 317 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline):GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEA KESG PTTYKVTSTLTI KESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSAEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 321).

[0266] In certain aspects, E403 of SEQ ID NO: 317 can be substituted with any amino acid. In certain aspects, E403 of SEQ ID NO: 317 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline):GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP R KSKLI CQATG FSP RQ I Q VSWLR EG KQVGSGVTTDQ VQAEA KESG PTTYKVTSTLTI KES D WL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEAEWNTGETYTCWAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 322).

[0267] In certain aspects, R344 of SEQ ID NO: 317 can be substituted with any amino acid. In certain aspects, R344 of SEQ ID NO: 317 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline):GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP RKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLAESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 323).

[0268] In certain aspects, E345 of SEQ ID NO: 317 can be substituted with any amino acid. In certain aspects, E345 of SEQ ID NO: 317 can be substituted with alanine (A) as follows (alanine substitution indicated by bold underline):GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGK YAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNP R KSKLI CQATG FSP RQ I Q VSWLR EG KQVGSGVTTDQ VQAEA KESG PTTYKVTSTLTI KES D WL SQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSV TISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTIS RPKGVALHRPDVYLLPPAREQLNLRASATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAP MPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVM SDTAGTCY (SEQ ID NO: 324).

[0269] As indicated, five IgM binding units can form a complex with a J-chain to form a pentameric IgM antibody. The precursor form of the human J-chain includes:MKNHLLFWGVLAVFIKAVHVKAQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLN NRENISDPTSPLRTRFVYHLSDLCKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKC YTAWPLVYGGETKMVETALTPDACYPD (SEQ ID NO: 325). The signal peptide extends from amino acid 1 to amino acid 22 of SEQ ID NO: 325 and the mature human J-chain extends from amino acid 23 to amino acid 159 of SEQ ID NO: 325.

[0270] The mature human J-chain includes the amino acid sequenceQEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAWPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 326).

[0271] The term “J-chain” as used herein refers to the J-chain of native sequence IgM or IgA antibodies of any animal species. When specified, it can also refer to any functional fragment thereof, derivative thereof, and / or variant thereof, including a mature human J-chain amino acid sequence provided herein as SEQ ID NO: 326. A functional fragment, derivative, and / or variant of a J-chain has at least 90% sequence identity to the reference J-chain and retains the multimerizing function of the reference J-chain.

[0272] In certain aspects, the J-chain of the IgM antibody as provided herein includes an amino acid substitution at the amino acid position corresponding to amino acid Y102, T103, N49 or S51 of SEQ ID NO: 326.

[0273] By “an amino acid corresponding to” a position of SEQ ID NO: 326 is meant the amino acid in the sequence of the J-chain of any species which is homologous to the referenced residue in the human J-chain. For example, the position corresponding to Y102 in SEQ ID NO: 326 is conserved in the J-chain amino acid sequences of at least 43 other species. The position corresponding to T103 in SEQ ID NO: 326 is conserved in the J-chain amino acid sequences of at least 37 other species. The positions corresponding to N49 and S51 in SEQ ID NO: 326 are conserved in the J-chain amino acid sequences of at least 43 other species. See FIG. 4 of U.S. Patent No. 9,951,134 and FIG. 2 of PCT / US2019 / 020374.

[0274] In certain aspects, the amino acid corresponding to Y102 of SEQ ID NO: 326 can be substituted with any amino acid. In certain aspects, the amino acid corresponding to Y102 of SEQ ID NO: 326 can be substituted with alanine (alanine substitution indicated by bold underline): QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCATYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 327),

[0275] With serine (serine substitution indicated by bold underline):QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCSTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 328),

[0276] Or with arginine (arginine substitution indicated by bold underline):QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCRTYDRNKCYTA VPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 329).

[0277] In certain aspects, the amino acid corresponding to T103 of SEQ ID NO: 326 can be substituted with any amino acid. In a particular aspect, the amino acid corresponding to T103 of SEQ ID NO: 326 can be substituted with alanine as follows (alanine substitution indicated by bold underline):QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYAYDRNKCYTAVVPLVYGGETKMVETALTP DACYPD (SEQ ID NO: 330).

[0278] In certain aspects, the variant J-chain or functional fragment thereof of the IgM antibody as provided herein includes an amino acid substitution at the amino acid position corresponding to amino acid N49 or amino acid S51 of SEQ ID NO: 326, provided that S51 is not substituted with threonine (T), or wherein the J-chain includes amino acid substitutions at the amino acid positions corresponding to both amino acids N49 and S51 of SEQ ID NO: 326.

[0279] The amino acids corresponding to N49 and S51 of SEQ ID NO: 326 along with the amino acid corresponding to 150 of SEQ ID NO: 326 include an N-linked glycosylation motif in the J- chain. Accordingly, mutations at N49 and / or S51 (with the exception of a single threonine substitution at S51) can prevent glycosylation at this motif. In certain aspects, the asparagine at the position corresponding to N49 of SEQ ID NO: 326 can be substituted with any amino acid. In certain aspects, the asparagine at the position corresponding to N49 of SEQ ID NO: 326 can be substituted with alanine (A), glycine (G), threonine (T), serine (S) or aspartic acid (D). In a particular aspect the position corresponding to N49 of SEQ ID NO: 326 can be substituted with alanine (A). In a particular aspect the J-chain is a variant human J-chain and includes the amino acid sequence:QEDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNREAISDPTSPLRTRFVYHLSDL CKKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPD ACYPD (SEQ ID NO: 331).

[0280] In certain aspects, the serine at the position corresponding to S51 of SEQ ID NO: 326 can be substituted with any amino acid except threonine. In certain aspects, the serine at the position corresponding to S51 of SEQ ID NO: 326 can be substituted with alanine (A) or glycine (G). In a particular aspect the position corresponding to S51 of SEQ ID NO: 326 can be substituted with alanine (A). In a particular aspect the variant J-chain or functional fragment thereof is a variant human J-chain and includes the amino acid sequence: EDERIVLVDNKCKCARITSRIIRSSEDPNEDIVERNIRIIVPLNNRENIADPTSPLRTRFVYHLSDLC KKCDPTEVELDNQIVTATQSNICDEDSATETCYTYDRNKCYTAVVPLVYGGETKMVETALTPDA CYPD (SEQ ID NO: 332).

[0281] Particular embodiments include a heterologous polypeptide (e.g., a single-domain antibody binding domain) fused to the J-chain or functional fragment thereof via a peptide linker, e.g., a peptide linker including at least 5 amino acids, but no more than 25 amino acids. In certain aspects, the peptide linker includes (GGGGS)n (SEQ ID NO: 259) wherein n is 1-5.

[0282] A single-domain antibody binding domain can be introduced into the J-chain at any location that allows the binding of the binding domain to its binding target without interfering with J-chain function or the function of an associated IgA, IgM, or hybrid IgG antibody. Insertion locations include at or near the C- terminus, at or near the N-terminus or at an internal location that, based on the three-dimensional structure of the J-chain, is accessible. In certain aspects, the antigen-binding domain can be introduced into the mature human J-chain of SEQ ID NO: 326 between cysteine residues 92 and 101 of SEQ ID NO: 326. In a further aspect, the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 326 at or near a glycosylation site. In a further aspect, the antigen-binding domain can be introduced into the human J-chain of SEQ ID NO: 326 within 10 amino acid residues from the C- terminus, or within 10 amino acids from the N-terminus.

[0283] In particular embodiments, the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 326 by chemical or chemo-enzymatic derivatization. In particular embodiments, the single-domain antibody is introduced into the native human J-chain sequence of SEQ ID NO: 326 by a chemical linker. In some embodiments, the chemical linker is a cleavable or non-cleavable linker. In particular embodiments, the cleavable linker is a chemically labile linker or an enzyme-labile linker. In some embodiments, the linker is selected from the group including N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-l-carboxylate (SMCC), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), iminothiolane (IT), afunctional derivatives of imidoesters, active esters, aldehydes, bis-azido compounds, bis-diazonium derivatives, diisocyanates, and bis-active fluorine compounds. In particular embodiments, the modified J-chain is modified by insertion of an enzyme recognition site, and by post-translationally attaching a binding moiety at the enzyme recognition site through a peptide or non-peptide linker.

[0284] In certain aspects the modified J-chain can include the formula X[Ln]J or J[Ln]X, where J includes a mature native J-chain or functional fragment thereof, X includes a heterologous binding domain, and [Ln] is a linker sequence including n amino acids, where n is a positive integer from 1 to 100, 1 to 50, or 1 to 25. In certain aspects N is 5, 10, 15, or 20.

[0285] J-chains from the following species can also be used in certain embodiments: Pan troglodytes, Pongo abelii, Callithrix jacchus, Macaca mulatta, Papio Anubis, Saimiri boliviensis,Tupaia chinensis, Tursiops truncatus, Orcinus orca, Loxodonta Africana, Leptonychotes weddellii, Ceratotherium simum, Felis catus, Canis familiaris, Ailuropoda melanoleuca, Mustela furo, Equus caballus, Cavia porcellus, Camelus ferus, Capra hircus, Chinchilla lanigera, Mesocricetus auratus, Ovis aries, Myotis lucifugus, Pantholops hodgsonii, Bos taurus, Mus musculus, Rattus norvegicus, Echinops telfairi, Oryctolagus cuniculus, Monodelphis domestica, Alligator mississippiensis, Chrysemys picta, Sarcophilus harrisii, Ornithorhynchus anatinus, Melopsittacus undulatus, Anas platyrhynchos, Gallus gallus, Meleagris gallopavo, Falco peregrinus, Zonotrichia albicollis, and Pteropus alecto.

[0286] (iv) Expression of Recombinant Proteins. Proteins (e.g., antibodies, antibody binding fragments, binding domains) can be produced by recombinant expression. Recombinant polynucleotide constructs typically include an expression control sequence operably linked to the coding sequences of the encoded protein, including naturally-associated or heterologous promoter regions. Preferably, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences, and the collection and purification of the expressed proteins.

[0287] In particular embodiments, mammalian cells are used as a host for expressing nucleotide segments encoding immunoglobulins or fragments thereof. See Winnacker, From Genes to Clones, (VCH Publishers, NY, 1987). A number of suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, and include CHO cell lines (e.g., DG44), various COS cell lines, HeLa cells, HEK293 cells, L cells, and non- antibody-producing myelomas including Sp2 / 0 and NSO. Preferably, the cells are nonhuman. Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, an enhancer (Queen et al., Immunol. Rev. 89:49 (1986)), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. In particular embodiments, expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, and bovine papillomavirus (see Co et al., J. Immunol. 1992, 148:1149).

[0288] Once expressed, proteins can be purified according to standard procedures of the art, including high-performance liquid chromatography (HPLC) purification, column chromatography, gel electrophoresis and the like (see generally, Scopes, Protein Purification (Springer- Verlag, NY, 1982)).

[0289] In particular embodiments, recombinant proteins are formed using the Daedalusexpression system as described in Pechman et al. (Am J Physiol 294: R1234-R1239, 2008). The Daedalus system utilizes inclusion of minimized ubiquitous chromatin opening elements in transduction vectors to reduce or prevent genomic silencing and to help maintain the stability of decigram levels of expression. This system can bypass tedious and time-consuming steps of other protein production methods by employing the secretion pathway of serum-free adapted human suspension cell lines, such as 293 Freestyle. Using optimized lentiviral vectors, yields of 20-100 mg / l of correctly folded and post- translational ly modified, endotoxin-free protein of up to 70 kDa in size, can be achieved in conventional, small-scale (100 ml) culture. At these yields, most proteins can be purified using a single size-exclusion chromatography step, immediately appropriate for use in structural, biophysical or therapeutic applications. Bandaranayake et al., Nucleic Acids Res., 39(21) 2011. In some instances, purification by chromatography may not be needed due to the purity of manufacture according to the methods described herein.

[0290] (v) Anti-CD45 Antibody Conjugates. Anti-CD45 antibody conjugates include an anti-CD45 antibody disclosed herein linked to another molecule, other than an additional binding domain. Examples of antibody conjugates include antibody radioisotope conjugates, antibody immunotoxins, antibody-drug conjugates (ADCs), antibody-detectable label conjugates, and antibody-particle conjugates.

[0291] Antibody-radioisotope conjugates include an anti-CD45 antibody linked to a radioisotope for use in nuclear medicine. Nuclear medicine refers to the diagnosis and / or treatment of conditions by administering radioactive isotopes (radioisotopes or radionuclides) to a subject. Therapeutic nuclear medicine is often referred to as radiation therapy or radioimmunotherapy (RIT).

[0292] Examples of radioactive isotopes that can be conjugated to anti-CD45 antibodies of the present disclosure include alpha-emitting radionuclides such as astatine-211 , actinium-225, bismuth-212 or bismuth-213. Additional examples include iodine-131 yttrium-90, arsenic-72, arsenic-74, iodine-131 , indium-1 11 , and lutetium-177.

[0293] 211At is described elsewhere herein.225Ac is a radionuclide with the half-life of ten days. As225Ac decays the daughter isotopes221Fr,213Bi, and209Pb are formed.227Th has a half-life of 19 days and forms the daughter isotope223Ra.

[0294] Additional examples of useful radioisotopes include228Ac,111Ag,124Am,74As,209At,194Au,128Ba,7Be,206Bi,245Bk,246Bk,76Br,11C,14C,47Ca,254Cf,242Cm,51Cr,67Cu,153Dy,157Dy,159Dy,165Dy,166Dy,171Er,250Es,254Es,147Eu,157Eu,52Fe,59Fe,251Fm,252Fm,253Fm,66Ga,72Ga,146Gd,153Gd,68Ge,3H,170Hf,171Hf,193Hg,193mHg,160mHo,130l,135l,114mln,185lr,42K,43K,76Kr,79Kr,81mKr,132La,262Lr,169Lu,174ml_u,176mLu,257Md,260Md,28Mg,52Mn,90Mo,24Na,95Nb,138Nd,57Ni,66Ni,234Np,150,1820s,189mOs,1910s,32P,201Pb,101Pd,143Pr,191Pt,243Pu,225Ra,81Rb,188Re,105Rh,211Rn,103Ru,35S,44Sc,72Se,153Sm,125Sn,91Sr,173Ta,154Tb,127Te,234Th,45Ti,166Tm,230U,237U,240U,48V, 178W, 181 w,188W,125Xe,127Xe,133Xe,133mXe,135Xe,85mY,86Y,93Y,169Yb,175Yb,65Zn,71mZn,86Zr,95Zr, and / or97Zr. Radioisotopes can be used as a type of detectable label called a radiolabel. In particular embodiments, a radioisotope includes131l,90Y, and / or211At. In particular embodiments, a radioisotope is selected that includes a half-life (ti / 2) that enables high-yield radiolabeling and drug delivery. In particular embodiments, a radioisotope is selected that includes a half-life (ti / 2) of 7.2 hours. In particular embodiments, a radioisotope is selected that does not emit daughter radionuclides that cause organ toxicity.

[0295] Methods for preparing radioimmunoconjugates are established in the art. Examples of radioimmunoconjugates are commercially available, including Zevalin™ (DEC Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the disclosure.

[0296] In particular embodiments, the anti-CD45 antibody can be formed as an antibody immunotoxin. Antibody immunotoxins include an anti-CD45 antibody disclosed herein conjugated to one or more cytotoxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof). A toxin can be any agent that is detrimental to cells. Frequently used plant toxins are divided into two classes: (1) holotoxins (or class II ribosome inactivating proteins), such as ricin, abrin, mistletoe lectin, and modeccin, and (2) hemitoxins (class I ribosome inactivating proteins), such as pokeweed antiviral protein (PAP), saporin, Bryodin 1 , bouganin, and gelonin. Commonly used bacterial toxins include diphtheria toxin (DT) and Pseudomonas exotoxin (PE). Kreitman, Current Pharmaceutical Biotechnology 2:313-325 (2001). The toxin may be obtained from essentially any source and can be a synthetic or a natural product.

[0297] Immunotoxins with multiple (e.g., four) cytotoxins per binding domain can be prepared by partial reduction of the binding domain with an excess of a reducing reagent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) at 37°C for 30 min, then the buffer can be exchanged by elution through SEPHADEX G-25 resin with 1 mM DTPA (diethylene triamine penta-acetic acid) in Dulbecco’s phosphate-buffered saline (DPBS). The eluent can be diluted with further DPBS, and the thiol concentration of the binding domain can be measured using 5,5'- dithiobis(2-nitrobenzoic acid) [Ellman's reagent]. An excess, for example 5-fold, of the linker- cytotoxin conjugate can be added at 4°C. for 1 hr, and the conjugation reaction can be quenched by addition of a substantial excess, for example 20-fold, of cysteine. The resulting immunotoxin mixture can be purified on SEPHADEX G-25 equilibrated in PBS to remove unreacted linker-cytotoxin conjugate, desalted if desired, and purified by size-exclusion chromatography. The resulting immunotoxin can then be sterile filtered, for example, through a 0.2 pm filter, and can be lyophilized if desired for storage.

[0298] Antibody-drug conjugates allow for the targeted delivery of a drug moiety to a CD45 expressing cell, in particular embodiments intracellular accumulation therein, where systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).

[0299] In particular embodiments, antibody-drug conjugates refer to targeted molecules which combine properties of both antibodies and cytotoxic drugs (e.g., chemotherapeutic drugs) by targeting potent cytotoxic drugs to antigen-expressing cells (Teicher, B. A. (2009) Current Cancer Drug Targets 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, P. J. and Senter P. D. (2008) The Cancer Jour. 14(3): 154- 169; Chari, R. V. (2008) Acc. Chem. Res. 41:98-107). See also Kamath & Iyer (Pharm Res. 32(11): 3470-3479, 2015), which describes considerations for the development of antibody-drug conjugates.

[0300] The drug moiety (D) of an antibody-drug conjugate may include any compound, moiety or group that has a cytotoxic or cytostatic effect. Drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding or intercalation, and inhibition of RNA polymerase, protein synthesis, and / or topoisomerase. Exemplary drugs include actinomycin D, anthracycline, auristatin, calicheamicin, camptothecin, CC1065, colchicin, cytochalasin B, daunorubicin, 1 -dehydrotestosterone, dihydroxy anthracinedione, dolastatin, doxorubicin, duocarmycin, elinafide, emetine, ethidium bromide, etoposide, gramicidin D, glucocorticoids, lidocaine, maytansinoid (including monomethyl auristatin E [MMAE]; vedotin), mithramycin, mitomycin, mitoxantrone, nemorubicin, PNU-159682, procaine, propranolol, puromycin, pyrrolobenzodiazepine (PBD), taxane, taxol, tenoposide, tetracaine, trichothecene, vinblastine, vinca alkaloid, vincristine, and stereoisomers, isosteres, analogs, and derivatives thereof that have cytotoxic activity.

[0301] The drug may be obtained from essentially any source; it may be synthetic or a natural product isolated from a selected source, e.g., a plant, bacterial, insect, mammalian or fungal source. The drug may also be a synthetically modified natural product or an analogue of a natural product.

[0302] In particular embodiments, the antibody-drug conjugates include an antibody conjugated, i.e., covalently attached, to the drug moiety. In particular embodiments, the anti-CD45 antibody is covalently attached to the drug moiety through a linker. A linker can include any chemical moietythat is capable of linking an antibody, antibody fragment (e.g., antigen binding fragments) or functional equivalent to another moiety, such as a drug moiety. Linkers can be susceptible to cleavage (cleavable linker), such as, acid-induced cleavage, photo-induced cleavage, peptidase- induced cleavage, esterase-induced cleavage, and disulfide bond cleavage, at conditions under which the compound or the antibody remains active. Alternatively, linkers can be substantially resistant to cleavage (e.g., stable linker or noncleavable linker). In some aspects, the linker is a procharged linker, a hydrophilic linker, or a dicarboxylic acid-based linker. The antibody-drug conjugate selectively delivers an effective dose of a drug to cells (e.g., cancer cells) whereby greater selectivity, i.e., a lower efficacious dose, may be achieved while increasing the therapeutic index (“therapeutic window”).

[0303] To prepare antibody-drug conjugates, linker-cytotoxin conjugates can be made by conventional methods analogous to those described by Doronina et al. (Bioconjugate Chem. 17: 114-124, 2006). Antibody-drug conjugates with multiple (e.g., four) drugs per antibody can be prepared by partial reduction of the antibody with an excess of a reducing reagent such as dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) at 37°C for 30 min, then the buffer can be exchanged by elution through SEPHADEX G-25 resin with 1 mM DTPA in Dulbecco’s phosphate-buffered saline (DPBS). The eluent can be diluted with further DPBS, and the thiol concentration of the antibody can be measured using 5,5'-dithiobis(2-nitrobenzoic acid) [Ellman's reagent]. An excess, for example 5-fold, of the linker-cytotoxin conjugate can be added at 4°C. for 1 hr, and the conjugation reaction can be quenched by addition of a substantial excess, for example 20-fold, of cysteine. The resulting ADC mixture can be purified on SEPHADEX G-25 equilibrated in PBS to remove unreacted linker-cytotoxin conjugate, desalted if desired, and purified by size-exclusion chromatography. The resulting ADC can then be sterile filtered, for example, through a 0.2 pm filter, and can be lyophilized if desired for storage. Methods used to produce immunotoxins can similarly be used to prepare antibody-drug conjugates.

[0304] Antibody-detectable label conjugates include an anti-CD45 antibody linked to a detectable label. Detectable labels can include any suitable label or detectable group detectable by, for example, optical, spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. In particular embodiments, detectable labels can include fluorescent labels, chemiluminescent labels, spectral colorimetric labels, enzymatic labels, and affinity tags.

[0305] Fluorescent labels can be particularly useful in cell staining, identification, imaging, and isolation uses. Exemplary fluorescent labels include blue fluorescent proteins (e.g. eBFP, eBFP2, Azurite, mKalamal , GFPuv, Sapphire, T-sapphire); cyan fluorescent proteins (e.g. eCFP, Cerulean, CyPet, AmCyanl, Midoriishi-Cyan, mTurquoise); green fluorescent proteins (e.g. GFP,GFP-2, tagGFP, turboGFP, EGFP, Emerald, Azami Green, Monomeric Azami Green (mAzamigreen)), CopGFP, AceGFP, avGFP, ZsGreenl, Oregon GreenTM(Thermo Fisher Scientific)); Luciferase; orange fluorescent proteins (mOrange, mKO, Kusabira-Orange, Monomeric Kusabira-Orange, mTangerine, tdTomato); red fluorescent proteins (mKate, mKate2, mPlum, DsRed monomer, mCherry, mRuby, mRFP1 , DsRed-Express, DsRed2, DsRed- Monomer, HcRed-Tandem, HcRedl, AsRed2, eqFP611 , mRaspberry, mStrawberry, Jred, Texas Red™ (Thermo Fisher Scientific)); far red fluorescent proteins (e.g., mPlum and mNeptune); yellow fluorescent proteins (e.g., YFP, eYFP, Citrine, SYFP2, Venus, YPet, PhiYFP, ZsYellowl); and tandem conjugates.

[0306] Chemiluminescent labels can include lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt, or oxalate ester.

[0307] Spectral colorimetric labels can include colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, and latex) beads.

[0308] Enzymatic labels can produce, for example, a chemiluminescent signal, a color signal, or a fluorescent signal. Enzymes can include malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI- phosphate dehydrogenase, glucoamylase and acetylcholinesterase.

[0309] Affinity tags can include, for example, His tag (HHHHHH (SEQ ID NO: 333)), Flag tag (DYKDDDD (SEQ ID NO: 334), Xpress tag (DLYDDDDK (SEQ ID NO: 335)), Avi tag (GLNDIFEAQKIEWHE (SEQ ID NO: 336)), Calmodulin binding peptide (CBP) tag (KRRWKKNFIAVSAANRFKKISSSGAL (SEQ ID NO: 337)), Polyglutamate tag (EEEEEE (SEQ ID NO: 338)), HA tag (YPYDVPDYA (SEQ ID NO: 339)), Myc tag (EQKLISEEDL (SEQ ID NO: 340)), Strep tag (WRHPQFGG (SEQ ID NO: 341)), STREP® tag II (WSHPQFEK (SEQ ID NO: 342); IBA Institut fur Bioanalytik, Germany; see, e.g., US 7,981,632), Softag 1 (SLAELLNAGLGGS (SEQ ID NO: 343)), Softag 3 (TQDPSRVG (SEQ ID NO: 344)), and V5 tag (GKPIPNPLLGLDST (SEQ ID NO: 345)).

[0310] Antibody-particle conjugates include an antibody linked to a particle. In particular embodiments, particles include microparticles, nanoparticles, nanoshells, nanobeads, microbeads, or nanodots. Particles can include, for example, latex beads, polystyrene beads, fluorescent beads, and / or colored beads, and can be made from organic matter and / or inorganic matter. They can be made of any suitable materials that allow for the conjugation of capture proteins, such as anti-CD45 antibodies disclosed herein, to their surface. Examples of suitablematerials include: ceramics, glass, polymers, and magnetic materials. Suitable polymers include polystyrene, poly-(methyl methacrylate), poly-(lactic acid), (poly-(lactic-co -glycolic acid)), polyesters, polyethers, polyolefins, polyalkylene oxides, polyamides, polyurethanes, polysaccharides, celluloses, polyisoprenes, methylstyrene, acrylic polymers, thoria sol, latex, nylon, Teflon cross- linked dextrans (e.g., Sepharose), chitosan, agarose, and cross-linked micelles. Additional examples include carbon graphited, titanium dioxide, and paramagnetic materials. See, e.g., "Microsphere Detection Guide" from Bangs Laboratories, Fishers Ind. In particular embodiments, microparticles can be made of one or more materials. In particular embodiments, microparticles are paramagnetic microparticles. Particular embodiments utilize carboxy-modified polystyrene latex (CML) flow cytometry beads and / or magnetic MagPlex® (Luminex, Austin, TX) flow cytometry beads. In particular embodiments, particles can carry a payload.

[0311] In particular embodiments, an antibody as disclosed herein can be linked to a conjugate by any method known in the art. In particular embodiments, the constant region can be modified to allow for site specific conjugation. Such techniques include the use of naturally occurring or engineered cysteine residues, disulfide bridges, poly-histidine sequences, glycoengineering tags, and transglutaminase recognition sequences. Antibody fragments can also be modified for sitespecific conjugation, see for example, Kim et al., Mol Cancer Ther 2008;7(8).

[0312] (vi) Recombinant Receptors. Anti-CD45 antibodies disclosed herein can be utilized within recombinant receptors such as chimeric antigen receptors (CAR) and / or engineered T cell receptors (eTCR).

[0313] CAR, for example, include several distinct subcomponents that allow genetically modified cells (e.g., regulatory T cells) to recognize and kill cells expressing an antigen (e.g., CD45). The subcomponents include at least an extracellular component and an intracellular component. The extracellular component includes a binding domain that binds a CD45 epitope that is preferentially present on the surface of cells or in the area thereof. When the binding domain binds such epitopes, the intracellular component activates the cell to destroy the bound cell. CAR additionally include a transmembrane domain that directly or indirectly links the extracellular component to the intracellular component, and other subcomponents that can increase the CAR’s function. For example, the inclusion of a spacer region and / or one or more linker sequences can allow the CAR to have additional conformational flexibility, often increasing the binding domain’s ability to bind the targeted epitope.

[0314] eTCR disclosed herein include an anti-CD45 antibody disclosed herein linked to the Caand / or Cp chains of a TCR. A TCR is a heterodimeric fusion protein that typically includes an aand chain. Each chain includes a variable region (Vaand Vp) and a constant region (Caand Cp). In particular embodiments, an eTCR does not include the native TCR variable region but does include the native TCR constant region. In particular embodiments, the eTCR includes an anti- CD45 antibody as the variable region of the a and 3 chain. In particular embodiments, eTCR include a Caand / or Cp chain sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% identical to an amino acid sequence of a known or identified TCR Caor Cp.

[0315] Particular embodiments of binding domains include an anti-CD45 antibody and / or the CDRs thereof as disclosed herein, such as those provided in Tables 1-5 (e.g., SEQ ID NOs: 346- 453, 456, 459, 467-529, 537-604, 612-653, 658-762, 777-784).

[0316] Recombinant receptors can additionally include spacer regions, transmembrane domains, intracellular effector domains, transduction markers, and tags.

[0317] Spacer regions are used to create appropriate distances and / or flexibility between subcomponents of a protein. Spacer regions typically include 10 to 250 amino acids, 10 to 200 amino acids, 10 to 150 amino acids, 10 to 100 amino acids, 10 to 50 amino acids, or 10 to 25 amino acids. Exemplary spacer regions include all or a portion of an immunoglobulin hinge region.

[0318] Transmembrane domains typically have a three-dimensional structure that is thermodynamically stable in a cell membrane, and generally ranges in length from 15 to 30 amino acids. The structure of a transmembrane domain can include an a helix, a 3 barrel, a 3 sheet, a 3 helix, or any combination thereof. Transmembrane domains can include at least the transmembrane region(s) of the a, 3 or chain of a T-cell receptor, CD28, CD27, CD3, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154.

[0319] A transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid within the extracellular region of the expressed protein (e.g., up to 15 amino acids of the extracellular region) and / or one or more additional amino acids within the intracellular region of the expressed protein (e.g., up to 15 amino acids of the intracellular components).

[0320] Intracellular effector domains activate the expressing cell when the binding domain binds the antigen (CD45). The term “effector domain” is thus meant to include any portion of the intracellular domain sufficient to transduce an activation signal.

[0321] An effector domain can include one, two, three or more intracellular signaling components (e.g., receptor signaling domains, cytoplasmic signaling sequences), co-stimulatory domains, or combinations thereof. Exemplary effector domains include signaling and stimulatory domainsselected from: 4-1 BB (CD137), CD3y, CD36, CD3s, CD3 , CD27, CD28, DAP10, ICOS, LAG3, NKG2D, NOTCH1 , 0X40, ROR2, SLAMF1 , TCRa, TCR , TRIM, Wnt, Zap70, or any combination thereof. In particular embodiments, exemplary effector domains include signaling and costimulatory domains selected from: CD86, FcyRlla, DAP12, CD30, CD40, PD-1 , lymphocyte function-associated antigen-1 (LFA-1), LIGHT, NKG2C, B7-H3, a ligand that binds with CD83, CDS, ICAM-1 , GITR, BAFFR, SLAMF7, NKp80 (KLRF1), CD127, CD19, CD4, CD8a, CD8 , IL2Rp, IL2Ry, IL7Ra, ITGA4, VLA1, CD49a, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, ITGAM, CD11b, ITGAX, CD11c, ITGB1 , CD29, ITGB2, CD18, ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), PSGL1 , CD100 (SEMA4D), CD69, SLAMF6 (NTB- A, Ly108), SLAM (CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, GADS, PAG / Cbp, NKp44, NKp30, or NKp46.

[0322] Intracellular signaling component sequences that act in a stimulatory manner may include iTAMs. Examples of iTAMs including primary cytoplasmic signaling sequences include those derived from CD3y, CD36, CD3s, CD3 , CD5, CD22, CD66d, CD79a, CD79b, and common FcRy (FCER1G), FcyRlla, FcR (Fes Rib), DAP10, and DAP12. In particular embodiments, variants of CD3^ retain at least one, two, three, or all ITAM regions.

[0323] A co- stimulatory domain is a domain whose activation can be required for an efficient lymphocyte response to cellular marker binding. Some molecules are interchangeable as intracellular signaling components or co-stimulatory domains. Examples of costimulatory domains include CD27, CD28, 4-1 BB (CD137), 0X40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), NKG2C, and a ligand that binds with CD83.

[0324] Transduction markers may be selected from, for example, at least one of a truncated CD19 (tCD19; see Budde et al., Blood 122: 1660, 2013); a truncated human EGFR (tEGFR; see Wang et al., Blood 118: 1255, 2011); an extracellular domain of human CD34; and / or RQR8 which combines target epitopes from CD34 (see Fehse et al, Mol. Therapy 1 (5 Pt 1); 448-456, 2000) and CD20 antigens (see Philip et al, Blood 124: 1277-1278). Methods to genetically modify cells to express CAR are well-known in the art.

[0325] Recombinant receptors can additionally include tags, such as the tags described as affinity tags elsewhere herein.

[0326] (vii) Immune Cells. The present disclosure describes cells genetically modified to express a recombinant protein, such as a recombinant receptor (e.g., CAR). Genetically modified cells can include T-cells, B cells, natural killer (NK) cells, NK-T cells, monocytes / macrophages, lymphocytes, hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPC), and / or amixture of HSC and HPC (i.e., HSPC). In particular embodiments, genetically modified cells include T-cells.

[0327] Several different subsets of T-cells have been discovered, each with a distinct function. For example, a majority of T-cells have a T-cell receptor (TCR) existing as a complex of several proteins. The actual T-cell receptor is composed of two separate peptide chains, which are produced from the independent T-cell receptor alpha and beta (TCRa and TCR ) genes and are called a- and P-TCR chains.

[0328] y8 T-cells represent a small subset of T-cells that possess a distinct T-cell receptor (TCR) on their surface. In y8 T-cells, the TCR is made up of one y-chain and one 5-chain. This group of T-cells is much less common (2% of total T-cells) than the a|3 T-cells.

[0329] CD3 is expressed on all mature T cells. Activated T-cells express 4-1 BB (CD137), CD69, and CD25. CD5 and transferrin receptor are also expressed on T-cells.

[0330] T-cells can further be classified into helper cells (CD4+ T-cells) and cytotoxic T-cells (CTLs, CD8+ T-cells), which include cytolytic T-cells. T helper cells assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and activation of cytotoxic T-cells and macrophages, among other functions. These cells are also known as CD4+ T-cells because they express the CD4 protein on their surface. Helper T-cells become activated when they are presented with peptide antigens by MHC class II molecules that are expressed on the surface of antigen presenting cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response.

[0331] Cytotoxic T-cells destroy virally infected cells and tumor cells and are also implicated in transplant rejection. These cells are also known as CD8+ T-cells because they express the CD8 glycoprotein on their surface. These cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of nearly every cell of the body.

[0332] "Central memory" T-cells (or "TCM") as used herein refers to an antigen experienced CTL that expresses CD62L or CCR7 and CD45RO on the surface thereof and does not express or has decreased expression of CD45RA as compared to naive cells. In particular embodiments, central memory cells are positive for expression of CD62L, CCR7, CD25, CD127, CD45RO, and CD95, and have decreased expression of CD45RA as compared to naive cells.

[0333] "Effector memory" T-cell (or "TEM") as used herein refers to an antigen experienced T- cell that does not express or has decreased expression of CD62L on the surface thereof as compared to central memory cells and does not express or has decreased expression of CD45RA as compared to a naive cell. In particular embodiments, effector memory cells are negative for expression of CD62L and CCR7, compared to naive cells or central memory cells, and havevariable expression of CD28 and CD45RA. Effector T-cells are positive for granzyme B and perforin as compared to memory or naive T-cells.

[0334] "Naive" T-cells as used herein refers to a non-antigen experienced T cell that expresses CD62L and CD45RA and does not express CD45RO as compared to central or effector memory cells. In particular embodiments, naive CD8+ T lymphocytes are characterized by the expression of phenotypic markers of naive T-cells including CD62L, CCR7, CD28, CD127, and CD45RA.

[0335] Natural killer cells (also known as NK cells, K cells, and killer cells) are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection. NK cells express CD8, CD16 and CD56 but do not express CD3.

[0336] NK cells include NK-T cells. NK-T cells are a specialized population of T cells that express a semi invariant T cell receptor (TCR ab) and surface antigens typically associated with natural killer cells. NK-T cells contribute to antibacterial and antiviral immune responses and promote tumor-related immunosurveillance or immunosuppression. Like natural killer cells, NK-T cells can also induce perforin-, Fas-, and TNF-related cytotoxicity. Activated NK-T cells are capable of producing IFN-y and IL-4. In particular embodiments, NK-T cells are CD3+ / CD56+.

[0337] Macrophages (and their precursors, monocytes) reside in every tissue of the body (in certain instances as microglia, Kupffer cells and osteoclasts) where they engulf apoptotic cells, pathogens and other non-self-components. Monocytes / macrophages express CD11b, F4 / 80; CD68; CD11c; IL-4Ra; and / or CD163.

[0338] Immature dendritic cells (i.e., pre-activation) engulf antigens and other non-self- components in the periphery and subsequently, in activated form, migrate to T-cell areas of lymphoid tissues where they provide antigen presentation to T cells. Dendritic cells express CD1a, CD1 b, CD1c, CD1d, CD21 , CD35, CD39, CD40, CD86, CD101 , CD148, CD209, and DEC-205.

[0339] Hematopoietic Stem / Progenitor Cells or HSPC refer to a combination of hematopoietic stem cells and hematopoietic progenitor cells.

[0340] Hematopoietic stem cells refer to undifferentiated hematopoietic cells that are capable of self-renewal either in vivo, essentially unlimited propagation in vitro, and capable of differentiation to all other hematopoietic cell types.

[0341] A hematopoietic progenitor cell is a cell derived from hematopoietic stem cells or fetal tissue that is capable of further differentiation into mature cell types. In certain embodiments, hematopoietic progenitor cells are CD24|0Lin_CD117+hematopoietic progenitor cells. HPC can differentiate into (i) myeloid progenitor cells which ultimately give rise to monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, ordendritic cells; or (ii) lymphoid progenitor cells which ultimately give rise to T-cells, B-cells, and NK-cells.

[0342] HSPC can be positive for a specific marker expressed in increased levels on HSPC relative to other types of hematopoietic cells. For example, such markers include CD34, CD43, CD45RO, CD45RA, CD59, CD90, CD109, CD117, CD133, CD166, HLA DR, or a combination thereof. Also, the HSPC can be negative for an expressed marker relative to other types of hematopoietic cells. For example, such markers include Lin, CD38, or a combination thereof. Preferably, the HSPC are CD34+ cells.

[0343] A statement that a cell or population of cells is "positive" for or expressing a particular marker refers to the detectable presence on or in the cell of the particular marker. When referring to a surface marker, the term can refer to the presence of surface expression as detected by flow cytometry, for example, by staining with an antibody that binds to the marker and detecting said antibody, wherein the staining is detectable by flow cytometry at a level substantially above the staining detected carrying out the same procedure with an isotype-matched control under otherwise identical conditions and / or at a level substantially similar to that for cell known to be positive for the marker, and / or at a level substantially higher than that for a cell known to be negative for the marker.

[0344] A statement that a cell or population of cells is "negative" for a particular marker or lacks expression of a marker refers to the absence of substantial detectable presence on or in the cell of a particular marker. When referring to a surface marker, the term can refer to the absence of surface expression as detected by flow cytometry, for example, by staining with an antibody that binds to the marker and detecting said antibody, wherein the staining is not detected by flow cytometry at a level substantially above the staining detected carrying out the same procedure with an isotype-matched control under otherwise identical conditions, and / or at a level substantially lower than that for cell known to be positive for the marker, and / or at a level substantially similar as compared to that for a cell known to be negative for the marker.

[0345] Cells to be genetically modified according to the teachings of the current disclosure can be patient-derived cells (autologous) or allogeneic when appropriate, and can also be in vivo or ex vivo. In particular embodiments, the immune cell is a CD4+ T cell or CD8+ T cell.

[0346] (viii) Cell Sample Collection and Cell Enrichment. Methods of sample collection and enrichment are known by those skilled in the art. In some embodiments, cells are derived from cell lines. The cells in some embodiments are obtained from a xenogeneic source, for example, from mouse, rat, non-human primate, or pig. In particular embodiments, cells are derived from humans, for example a patient to be treated.

[0347] In some embodiments, T cells are derived or isolated from samples such as whole blood, peripheral blood mononuclear cells (PBMCs), leukocytes, bone marrow, thymus, tissue biopsy, tumor, lymph node, gut associated lymphoid tissue, mucosa associated lymphoid tissue, spleen, other lymphoid tissues, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, cervix, testes, ovaries, tonsil, or other organ, and / or cells derived therefrom. In particular embodiments, cells from the circulating blood of a subject are obtained, e.g., by apheresis or leukapheresis. The samples, in particular embodiments, contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, HSC, HPC, HSPC, red blood cells, and / or platelets, and in some aspects contains cells other than red blood cells and platelets and further processing is necessary. In particular embodiments, T cells are derived from PBMCs.

[0348] In some embodiments, blood cells collected from a subject are washed, e.g., to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps. In particular embodiments, the cells are washed with phosphate buffered saline (PBS). In some embodiments, the wash solution lacks calcium and / or magnesium and / or many or all divalent cations. Washing can be accomplished using a semi-automated "flow-through" centrifuge (for example, the Cobe 2991 cell processor, Baxter) according to the manufacturer's instructions. Tangential flow filtration (TFF) can also be performed. In particular embodiments, cells can be re-suspended in a variety of biocompatible buffers after washing, such as, Ca++ / Mg++ free PBS.

[0349] The isolation can include one or more of various cell preparation and separation steps, including separation based on one or more properties, such as size, density, sensitivity or resistance to particular reagents, and / or affinity, e.g., immunoaffinity, to antibodies or other binding partners. In particular embodiments, the isolation is carried out using the same apparatus or equipment sequentially in a single process stream and / or simultaneously. In particular embodiments, the isolation, culture, and / or engineering of the different populations is carried out from the same starting composition or material, such as from the same sample.

[0350] In particular embodiments, a sample can be enriched for T cells by using density-based cell separation methods and related methods. For example, white blood cells can be separated from other cell types in the peripheral blood by lysing red blood cells and centrifuging the sample through a Percoll or Ficoll gradient.

[0351] In particular embodiments, a bulk T cell population can be used that has not been enriched for a particular T cell type. In particular embodiments, a selected T cell type can be enriched for and / or isolated based on cell-marker based positive and / or negative selection. In positiveselection, cells having bound cellular markers are retained for further use. In negative selection, cells not bound by a capture agent, such as an antibody to a cellular marker are retained for further use. In some examples, both fractions can be retained for a further use. In particular embodiments, CD4+ and / or CD8+ T cells are enriched from PBMCs.

[0352] The separation need not result in 100% enrichment or removal of a particular cell population or cells expressing a particular marker. For example, positive selection of or enrichment for cells of a particular type refers to increasing the number or percentage of such cells but need not result in a complete absence of cells not expressing the marker. Likewise, negative selection, removal, or depletion of cells of a particular type refers to decreasing the number or percentage of such cells but need not result in a complete removal of all such cells.

[0353] In some examples, multiple rounds of separation steps are carried out, where the positively or negatively selected fraction from one step is subjected to another separation step, such as a subsequent positive or negative selection.

[0354] In some embodiments, an antibody or binding domain for a cellular marker is bound to a solid support or matrix, such as a magnetic bead or paramagnetic bead, to allow for separation of cells for positive and / or negative selection. For example, in some embodiments, the cells and cell populations are separated or isolated using immunomagnetic (or affinity magnetic) separation techniques (reviewed in Methods in Molecular Medicine, vol. 58: Metastasis Research Protocols, Vol. 2: Cell Behavior In Vitro and In Vivo, p 17-25 Edited by: S. A. Brooks and U. Schumacher © Humana Press Inc., Totowa, NJ); see also US 4,452,773; US 4,795,698; US 5,200,084; and EP 452342.

[0355] In some embodiments, affinity-based selection is via magnetic-activated cell sorting (MACS) (Miltenyi Biotec, Auburn, CA). MACS systems are capable of high-purity selection of cells having magnetized particles attached thereto. In certain embodiments, MACS operates in a mode wherein the non-target and target species are sequentially eluted after the application of the external magnetic field. That is, the cells attached to magnetized particles are held in place while the unattached species are eluted. Then, after this first elution step is completed, the species that were trapped in the magnetic field and were prevented from being eluted are freed in some manner such that they can be eluted and recovered. In certain embodiments, the non-target cells are labelled and depleted from the heterogeneous population of cells.

[0356] In some embodiments, a cell population described herein is collected and enriched (or depleted) via flow cytometry, in which cells stained for multiple cell surface markers are carried in a fluidic stream. In some embodiments, a cell population described herein is collected and enriched (or depleted) via preparative scale (FACS)-sorting. In certain embodiments, a cellpopulation described herein is collected and enriched (or depleted) by use of microelectromechanical systems (MEMS) chips in combination with a FACS-based detection system (see, e.g., WO 2010 / 033140, Cho et al. (2010) Lab Chip 10, 1567-1573; and Godin et al. (2008) J Biophoton. 1(5):355 — 376). In both cases, cells can be labeled with multiple markers, allowing for the isolation of well-defined cell subsets at high purity.

[0357] Cell-markers for different T cell subpopulations are described above. In particular embodiments, specific subpopulations of T cells, such as cells positive or expressing high levels of one or more surface markers, e.g., CCR7, CD45RO, CD8, CD27, CD28, CD62L, CD127, CD4, and / or CD45RA T cells, are isolated by positive or negative selection techniques.

[0358] CD3+, CD28+ T cells can be positively selected for and expanded using anti-CD3 / anti- CD28 conjugated magnetic beads (e.g., DYNABEADS® (Life Technologies AS, Norway) M-450 CD3 / CD28 T Cell Expander).

[0359] In particular embodiments, a CD8+ or CD4+ selection step is used to separate CD4+ helper and CD8+ cytotoxic T cells. Such CD8+ and CD4+ populations can be further sorted into sub-populations by positive or negative selection for markers expressed or expressed to a relatively higher degree on one or more naive, memory, and / or effector T cell subpopulations.

[0360] In some embodiments, enrichment for central memory T (TCM) cells is carried out. In particular embodiments, memory T cells are present in both CD62L subsets of CD8+ peripheral blood lymphocytes. PBMC can be enriched for or depleted of CD62L, CD8 and / or CD62L+CD8+ fractions, such as by using anti-CD8 and anti-CD62L antibodies.

[0361] In some embodiments, the enrichment for central memory T (TCM) cells is based on positive or high surface expression of CCR7, CD45RO, CD27, CD62L, CD28, CD3, and / or CD127; in some aspects, it is based on negative selection for cells expressing or highly expressing CD45RA and / or granzyme B. In some aspects, isolation of a CD8+ population enriched for TCM cells is carried out by depletion of cells expressing CD4, CD14, CD45RA, and positive selection or enrichment for cells expressing CCR7, CD45RO, and / or CD62L. In one aspect, enrichment for central memory T (TCM) cells is carried out starting with a negative fraction of cells selected based on CD4 expression, which is subjected to a negative selection based on expression of CD14 and CD45RA, and a positive selection based on CD62L. Such selections in some aspects are carried out simultaneously and in other aspects are carried out sequentially, in either order. In some aspects, the same CD4 expression-based selection step used in preparing the CD8+ cell population or subpopulation, also is used to generate the CD4+ cell population or sub-population, such that both the positive and negative fractions from the CD4-based separation are retained, optionally following one or more further positive or negative selection steps.

[0362] Other cell types can be enriched based on known marker profiles and techniques. For example, CD34+ HSC, HSP, and HSPC can be enriched using anti-CD34 antibodies directly or indirectly conjugated to magnetic particles in connection with a magnetic cell separator, for example, the CliniMACS® Cell Separation System (Miltenyi Biotec, Bergisch Gladbach, Germany).

[0363] (ix) Genetic Engineering Techniques. Desired genes or genetic constructs disclosed herein can be introduced into cells by any method known in the art, including transfection, electroporation, microinjection, lipofection, calcium phosphate mediated transfection, infection with a viral or bacteriophage vector including the gene sequences, cell fusion, chromosome- mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, in vivo nanoparticle-mediated delivery, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see e.g., Loeffler and Behr, 1993, Meth. Enzymol. 217:599-618; Cohen, et al., 1993, Meth. Enzymol. 217:618-644; Cline, 1985, Pharmac. Then 29:69-92) and may be used, provided that the necessary developmental and physiological functions of the recipient cells are not unduly disrupted. The technique can provide for the stable transfer of the gene to the cell, so that the gene is expressible by the cell and, in certain instances, preferably heritable and expressible by its cell progeny.

[0364] The term “gene” refers to a nucleic acid sequence (used interchangeably with polynucleotide or nucleotide sequence). The gene can encode a binding domain disclosed herein (e.g., anti-CD45 antibodies). This definition includes various sequence polymorphisms, mutations, and / or sequence variants wherein such alterations do not substantially affect the function of the encoded genetic construct. The term “gene” may include not only coding sequences but also regulatory regions such as promoters, enhancers, and termination regions. Gene sequences encoding the molecule can be DNA or RNA that directs the expression of the open reading frame(s) within the genetic construct. These nucleic acid sequences may be a DNA strand sequence that is transcribed into RNA or an RNA sequence that is translated into protein. The nucleic acid sequences include both the full-length nucleic acid sequences as well as nonfull-length sequences derived from the full-length protein. The sequences can also include degenerate codons of the native sequence or sequences that may be introduced to provide codon preference in a specific cell type. Portions of complete gene sequences are referenced throughout the disclosure as is understood by one of ordinary skill in the art.

[0365] Gene sequences encoding genetic constructs are provided herein and can also be readily prepared by synthetic or recombinant methods from the relevant amino acid sequences and other description provided herein. In embodiments, the gene sequence encoding any of thesesequences can also have one or more restriction enzyme sites at the 5' and / or 3' ends of the coding sequence in order to provide for easy excision and replacement of the gene sequence encoding the sequence with another gene sequence encoding a different sequence. In embodiments, the gene sequence encoding the sequences can be codon optimized for expression in mammalian cells.

[0366] "Encoding” refers to the property of specific sequences of nucleotides in a gene, such as a cDNA, or an mRNA, to serve as templates for the synthesis of other macromolecules such as a defined sequence of amino acids. Thus, a gene codes for a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. A "gene sequence encoding a protein" includes all nucleotide sequences that are degenerate versions of each other and that code for the same amino acid sequence or amino acid sequences of substantially similar form and function.

[0367] Polynucleotide gene sequences encoding more than one portion of an expressed genetic constructs can be operably linked to each other and relevant regulatory sequences. For example, there can be a functional linkage between a regulatory sequence and an exogenous nucleic acid sequence resulting in expression of the latter. For another example, a first nucleic acid sequence can be operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary or helpful, join coding regions, into the same reading frame.

[0368] A "vector" is a nucleic acid molecule that is capable of transporting another nucleic acid. Vectors may be, e.g., plasmids, cosmids, viruses, or phage. An "expression vector" is a vector that is capable of directing the expression of a protein encoded by one or more genes carried by the vector when it is present in the appropriate environment.

[0369] "Lentivirus" refers to a genus of retroviruses that are capable of infecting dividing and nondividing cells. Several examples of lentiviruses include HIV (human immunodeficiency virus: including HIV type 1, and HIV type 2); equine infectious anemia virus; feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV).

[0370] A lentiviral vector is a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al, Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include: the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available andwould be known to one skilled in the art. In particular embodiments, cells are genetically engineered to express genetic constructs using a lentivirus or lentiviral vector.

[0371] "Retroviruses" are viruses having an RNA genome. "Gammaretrovirus" refers to a genus of the retroviridae family. Exemplary gammaretroviruses include mouse stem cell virus, murine leukemia virus, feline leukemia virus, feline sarcoma virus, and avian reticuloendotheliosis viruses.

[0372] Retroviral vectors (see Miller, et a!., 1993, Meth. Enzymol. 217:581-599) can be used. In such embodiments, the gene to be expressed is cloned into the retroviral vector for its delivery into cells. In particular embodiments, a retroviral vector includes all of the cis-acting sequences necessary for the packaging and integration of the viral genome, i.e. , (a) a long terminal repeat (LTR), or portions thereof, at each end of the vector; (b) primer binding sites for negative and positive strand DNA synthesis; and (c) a packaging signal, necessary for the incorporation of genomic RNA into virions. More detail about retroviral vectors can be found in Boesen, et al., 1994, Biotherapy 6:291-302; Clowes, et al., 1994, J. Clin. Invest. 93:644-651 ; Kiem, et al., 1994, Blood 83:1467-1473; Salmons and Gunzberg, 1993, Human Gene Therapy 4:129-141 ; and Grossman and Wilson, 1993, Curr. Opin. in Genetics and Devel. 3:110-114. Adenoviruses, adeno-associated viruses (AAV) and alphaviruses can also be used. See Kozarsky and Wilson, 1993, Current Opinion in Genetics and Development 3:499-503, Rosenfeld, et al., 1991 , Science 252:431-434; Rosenfeld, et al., 1992, Cell 68:143-155; Mastrangeli, et al., 1993, J. Clin. Invest. 91 :225-234; Walsh, et al., 1993, Proc. Soc. Exp. Bioi. Med. 204:289-300; and Lundstrom, 1999, J. Recept. Signal Transduct. Res. 19: 673-686. Other methods of gene delivery include use of mammalian artificial chromosomes (Vos, 1998, Curr. Op. Genet. Dev. 8:351-359); liposomes (Tarahovsky and Ivanitsky, 1998, Biochemistry (Mose) 63:607-618); ribozymes (Branch and Klotman, 1998, Exp. Nephrol. 6:78-83); and triplex DNA (Chan and Glazer, 1997, J. Mol. Med. 75:267-282).

[0373] There are a large number of available viral vectors suitable within the current disclosure, including those identified for human gene therapy applications (see Pfeifer and Verma, 2001, Ann. Rev. Genomics Hum. Genet. 2:177). Methods of using retroviral and lentiviral viral vectors and packaging cells for transducing mammalian host cells with viral particles including transgenes are described in, e.g., US 8,119,772; Walchli, et al., 2011 , PLoS One 6:327930; Zhao, et al., 2005, J. Immunol. 174:4415; Engels, et al., 2003, Hum. Gene Ther. 14:1155; Frecha, et al., 2010, Mol. The 18:1748; and Verhoeyen, et al., 2009, Methods Mol. Biol. 506:97. Retroviral and lentiviral vector constructs and expression systems are also commercially available.

[0374] Targeted genetic engineering approaches may also be utilized. The CRISPR (ClusteredRegularly Interspaced Short Palindromic Repeats) / Cas (CRISPR-associated protein) nuclease system is an engineered nuclease system used for genetic engineering that is based on a bacterial system. Information regarding CRISPR-Cas systems and components thereof are described in, for example, US8697359, US8771945, US8795965, US8865406, US8871445, US8889356, US8889418, US8895308, US8906616, US8932814, US8945839, US8993233 andUS8999641 and applications related thereto; and WO2014 / 018423, WO2014 / 093595, WO2014 / 093622, WO2014 / 093635, WO2014 / 093655, WO2014 / 093661, WO2014 / 093694, WO2014 / 093701 , WO2014 / 093709, WO2014 / 093712, WO2014 / 093718, WO2014 / 145599, WO2014 / 204723, WO2014 / 204724, WO2014 / 204725, WO2014 / 204726, WO2014 / 204727, WO2014 / 204728, WO2014 / 204729, WO2015 / 065964, WO2015 / 089351, WO2015 / 089354, WO2015 / 089364, WO2015 / 089419, WO2015 / 089427, WO2015 / 089462, WO2015 / 089465, WO2015 / 089473 and WO2015 / 089486, W02016205711 , WO2017 / 106657, WO2017 / 127807 and applications related thereto.

[0375] Particular embodiments utilize zinc finger nucleases (ZFNs) as gene editing agents. ZFNs are a class of site-specific nucleases engineered to bind and cleave DNA at specific positions. ZFNs are used to introduce double stranded breaks (DSBs) at a specific site in a DNA sequence which enables the ZFNs to target unique sequences within a genome in a variety of different cells. A zinc finger is a domain of 30 amino acids within the zinc finger binding domain whose structure is stabilized through coordination of a zinc ion. Examples of zinc fingers include C2H2 zinc fingers, C3H zinc fingers, and C4 zinc fingers. A designed zinc finger domain is a domain not occurring in nature whose design / composition results principally from rational criteria, e.g., application of substitution rules and computerized algorithms for processing information in a database storing information of existing ZFP designs and binding data. A well-known example of a ZFN is a fusion of the Fokl nuclease with a zinc finger DNA binding domain. For additional information regarding ZFNs and ZFNs useful within the teachings of the current disclosure, see, e.g., US 6,534,261 ; US 6,607,882; US 6,746,838; US 6,794, 136; US 6,824,978; 6,866,997; US 6,933,113; 6,979,539; US 7,013,219; US 7,030,215; US 7,220,719; US 7,241 ,573; US 7,241 ,574; US 7,585,849; US 7,595,376; US 6,903,185; US 6,479,626; US 2003 / 0232410 and US 2009 / 0203140 as well as Gaj et al., Nat Methods, 2012, 9(8):805-7; Ramirez et al., Nucl Acids Res, 2012, 40(12):5560-8; Kim et al., Genome Res, 2012, 22(7): 1327-33; Umov et al., Nature Reviews Genetics, 2010, 11 :636-646; Miller, etal. Nature biotechnology 25, 778-785 (2007); Bibikova, etal. Science 300, 764 (2003); Bibikova, et al. Genetics 161 , 1169-1175 (2002); Wolfe, etal. Annual review of biophysics and biomolecular structure 29, 183-212 (2000); Kim, et al. Proceedings of the National Academy of Sciences of the United States of America 93, 1156-1160 (1996); and Miller, et al. The EMBOjournal 4, 1609-1614 (1985).

[0376] Particular embodiments can use transcription activator like effector nucleases (TALENs) as gene editing agents. TALENs refer to fusion proteins including a transcription activator-like effector (TALE) DNA binding protein and a DNA cleavage domain. TALENs are used to edit genes and genomes by inducing double DSBs in the DNA, which induce repair mechanisms in cells. Generally, two TALENs must bind and flank each side of the target DNA site for the DNA cleavage domain to dimerize and induce a DSB. For additional information regarding TALENs, see US 8,440,431 ; US 8,440,432; US 8,450,471 ; US 8,586,363; and US 8,697,853; as well as Joung and Sander, Nat Rev Mol Cell Biol, 2013, 14(l):49-55; Beurdeley et al., Nat Commun, 2013, 4: 1762; Scharenberg et al., Curr Gene Ther, 2013, 13(4):291-303; Gaj et al., Nat Methods, 2012, 9(8):805-7; Miller, et al. Nature biotechnology 29, 143-148 (2011); Christian, et al. Genetics 186, 757-761 (2010); Boch, etal. Science 326, 1509-1512 (2009); and Moscou, & Bogdanove, Science 326, 1501 (2009).

[0377] Particular embodiments can utilize MegaTALs as gene editing agents. MegaTALs have a sc rare-cleaving nuclease structure in which a TALE is fused with the DNA cleavage domain of a meganuclease. Meganucleases, also known as homing endonucleases, are single peptide chains that have both DNA recognition and nuclease function in the same domain. In contrast to the TALEN, the megaTAL only requires the delivery of a single peptide chain for functional activity.

[0378] Particular embodiments can use transposon-based systems as gene editing agents to mediate the integration of a genetic construct into cells. Generally, such methods will involve introducing into cells (i) a first vector encoding a transposase (or a transposase polypeptide) and (ii) a second vector encoding a desired genetic element that is flanked by transposon repeats. Transposons or transposable elements include a (short) nucleic acid sequence with terminal repeat sequences upstream and downstream thereof and encode enzymes that facilitate the excision and insertion of the nucleic acid into target DNA sequences.

[0379] Several transposon / transposase systems have been adapted for genetic insertions of heterologous DNA sequences. Examples of such transposases include sleeping beauty (“SB”, e.g., derived from the genome of salmonid fish); piggyback (e.g., derived from lepidopteran cells and / or the Myotis lucifugus)', mariner (e.g., derived from Drosophila); frog prince (e.g., derived from Rana pipiens , Toll ; Tol2 (e.g., derived from medaka fish); TcBuster (e.g., derived from the red flour beetle Tribolium castaneum), Helraiser, Himarl , Passport, Minos, Ac / Ds, PIF, Harbinger, Harbinger3-DR, HSmarl , and spinON. Transposases and transposon systems are further described in U.S. Pat. Nos. 6,489,458; 7,148,203; 8,227,432; and 9,228,180.

[0380] (x) Nanoparticles. Particular embodiments disclosed herein utilize nanoparticles to carryor deliver components (e.g., genetic constructs encoding antibodies, recombinant receptors, gene knockouts). One example of a nanoparticle includes a liposome. Liposomes are microscopic vesicles including at least one concentric lipid bilayer. Vesicle-forming lipids are selected to achieve a specified degree of fluidity or rigidity of the final complex. In particular embodiments, liposomes provide a lipid composition that is an outer layer surrounding a porous particle.

[0381] Liposomes can be neutral (cholesterol) or bipolar and include phospholipids, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and sphingomyelin (SM) and other type of bipolar lipids including dioleoylphosphatidylethanolamine (DOPE), with a hydrocarbon chain length in the range of 14-22, and saturated or with one or more double C=C bonds. Examples of lipids capable of producing a stable liposome, alone, or in combination with other lipid components are phospholipids, such as hydrogenated soy phosphatidylcholine (HSPC), lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cephalin, cardiolipin, phosphatidic acid, cerebro sides, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE) and dioleoylphosphatidylethanolamine 4-(N-maleimido-methyl)cyclohexane-1-carboxylate (DOPE-mal). Additional non-phosphorous containing lipids that can become incorporated into liposomes include stearylamine, dodecylamine, hexadecylamine, isopropyl myristate, triethanolamine-lauryl sulfate, alkyl-aryl sulfate, acetyl palmitate, glycerol ricinoleate, hexadecyl stereate, amphoteric acrylic polymers, polyethyloxylated fatty acid amides, DDAB, dioctadecyl dimethyl ammonium chloride (DODAC), 1 ,2-dimyristoyl-3-trimethylammonium propane (DMTAP), DOTAP, DOTMA, DC-Chol, phosphatidic acid (PA), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylglycerol, DOPG, and dicetylphosphate. In particular embodiments, lipids used to create liposomes disclosed herein include cholesterol, hydrogenated soy phosphatidylcholine (HSPC) and, the derivatized vesicle-forming lipid PEG-DSPE.

[0382] Methods of forming liposomes are described in, for example, US Patent Nos. 4,229,360; 4,224,179; 4,241,046; 4,737,323; 4,078,052; 4,235,871 ; 4,501 ,728; and 4,837,028, as well as in Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980) and Hope et al., Chem. Phys. Lip. 40:89 (1986).

[0383] Particular embodiments can utilize lipid nanoparticles (LNPs) as described in US2018 / 0303925. Particles as described in Pardi et al., Nature Communications (2018) 9:3361 can also be used. Particular embodiments can include mRNA and poly(C) RNA (Sigma) encapsulated in LNPs using a self-assembly process. In particular embodiments, an aqueoussolution of mRNA at pH = 4.0 can be rapidly mixed with a solution of lipids dissolved in ethanol, as described in Maier, et al., Mol. Then 21 ,1570-1578 (2013). The LNPs can include an ionizable cationic lipid including phosphatidylcholine / cholesterol / PEG-lipid (50:10:38.5:1.5 mol / mol) with RNA encapsulated at an RNA to total lipid ratio of 0.05 (wt / wt). Particular embodiments can utilize LNPs with a diameter of 80 nm as measured by dynamic light scattering using a Zetasizer Nano ZS (Malvern Instruments Ltd., Malvern, UK) instrument.

[0384] In particular embodiments, particles can include features that enhance the delivery and / or expression of a nucleic acid. For example, in particular embodiments, the particle includes a carrier molecule that condenses and protects a nucleic acid from enzymatic degradation. Such carriers are positively charged (e.g., poly(P-amino ester)). Additional examples of positively charged polymers include polyamines; polyorganic amines (e.g., polyethyleneimine (PEI), polyethyleneimine celluloses); poly(amidoamines) (PAMAM); polyamino acids (e.g., polylysine (PLL), polyarginine); polysaccharides (e.g, cellulose, dextran, DEAE dextran, starch); spermine, spermidine, poly(vinylbenzyl trialkyl ammonium), poly(4-vinyl-N-alkyl-pyridiumiun), poly(acryloyl- trialkyl ammonium), and Tat proteins.

[0385] Examples of positively charged lipids include esters of phosphatidic acid with an aminoalcohol, such as an ester of dipalmitoyl phosphatidic acid or distearoyl phosphatidic acid with hydroxyethylenediamine. More particular examples of positively charged lipids include 3 - [N-(N',N'-dimethylaminoethyl)carbamoyl) cholesterol (DC-chol); N,N'-dimethyl-N,N'-dioctacyl ammonium bromide (DDAB); N,N'-dimethyl-N,N'-dioctacyl ammonium chloride (DDAC); 1 ,2- dioleoyloxypropyl-3-dimethyl-hydroxyethyl ammonium chloride (DORI); 1 ,2-dioleoyloxy-3- [trimethylammonio]-propane (DOTAP); N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); dipalmitoylphosphatidylcholine (DPPC); 1,2-dioctadecyloxy-3- [trimethylammonio]-propane (DSTAP); and the cationic lipids described in e.g. Martin et al., Current Pharmaceutical Design 2005, 11 , 375-394.

[0386] Examples of negatively charged polymers include alginic acids; carboxylic acid polysaccharides; carboxymethyl cellulose; carboxymethyl cellulose-cysteine; carrageenan (e.g., Gelcarin® 209, Gelcarin® 379); chondroitin sulfate; glycosaminoglycans; mucopolysaccharides; negatively charged polysaccharides (e.g., dextran sulfate); poly(acrylic acid); poly(D-aspartic acid); poly(L-aspartic acid); poly(L-aspartic acid) sodium salt; poly(D-glutamic acid); poly(L- glutamic acid); poly(L-glutamic acid) sodium salt; poly(methacrylic acid); sodium alginate (e.g., Protanal® LF 120M, Protanal® LF 200M, Protanal® LF 200D); sodium carboxymethyl cellulose (CMC); sulfated polysaccharides (heparins, agaropectins); pectin, gelatin and hyalouronic acid.

[0387] Neutrally charged polymers include zwitterionic polymers. Zwitterionic refers to theproperty of overall charge neutrality while having both a positive and a negative electrical charge. Zwitterionic polymers can behave like regions of cell membranes that resist cell and protein adhesion.

[0388] Zwitterionic polymers include zwitterionic constitutional units including pendant groups (i.e., groups pendant from the polymer backbone) with zwitterionic groups. Exemplary zwitterionic pendant groups include carboxybetaine groups (e.g., -Ra-N+(Rb)(Rc)-Rd-CO2-, where Ra is a linker group that covalently couples the polymer backbone to the cationic nitrogen center of the carboxybetaine groups, Rb and Rc are nitrogen substituents, and Rd is a linker group that covalently couples the cationic nitrogen center to the carboxy group of the carboxybetaine group).

[0389] In particular embodiments, polymers can include "star shaped polymers," which refer to branched polymers in which two or more polymer branches extend from a core. The core is a group of atoms having two or more functional groups from which the branches can be extended by polymerization.

[0390] In particular embodiments, the branches are zwitterionic or negatively-charged polymeric branches. For star polymers, the branch precursors can be converted to zwitterionic or negatively- charged polymers via hydrolysis, ultraviolet irradiation, or heat. The polymers also may be obtained by any polymerization method effective for polymerization of unsaturated monomers, including atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer polymerization (RAFT), photo-polymerization, ring-opening polymerization (ROP), condensation, Michael addition, branch generation / propagation reaction, or other reactions.

[0391] Blends of lipids and polymers in any concentration and in any ratio can also be used. Blending different polymer types in different ratios using various grades can result in characteristics that borrow from each of the contributing polymers. Various terminal group chemistries can also be adopted.

[0392] Without limiting the foregoing, particular embodiments disclosed herein can also utilize porous particles constructed from any material capable of forming a porous network. Exemplary materials include metals, transition metals and metalloids. Exemplary metals, transition metals and metalloids include lithium, magnesium, zinc, aluminum and silica. In particular embodiments, the porous nanocarriers include silica. The exceptionally high surface area of mesoporous silica (exceeding 1,000 m2 / g) enables nucleic acid loading at levels exceeding conventional DNA carriers such as liposomes.

[0393] Particles can be formed in a variety of different shapes, including spheroidal, cuboidal, pyramidal, oblong, cylindrical, toroidal, and the like.

[0394] (xi) Compositions and Formulations. Any of the antibodies described herein (e.g., anti-CD45 antibodies, multi-domain binding molecules, antibody conjugates) in any exemplary format can be formulated alone or in combination into compositions for administration to subjects. Additionally, nucleic acids encoding the antibodies can also be formulated into compositions for administration (e.g., nucleic acids encapsulated within nanoparticles (e.g., liposomes or polymer- based nanoparticles) and / or as part of a vector delivery system (e.g., a viral vector or plasmid). Antibodies (e.g., anti-CD45 antibodies, multi-domain binding molecules, antibody conjugates) and / or nucleic acids encoding antibodies are collectively referred to herein as “active ingredients”. Certain examples may include formulations. Formulations include cells genetically modified to express an antibody disclosed herein within a pharmaceutically acceptable carrier.

[0395] Salts and / or pro-drugs of the active ingredients can also be used.

[0396] A pharmaceutically acceptable salt includes any salt that retains the activity of the active ingredient and is acceptable for pharmaceutical use. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.

[0397] Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids.

[0398] Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine, lysine, arginine and procaine.

[0399] A prodrug includes an active ingredient which is converted to a therapeutically active compound after administration, such as by cleavage or by hydrolysis of a biologically labile group.

[0400] Exemplary generally used pharmaceutically acceptable carriers include any and all absorption delaying agents, antioxidants, binders, buffering agents, bulking agents or fillers, chelating agents, coatings, disintegration agents, dispersion media, gels, isotonic agents, lubricants, preservatives, salts, solvents or co-solvents, stabilizers, surfactants, and / or delivery vehicles.

[0401] Exemplary antioxidants include ascorbic acid, methionine, and vitamin E.

[0402] Exemplary buffering agents include citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, gluconate buffers, oxalate buffers, lactate buffers, acetate buffers, phosphate buffers, histidine buffers, and / or trimethylamine salts.

[0403] An exemplary chelating agent is EDTA (ethylene-diamine-tetra-acetic acid).

[0404] Exemplary isotonic agents include polyhydric sugar alcohols including trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, or mannitol.

[0405] Exemplary preservatives include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides, hexamethonium chloride, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0406] Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the antibodies or helps to prevent denaturation or adherence to the container wall. Typical stabilizers can include polyhydric sugar alcohols; amino acids, such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L- leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, and cyclitols, such as inositol; PEG; amino acid polymers; sulfur-containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, o-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (i.e., <10 residues); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; monosaccharides such as xylose, mannose, fructose and glucose; disaccharides such as lactose, maltose and sucrose; trisaccharides such as raffinose, and polysaccharides such as dextran. Stabilizers are typically present in the range of from 0.1 to 10,000 parts by weight based on therapeutic weight.

[0407] The formulations and / or compositions disclosed herein can be formulated for administration by, for example, injection, inhalation, infusion, perfusion, lavage, or ingestion. The formulations and / or compositions disclosed herein can further be formulated for intravenous, intradermal, intraarterial, intranodal, intralymphatic, intraperitoneal, intralesional, intraprostatic, intravaginal, intrarectal, topical, intrathecal, intratumoral, intramuscular, intravesicular, oral, sublingual, and / or subcutaneous administration.

[0408] For injection, compositions and / or formulations can be formulated as aqueous solutions, such as in buffers including Hanks' solution, Ringer's solution, or physiological saline. The aqueous solutions can include formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the composition can be in lyophilized and / or powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0409] For oral administration, the compositions can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like. For oral solid compositions suchas powders, capsules and tablets, suitable excipients include binders (gum tragacanth, acacia, cornstarch, gelatin), fillers such as sugars, e.g., lactose, sucrose, mannitol and sorbitol; dicalcium phosphate, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxy-methylcellulose, and / or polyvinylpyrrolidone (PVP); granulating agents; and binding agents. If desired, disintegrating agents can be added, such as corn starch, potato starch, alginic acid, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. If desired, solid dosage forms can be sugar-coated or enteric-coated using standard techniques. Flavoring agents, such as peppermint, oil of Wintergreen, cherry flavoring, orange flavoring, etc. can also be used.

[0410] Compositions can be formulated as an aerosol. In particular embodiments, the aerosol is provided as part of an anhydrous, liquid or dry powder inhaler. Aerosol sprays from pressurized packs or nebulizers can also be used with a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, a dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may also be formulated including a powder mix of the composition and a suitable powder base such as lactose or starch.

[0411] Compositions and / or formulations can also be formulated as depot preparations. Depot preparations can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0412] Additionally, compositions and / or formulations can be formulated as sustained-release systems utilizing semipermeable matrices of solid polymers including at least one type of antibody. Various sustained-release materials have been established and are well known by those of ordinary skill in the art. Sustained-release systems may, depending on their chemical nature, release one or more antibodies following administration for a few weeks up to over 100 days. Depot preparations can be administered by injection; parenteral injection; instillation; or implantation into soft tissues, a body cavity, or occasionally into a blood vessel with injection through fine needles.

[0413] Depot compositions and / or formulations can include a variety of bioerodible polymers including poly(lactide), poly(glycolide), poly(caprolactone) and poly(lactide)-co(glycolide) (PLG) of desirable lactide:glycolide ratios, average molecular weights, polydispersities, and terminalgroup chemistries. Blending different polymer types in different ratios using various grades can result in characteristics that borrow from each of the contributing polymers.

[0414] The use of different solvents (for example, dichloromethane, chloroform, ethyl acetate, triacetin, N-methyl pyrrolidone, tetrahydrofuran, phenol, or combinations thereof) can alter microparticle size and structure in order to modulate release characteristics. Other useful solvents include water, ethanol, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetone, methanol, isopropyl alcohol (IPA), ethyl benzoate, and benzyl benzoate.

[0415] Exemplary release modifiers can include surfactants, detergents, internal phase viscosity enhancers, complexing agents, surface active molecules, co-solvents, chelators, stabilizers, derivatives of cellulose, (hydroxypropyl)methyl cellulose (HPMC), HPMC acetate, cellulose acetate, pluronics (e.g., F68 / F127), polysorbates, Span® (Croda Americas, Wilmington, Delaware), poly(vinyl alcohol) (PVA), Brij® (Croda Americas, Wilmington, Delaware), sucrose acetate isobutyrate (SAIB), salts, and buffers.

[0416] Excipients that partition into the external phase boundary of nanoparticles such as surfactants including polysorbates, dioctylsulfosuccinates, poloxamers, PVA, can also alter properties including particle stability and erosion rates, hydration and channel structure, interfacial transport, and kinetics in a favorable manner.

[0417] Additional processing of the disclosed sustained release depot compositions and / or formulations can utilize stabilizing excipients including mannitol, sucrose, trehalose, and glycine with other components such as polysorbates, PVAs, and dioctylsulfosuccinates in buffers such as Tris, citrate, or histidine. A freeze-dry cycle can also be used to produce very low moisture powders that reconstitute to similar size and performance characteristics of the original suspension.

[0418] In particular embodiments, the compositions include active ingredients of at least 0.1% w / v or w / w of the composition; at least 1% w / v or w / w of composition; at least 10% w / v or w / w of composition; at least 20% w / v or w / w of composition; at least 30% w / v or w / w of composition; at least 40% w / v or w / w of composition; at least 50% w / v or w / w of composition; at least 60% w / v or w / w of composition; at least 70% w / v or w / w of composition; at least 80% w / v or w / w of composition; at least 90% w / v or w / w of composition; at least 95% w / v or w / w of composition; or at least 99% w / v or w / w of composition.

[0419] In certain examples, cells are genetically modified to express a binding domain (e.g., an antibody) disclosed herein, for example, as part of a recombinant receptor (e.g., CAR or eTCR). In these embodiments, genetically modified cells can be prepared as formulations for delivery in buffers such as Hanks' solution, Ringer's solution, or physiological saline. Cells can be geneticallymodified using methods known in the art. Exemplary targeted genetic engineering approaches include the use of CRISPR / Cas nuclease systems, zinc finger nucleases (ZFNs), and / or transcription activator like effector nucleases (TALENs). In particular embodiments, the cells are B cells genetically modified to express an antibody. Methods to genetically modify a B cell to express an antibody are described in PCT / US2018 / 056789.

[0420] Therapeutically effective amounts of cells within formulations can be greater than 102cells, greater than 103cells, greater than 104cells, greater than 105cells, greater than 106cells, greater than 107cells, greater than 108cells, greater than 109cells, greater than 1010cells, or greater than 1011cells.

[0421] In particular embodiments, cells are in a formulation volume of a liter or less, 500 ml or less, 250 ml or less, or 100 ml or less. Hence, the density of administered cells is typically greater than 104cells / ml, 105cells / ml, 106cells / ml, 107cells / ml, or 108cells / ml.

[0422] Any composition or formulation disclosed herein can advantageously include any other pharmaceutically acceptable carriers which include those that do not produce significantly adverse, allergic, or other untoward reactions that outweigh the benefit of administration. Exemplary pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990. Moreover, compositions and formulations can be prepared to meet sterility, pyrogenicity, general safety, and purity standards as required by U.S. FDA Office of Biological Standards and / or other relevant foreign regulatory agencies.

[0423] (xii) Methods of Use. Methods disclosed herein include treating subjects. Subjects include, e.g., humans, veterinary animals (dogs, cats, reptiles, birds) livestock (e.g., horses, cattle, goats, pigs, chickens) and research animals (e.g., monkeys, rats, mice, fish). Treating subjects includes delivering therapeutically effective amounts. Therapeutically effective amounts include those that provide effective amounts, prophylactic treatments and / or therapeutic treatments.

[0424] An "effective amount" is the amount of a composition or formulation necessary to result in a desired physiological change in the subject. Effective amounts are often administered for research purposes. Effective amounts disclosed herein can cause a statistical ly-significant effect in an animal model or in vitro assay relevant to the assessment of a condition’s development, progression, and / or resolution. In particular embodiments, a condition is a CD45-related condition.

[0425] Exemplary CD45-related conditions include any condition in which CD45 is expressed on the surface of the cell (CD45-positive cell). In particular embodiments, a CD45-related condition or conditions that can be targeted by targeting CD45 includes a hematologic malignancy. In particular embodiments, a hematologic malignancy includes leukemia, myeloma, or lymphoma. In particular embodiments, leukemia includes acute myelogenous leukemia (AML), acutelymphocytic leukemia (ALL), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML), acute promyelocytic leukemia, acute mixed lineage leukemia, hairy cell leukemia, and large granular lymphocytic leukemia. In particular embodiments, myeloma includes multiple myeloma. In particular embodiments, lymphomas include Hodgkin's lymphoma, non-Hodgkin lymphoma (NHL), primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, transformed follicular lymphoma, splenic marginal zone lymphoma, lymphocytic lymphoma, T-cell lymphoma, and other B- cell malignancies. In particular embodiments, a CD45-related condition includes AML. In particular embodiments, AML includes relapsed AML or refractory AML.

[0426] A "prophylactic treatment" includes a treatment administered to a subject who does not display signs or symptoms of a condition or displays only early signs or symptoms of a condition such that treatment is administered for the purpose of diminishing or decreasing the risk of developing the condition further. Thus, a prophylactic treatment functions as a preventative treatment against a condition. In particular embodiments, prophylactic treatments reduce, delay, or prevent the worsening of a condition.

[0427] A "therapeutic treatment" includes a treatment administered to a subject who displays symptoms or signs of a condition and is administered to the subject for the purpose of diminishing or eliminating those signs or symptoms of the condition. The therapeutic treatment can reduce, control, or eliminate the presence or activity of the condition and / or reduce control or eliminate side effects of the condition.

[0428] Function as an effective amount, prophylactic treatment, or therapeutic treatment are not mutually exclusive, and in particular embodiments, administered dosages may accomplish more than one treatment type.

[0429] In particular embodiments, therapeutically effective amounts provide anti-cancer effects. Anti-cancer effects include a decrease in the number of cancer cells, an increase in life expectancy, prolonged subject life, induced chemo- or radiosensitivity in cancer cells, inhibited cancer cell proliferation, reduced cancer-associated pain, and / or reduced relapse or reoccurrence of cancer following treatment.

[0430] In particular embodiments, therapeutically effective amounts induce an immune response. The immune response can be against a cancer cell, such as a CD45-expressing cancer cell.

[0431] In particular embodiments, anti-CD45 conjugates can be used as a conditioning treatment in patients before they undergo allogeneic or autologous hematopoietic cell transplant (HCT). In particular embodiments, an anti-CD45 conjugated to a radioisotope selected from211At ,131l, and90Y, and can be used as a conditioning treatment in patients before they undergo allogeneic orautologous HCT. In particular embodiments, an anti-CD45 conjugated to drug or immunotoxin can be used as a conditioning treatment in patients before they undergo allogeneic or autologous HCT. In particular embodiments, anti-CD45 conjugates improve the engraftment of gene edited stem cell products and tolerability of HCT. In particular embodiments, treatment with anti-CD45 conjugates result in minimal residual disease burden. In particular embodiments, anti-CD45 antibodies can be used to augment allogeneic transplantation. In particular embodiments, anti- CD45 conjugates including a radioisotope can be used to augment allogeneic transplantation. In particular embodiments, anti-CD45 antibodies can be used for the restoration of hematopoietic capacity and / or the development of anti-tumor immune responses (e.g., graft-versus-tumor effects).

[0432] In particular embodiments, treatments for a subject in need thereof are provided. In particular embodiments, subjects that are “in need of” a hematopoietic stem cell transplant include patients that exhibit a defect or deficiency in one or more blood cell types, as well as patients having a stem cell disorder, cancer, inherited blood disorder, autoimmune disease, metabolic storage disorder, immunodeficiency, or other pathology described herein. Hematopoietic stem cells generally exhibit 1) multi-potency, and can thus differentiate into multiple different blood lineages including granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), erythrocytes (e.g., reticulocytes, erythrocytes), thrombocytes (e.g., megakaryoblasts, platelet producing megakaryocytes, platelets), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B-cells and T-cells), 2) self-renewal, and can thus give rise to daughter cells that have equivalent potential as the mother cell, and 3) the ability to be reintroduced into a transplant recipient whereupon they home to the hematopoietic stem cell niche and re-establish productive and sustained hematopoiesis. Hematopoietic stem cells can thus be administered to a subject defective or deficient in one or more cell types of the hematopoietic lineage in order to re-constitute the defective or deficient population of cells in vivo.

[0433] Additionally or alternatively, a subject “in need of” a hematopoietic stem cell transplant may be one that is or is not suffering from one of the pathologies (e.g., stem cell disorder, cancer, inherited blood disorder, autoimmune disease, metabolic storage disorder, immunodeficiency) described herein, but nonetheless exhibits a reduced level (e.g., as compared to that of an otherwise healthy subject) of one or more endogenous cell types within the hematopoietic lineage, such as megakaryocytes, thrombocytes, platelets, erythrocytes, mast cells, myeoblasts, basophils, neutrophils, eosinophils, microglia, granulocytes, monocytes, osteoclasts, antigen- presenting cells, macrophages, dendritic cells, natural killer cells, T-lymphocytes, and B- lymphocytes. One of skill in the art can readily determine whether one's level of one or more ofthe foregoing cell types, or other blood cell type, is reduced with respect to an otherwise healthy subject, for instance, by way of flow cytometry and fluorescence activated cell sorting (FACS) methods, among other procedures, known in the art

[0434] In particular embodiments, the phrase “stem cell disorder” broadly refers to any disease, disorder, or condition that may be treated or cured by conditioning a subject's target tissues, and / or by ablating an endogenous stem cell population in a target tissue (e.g., ablating an endogenous hematopoietic stem or progenitor cell population from a subject's bone marrow tissue) and / or by engrafting or transplanting stem cells in a subject’s target tissues. In particular embodiments, the stem cell disorder includes a hematopoietic malignancy. For example, Type I diabetes has been shown to be cured by hematopoietic stem cell transplant and may benefit from conditioning in accordance with the compositions and methods described herein.

[0435] In particular embodiments, the subject may be suffering from cancer, and the deficiency may be caused by administration of a chemotherapeutic agent or other medicament that depletes, either selectively or non-specifically, the cancerous cell population. In particular embodiments, the cancer includes neuroblastoma or a hematologic cancer. In particular embodiments, the hematologic cancer includes leukemia, lymphoma, and myeloma. In particular embodiments, the hematologic cancer includes acute myeloid leukemia (AML), acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. In particular embodiments, the AML includes relapsed or refractory AML. In some embodiments, the cancer is a myelodysplastic syndrome.

[0436] In particular embodiments, the subject may be suffering from an inherited blood disorder. In particular embodiments, the inherited blood disorder includes a hemoglobinopathy (e.g., a non- malignant hemoglobinopathy). In particular embodiments, an inherited blood disorder includes sickle cell anemia, thalassemia (e.g., thalassemia major), Fanconi anemia, aplastic anemia, and Diamond-Blackfan anemia.

[0437] In particular embodiments, the subject may be suffering from an autoimmune disease. In some embodiments, the autoimmune disease includes scleroderma, multiple sclerosis, ulcerative colitis, Crohn's disease, Type 1 diabetes, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoid arthritis, or another autoimmune pathology described herein.

[0438] In particular embodiments, the subject may be suffering from a metabolic storage disorder. In some embodiments, the metabolic storage disorder includes glycogen storage diseases, lysosomal storage diseases (e.g., metachromatic leukodystrophy, mucopolysaccharidoses (e.g., Hurlers Disease), Gaucher's Disease, Fabry disease, Niemann-Pick disease, Pompe disease,Tay-Sachs disease), lipid storage diseases (e.g., sphingolpidoses), or any other storage diseases or disorders which may benefit from the treatments and therapies disclosed herein.

[0439] In particular embodiments, the subject may be suffering from an immunodeficiency. In some embodiments, the immunodeficiency includes severe combined immunodeficiency (SCID), adenosine deaminase severe combined immunodeficiency (ADA SCID), acquired immunodeficiency syndrome (AIDS), Wiscott-Aldrich syndrome, hyper immunoglobin M (IgM) syndrome, Chediak-Higashi disease, or any other immunodeficiency disorders which may benefit from the treatments or therapies disclosed herein.

[0440] In some embodiments, other pathologies that may benefit from the treatments or therapies disclosed herein include Schwachman-Diamond syndrome, hereditary lymphohistiocytosis, osteopetrosis, or osteogenesis imperfecta or those diseases or disorders described in “Bone Marrow Transplantation for Non-Malignant Disease,” ASH Education Book, 1 :319-338 (2000)..

[0441] In particular embodiments, a hematopoietic stem cell transplant includes gene-edited cells. In particular embodiments, the gene-edited cells express a recombinant receptor (e.g., CAR or eTCR). In particular embodiments, the gene-edited cells do not express CD45. In particular embodiments, a genetically modified cell expressing a recombinant receptor that binds CD45 should be further engineered to not express CD45 (or the genetically modified cell will target and kill cells of its own population). Methods to knockout CD45 are known to those of skill in the art. For example, any of the genetic engineering techniques described in section (ix) can be used such as CRISPR-Cas9 gene editing to knockout CD45 expression. In other embodiments, CD45 expression is knocked out using RNA interference (RNAi) (e.g., siRNA or shRNA), antisense oligonucleotides (ASOs), or providing dominant negative or decoy forms of CD45 (e.g., mutated CD45 so that the antibodies disclosed herein do not recognize or bind the mutated CD45).

[0442] For administration, therapeutically effective amounts (also referred to herein as doses) can be initially estimated based on results from in vitro assays and / or animal model studies. Such information can be used to more accurately determine useful doses in subjects of interest. The actual dose amount administered to a particular subject can be determined by a physician, veterinarian or researcher taking into account parameters such as physical and physiological factors including target, body weight, severity of condition, type of condition, stage of condition, previous or concurrent therapeutic interventions, idiopathy of the subject and route of administration.

[0443] Useful doses can range from 0.1 to 5 pg / kg or from 0.5 to 1 pg / kg. In other examples, a dose can include 1 pg / kg, 15 pg / kg, 30 pg / kg, 50 pg / kg, 55 pg / kg, 70 pg / kg, 90 pg / kg, 150 pg / kg, 350 pg / kg, 500 pg / kg, 750 pg / kg, 1000 pg / kg, 0.1 to 5 mg / kg or from 0.5 to 1 mg / kg. In otherexamples, a dose can include 1 mg / kg, 10 mg / kg, 30 mg / kg, 50 mg / kg, 70 mg / kg, 100 mg / kg, 300 mg / kg, 500 mg / kg, 700 mg / kg, 1000 mg / kg or more.

[0444] Useful doses can range from 0.1 to 5 pCi / kg or from 0.5 to 1 pCi / kg. In other examples, a dose can include 1 pCi / kg, 15 pCi / kg, 30 pCi / kg, 50 pCi / kg, 55 pCi / kg, 70 pCi / kg, 90 pCi / kg, 150 pCi / kg, 350 pCi / kg, 500 pCi / kg, 750 pCi / kg, or 1000 pCi / kg. In particular embodiments, a dose includes up to 500 pCi / kg.

[0445] Exemplary doses of cell-based formulations can include 104to 109cells / kg body weight, or 103to 1011cells / kg body weight. Therapeutically effective amounts to administer can include greater than 102cells, greater than 103cells, greater than 104cells, greater than 105cells, greater than 106cells, greater than 107cells, greater than 108cells, greater than 109cells, greater than 1010cells, or greater than 1011cells.

[0446] Therapeutically effective amounts can be achieved by administering single or multiple doses during the course of a treatment regimen (e.g., daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months or yearly). In particular embodiments, the treatment protocol may be dictated by a clinical trial protocol or an FDA- approved treatment protocol.

[0447] The compositions described herein can be administered by, for example, injection, inhalation, infusion, perfusion, lavage, or ingestion. Routes of administration can include intravenous, intradermal, intraarterial, intranodal, intravesicular, intrathecal, intraperitoneal, intraparenteral, intranasal, intralesional, intramuscular, oral, subcutaneous, and / or sublingual administration. Formulations are generally be administered by injection.

[0448] (xiii) Kits. The current disclosure also includes kits. Kits can include various components to practice methods disclosed herein. For example, depending on the aspect of the methods practiced, kits could include one or more of nucleic acids forming a genetic construct disclosed herein; a protein or encoding sequence disclosed herein (e.g., antibodies, multi-domain binding molecules, antibody conjugates); nucleic acids creating a CD45 knockout; nucleic acids encoding a self-cleaving peptide; nucleic acids encoding recombinant receptors; nucleic acids encoding chimeric antigen receptors (CAR); lentiviral genetic constructs; a nucleic acid encoding an scFv; a nucleic acid encoding a VL; a nucleic acid encoding a VH; a nucleic acid encoding a transmembrane domain; cells (e.g., immune cells, T-cells, CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells, NK-T cells, monocytes / macrophages, lymphocytes, hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPC), and / or a mixture of HSC and HPC (i.e.,HSPC), untransduced T cells, anti-CD45 CAR T cells, CD45 knockout cells); cell lines; tissue samples (e.g., peripheral blood mononuclear cells (PBMCs)), leukocytes, bone marrow, thymus, tissue biopsy, tumor, or other organ, and / or cells derived therefrom); genetic expression components (e.g., genes for expression provided by vectors (e.g., lentiviral vector, retroviral vector), CRISPR components, ZFNs, TALENs, MegaTALs, targeted viral vectors and / or nanoparticles); cell formulation or activation components (e.g., saline, buffered saline, phosphate buffered saline (PBS); biocompatible buffers such as, Ca++ / Mg++ free PBS; physiological saline, water, Hanks' solution, Ringer's solution, T cell stimulating epitopes (e.g., anti-CD3 / anti-CD28 conjugated beads; OKT3, TGN1412), culture-initiating compositions, RPMI, non-essential amino acids, sodium pyruvate, penicillin / streptomycin, human serum albumin (HSA) or other human serum components or fetal bovine serum, dextrose, stabilizers, preservatives); an antibody conjugate; PCR amplification sequences; culture vessels; GAPDH; IFN-y enzyme-linked immunosorbent assay (ELISA); culture plates; etc.

[0449] The kit may include material(s), which may be desirable from a user standpoint, such as a buffer(s), a diluent(s), a standard(s), and / or other materials useful in sample processing, washing, or conducting any other step of the methods described herein. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, in which notice reflects approval by the agency of manufacture, use, or sale for human administration.

[0450] The kit according to the present disclosure may also include instructions for carrying out the method. Instructions included in the kit of the present disclosure may be affixed to packaging material or may be included as a package insert. While instructions are typically written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term “instructions” can include the address of an internet site which provides instructions.

[0451] Exemplary Embodiments below are included to demonstrate particular embodiments of the disclosure. Those of ordinary skill in the art should recognize in light of the present disclosure that many changes can be made to the specific embodiments disclosed herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0452] (xiv) Exemplary Embodiments.1. An antibody or fragment thereof that binds human CD45, the antibody or fragment thereof including a variable light chain including a complementarity determining region (CDR) light(L)1, CDRL2, and CDRL3 and a variable heavy chain including a CDR heavy (H)1 , CDRH2, and CDRH3, wherein: the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 350, and the CDRH3 has the sequence of SEQ ID NO: 351 , according to North; the CDRL1 has the sequence of SEQ ID NO: 475, the CDRL2 includes the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 477, and the CDRH3 has the sequence of SEQ ID NO: 351 , according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 540, and the CDRH3 has the sequence of SEQ ID NO: 541 , according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 619, and the CDRH3 has the sequence of SEQ ID NO: 541 , according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 661 , the CDRL2 has the sequence of SEQ ID NO: 662, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 665, and the CDRH3 has the sequence of SEQ ID NO: 666, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 353, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 354, the CDRH2 has the sequence of SEQ ID NO: 355, and the CDRH3 has the sequence of SEQ ID NO: 356, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 includes the sequence DTS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 479, the CDRH2 has the sequence of SEQ ID NO: 480, and the CDRH3 has the sequence of SEQ ID NO: 356, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 542, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 543, the CDRH2 has the sequence of SEQ ID NO: 544, and the CDRH3 has the sequence of SEQ ID NO: 545, according to Kabat;the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 542, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 620, the CDRH2 has the sequence of SEQ ID NO: 621 , and the CDRH3 has the sequence of SEQ ID NO: 545, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 668, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 669, the CDRH2 has the sequence of SEQ ID NO: 670, and the CDRH3 has the sequence of SEQ ID NO: 671 , according to Contact; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 358, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 360, the CDRH2 has the sequence of SEQ ID NO: 361 , and the CDRH3 has the sequence of SEQ ID NO: 362, according to North; the CDRL1 has the sequence of SEQ ID NO: 481, the CDRL2 includes the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 482, the CDRH2 has the sequence of SEQ ID NO: 483, and the CDRH3 has the sequence of SEQ ID NO: 362, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 546, the CDRH2 has the sequence of SEQ ID NO: 547, and the CDRH3 has the sequence of SEQ ID NO: 548, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 623, and the CDRH3 has the sequence of SEQ ID NO: 548, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 672, the CDRL2 has the sequence of SEQ ID NO: 673, the CDRL3 has the sequence of SEQ ID NO: 674, the CDRH1 has the sequence of SEQ ID NO: 675, the CDRH2 has the sequence of SEQ ID NO: 676, and the CDRH3 has the sequence of SEQ ID NO: 677, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 363, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 364, and the CDRH3 has the sequence of SEQ ID NO: 365, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 includes the sequence SAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has thesequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 484, and the CDRH3 has the sequence of SEQ ID NO: 365, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 549, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 550, and the CDRH3 has the sequence of SEQ ID NO: 551 , according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 549, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 624, and the CDRH3 has the sequence of SEQ ID NO: 551 , according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 678, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 679, and the CDRH3 has the sequence of SEQ ID NO: 680, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 367, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 369, the CDRH2 has the sequence of SEQ ID NO: 370, and the CDRH3 has the sequence of SEQ ID NO: 371 , according to North; the CDRL1 has the sequence of SEQ ID NO: 485, the CDRL2 includes the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 482, the CDRH2 has the sequence of SEQ ID NO: 483, and the CDRH3 has the sequence of SEQ ID NO: 371 , according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 552, the CDRH2 has the sequence of SEQ ID NO: 553, and the CDRH3 has the sequence of SEQ ID NO: 554, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 623, and the CDRH3 has the sequence of SEQ ID NO: 554, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 681 , the CDRL2 has the sequence of SEQ ID NO: 682, the CDRL3 has the sequence of SEQ ID NO: 683, the CDRH1 has the sequence of SEQ ID NO: 684, the CDRH2 has the sequence of SEQ ID NO: 685, and the CDRH3 has the sequence of SEQ ID NO: 686, according to Contact;the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 373, and the CDRH3 has the sequence of SEQ ID NO: 374, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 includes the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 484, and the CDRH3 has the sequence of SEQ ID NO: 374, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 555, and the CDRH3 has the sequence of SEQ ID NO: 556, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 624, and the CDRH3 has the sequence of SEQ ID NO: 556, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 662, the CDRL3 has the sequence of SEQ ID NO: 687, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 688, and the CDRH3 has the sequence of SEQ ID NO: 689, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 376, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 378, the CDRH2 has the sequence of SEQ ID NO: 379, and the CDRH3 has the sequence of SEQ ID NO: 380, according to North; the CDRL1 has the sequence of SEQ ID NO: 486, the CDRL2 includes the sequence RAS, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 487, the CDRH2 has the sequence of SEQ ID NO: 488, and the CDRH3 has the sequence of SEQ ID NO: 380, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 557, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 558, the CDRH2 has the sequence of SEQ ID NO: 559, and the CDRH3 has the sequence of SEQ ID NO: 560, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 557, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 hasthe sequence of SEQ ID NO: 625, the CDRH2 has the sequence of SEQ ID NO: 626, and the CDRH3 has the sequence of SEQ ID NO: 560, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 690, the CDRL2 has the sequence of SEQ ID NO: 691 , the CDRL3 has the sequence of SEQ ID NO: 692, the CDRH1 has the sequence of SEQ ID NO: 693, the CDRH2 has the sequence of SEQ ID NO: 694, and the CDRH3 has the sequence of SEQ ID NO: 695, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 382, the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 384, the CDRH2 has the sequence of SEQ ID NO: 385, and the CDRH3 has the sequence of SEQ ID NO: 386, according to North; the CDRL1 has the sequence of SEQ ID NO: 489, the CDRL2 includes the sequence GAF, the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 490, the CDRH2 has the sequence of SEQ ID NO: 491 , and the CDRH3 has the sequence of SEQ ID NO: 386, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 561 , the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 562, the CDRH2 has the sequence of SEQ ID NO: 563, and the CDRH3 has the sequence of SEQ ID NO: 564, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 561 , the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 627, the CDRH2 has the sequence of SEQ ID NO: 628, and the CDRH3 has the sequence of SEQ ID NO: 564, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 696, the CDRL2 has the sequence of SEQ ID NO: 697, the CDRL3 has the sequence of SEQ ID NO: 698, the CDRH1 has the sequence of SEQ ID NO: 699, the CDRH2 has the sequence of SEQ ID NO: 700, and the CDRH3 has the sequence of SEQ ID NO: 701 , according to Contact; the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 389, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 391 , the CDRH2 has the sequence of SEQ ID NO: 392, and the CDRH3 has the sequence of SEQ ID NO: 393, according to North; the CDRL1 has the sequence of SEQ ID NO: 492, the CDRL2 includes the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 493, the CDRH2 has the sequence of SEQ ID NO: 494, and the CDRH3 has the sequence of SEQ ID NO: 393, according to IMGT;the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 565, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 566, the CDRH2 has the sequence of SEQ ID NO: 567, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 565, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 629, the CDRH2 has the sequence of SEQ ID NO: 630, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 702, the CDRL2 has the sequence of SEQ ID NO: 703, the CDRL3 has the sequence of SEQ ID NO: 704, the CDRH1 has the sequence of SEQ ID NO: 705, the CDRH2 has the sequence of SEQ ID NO: 706, and the CDRH3 has the sequence of SEQ ID NO: 707, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 397, the CDRH2 has the sequence of SEQ ID NO: 398, and the CDRH3 has the sequence of SEQ ID NO: 399, according to North; the CDRL1 has the sequence of SEQ ID NO: 495, the CDRL2 includes the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 496, the CDRH2 has the sequence of SEQ ID NO: 497, and the CDRH3 has the sequence of SEQ ID NO: 399, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 570, the CDRH2 has the sequence of SEQ ID NO: 571 , and the CDRH3 has the sequence of SEQ ID NO: 572, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 631 , the CDRH2 has the sequence of SEQ ID NO: 632, and the CDRH3 has the sequence of SEQ ID NO: 572, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 708, the CDRL2 has the sequence of SEQ ID NO: 709, the CDRL3 has the sequence of SEQ ID NO: 710, the CDRH1 has the sequence of SEQ ID NO: 711 , the CDRH2 has the sequence of SEQ ID NO: 712, and the CDRH3 has the sequence of SEQ ID NO: 713, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 hasthe sequence of SEQ ID NO: 402, the CDRH2 has the sequence of SEQ ID NO: 403, and the CDRH3 has the sequence of SEQ ID NO: 404, according to North; the CDRL1 has the sequence of SEQ ID NO: 498, the CDRL2 includes the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 has the sequence of SEQ ID NO: 499, the CDRH2 has the sequence of SEQ ID NO: 500, and the CDRH3 has the sequence of SEQ ID NO: 404, according to IMGT; the CDRL1 has ...

Claims

CLAIMSWhat is claimed is:

1. An antibody or fragment thereof that binds human CD45, the antibody or fragment thereof comprising a variable light chain comprising a complementarity determining region (CDR) light (L)1 , CDRL2, and CDRL3 and a variable heavy chain comprising a CDR heavy (H)1 , CDRH2, and CDRH3, wherein: the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 441 , the CDRH2 has the sequence of SEQ ID NO: 442, and the CDRH3 has the sequence of SEQ ID NO: 443, according to North; the CDRL1 has the sequence of SEQ ID NO: 519, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 520, the CDRH2 has the sequence of SEQ ID NO: 521 , and the CDRH3 has the sequence of SEQ ID NO: 443, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 596, the CDRH2 has the sequence of SEQ ID NO: 597, and the CDRH3 has the sequence of SEQ ID NO: 598, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 648, the CDRH2 has the sequence of SEQ ID NO: 649, and the CDRH3 has the sequence of SEQ ID NO: 598, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 750, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 751 , the CDRH2 has the sequence of SEQ ID NO: 752, and the CDRH3 has the sequence of SEQ ID NO: 753, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 353, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 354, the CDRH2 has the sequence of SEQ ID NO: 355, and the CDRH3 has the sequence of SEQ ID NO: 356, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 comprises the sequence DTS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 479, the CDRH2 has the sequence of SEQ ID NO: 480, and the CDRH3 has the sequence of SEQ ID NO: 356, according to IMGT;the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 542, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 543, the CDRH2 has the sequence of SEQ ID NO: 544, and the CDRH3 has the sequence of SEQ ID NO: 545, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 542, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 620, the CDRH2 has the sequence of SEQ ID NO: 621 , and the CDRH3 has the sequence of SEQ ID NO: 545, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 668, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 669, the CDRH2 has the sequence of SEQ ID NO: 670, and the CDRH3 has the sequence of SEQ ID NO: 671 , according to Contact; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 382, the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 384, the CDRH2 has the sequence of SEQ ID NO: 385, and the CDRH3 has the sequence of SEQ ID NO: 386, according to North; the CDRL1 has the sequence of SEQ ID NO: 489, the CDRL2 comprises the sequence GAF, the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 490, the CDRH2 has the sequence of SEQ ID NO: 491 , and the CDRH3 has the sequence of SEQ ID NO: 386, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 561 , the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 562, the CDRH2 has the sequence of SEQ ID NO: 563, and the CDRH3 has the sequence of SEQ ID NO: 564, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 381 , the CDRL2 has the sequence of SEQ ID NO: 561 , the CDRL3 has the sequence of SEQ ID NO: 383, the CDRH1 has the sequence of SEQ ID NO: 627, the CDRH2 has the sequence of SEQ ID NO: 628, and the CDRH3 has the sequence of SEQ ID NO: 564, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 696, the CDRL2 has the sequence of SEQ ID NO: 697, the CDRL3 has the sequence of SEQ ID NO: 698, the CDRH1 has the sequence of SEQ ID NO: 699, the CDRH2 has the sequence of SEQ ID NO: 700, and the CDRH3 has the sequence of SEQ ID NO: 701 , according to Contact; the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 hasthe sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 350, and the CDRH3 has the sequence of SEQ ID NO: 351 , according to North; the CDRL1 has the sequence of SEQ ID NO: 475, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 477, and the CDRH3 has the sequence of SEQ ID NO: 351 , according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 540, and the CDRH3 has the sequence of SEQ ID NO: 541 , according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 346, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 619, and the CDRH3 has the sequence of SEQ ID NO: 541 , according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 661 , the CDRL2 has the sequence of SEQ ID NO: 662, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 665, and the CDRH3 has the sequence of SEQ ID NO: 666, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 358, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 360, the CDRH2 has the sequence of SEQ ID NO: 361 , and the CDRH3 has the sequence of SEQ ID NO: 362, according to North; the CDRL1 has the sequence of SEQ ID NO: 481 , the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 482, the CDRH2 has the sequence of SEQ ID NO: 483, and the CDRH3 has the sequence of SEQ ID NO: 362, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 546, the CDRH2 has the sequence of SEQ ID NO: 547, and the CDRH3 has the sequence of SEQ ID NO: 548, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 357, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 359, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 623, and the CDRH3 has the sequence of SEQ ID NO: 548, according to Chothia;the CDRL1 has the sequence of SEQ ID NO: 672, the CDRL2 has the sequence of SEQ ID NO: 673, the CDRL3 has the sequence of SEQ ID NO: 674, the CDRH1 has the sequence of SEQ ID NO: 675, the CDRH2 has the sequence of SEQ ID NO: 676, and the CDRH3 has the sequence of SEQ ID NO: 677, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 363, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 364, and the CDRH3 has the sequence of SEQ ID NO: 365, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 comprises the sequence SAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 484, and the CDRH3 has the sequence of SEQ ID NO: 365, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 549, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 550, and the CDRH3 has the sequence of SEQ ID NO: 551 , according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 549, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 624, and the CDRH3 has the sequence of SEQ ID NO: 551 , according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 678, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 679, and the CDRH3 has the sequence of SEQ ID NO: 680, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 367, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 369, the CDRH2 has the sequence of SEQ ID NO: 370, and the CDRH3 has the sequence of SEQ ID NO: 371 , according to North; the CDRL1 has the sequence of SEQ ID NO: 485, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 482, the CDRH2 has the sequence of SEQ ID NO: 483, and the CDRH3 has the sequence of SEQ ID NO: 371 , according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 hasthe sequence of SEQ ID NO: 552, the CDRH2 has the sequence of SEQ ID NO: 553, and the CDRH3 has the sequence of SEQ ID NO: 554, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 366, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 368, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 623, and the CDRH3 has the sequence of SEQ ID NO: 554, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 681 , the CDRL2 has the sequence of SEQ ID NO: 682, the CDRL3 has the sequence of SEQ ID NO: 683, the CDRH1 has the sequence of SEQ ID NO: 684, the CDRH2 has the sequence of SEQ ID NO: 685, and the CDRH3 has the sequence of SEQ ID NO: 686, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 349, the CDRH2 has the sequence of SEQ ID NO: 373, and the CDRH3 has the sequence of SEQ ID NO: 374, according to North; the CDRL1 has the sequence of SEQ ID NO: 478, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 476, the CDRH2 has the sequence of SEQ ID NO: 484, and the CDRH3 has the sequence of SEQ ID NO: 374, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 539, the CDRH2 has the sequence of SEQ ID NO: 555, and the CDRH3 has the sequence of SEQ ID NO: 556, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 352, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 372, the CDRH1 has the sequence of SEQ ID NO: 618, the CDRH2 has the sequence of SEQ ID NO: 624, and the CDRH3 has the sequence of SEQ ID NO: 556, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 662, the CDRL3 has the sequence of SEQ ID NO: 687, the CDRH1 has the sequence of SEQ ID NO: 664, the CDRH2 has the sequence of SEQ ID NO: 688, and the CDRH3 has the sequence of SEQ ID NO: 689, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 376, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 378, the CDRH2 has the sequence of SEQ ID NO: 379, and the CDRH3 has the sequence of SEQ ID NO: 380, according to North;the CDRL1 has the sequence of SEQ ID NO: 486, the CDRL2 comprises the sequence RAS, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 487, the CDRH2 has the sequence of SEQ ID NO: 488, and the CDRH3 has the sequence of SEQ ID NO: 380, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 557, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 558, the CDRH2 has the sequence of SEQ ID NO: 559, and the CDRH3 has the sequence of SEQ ID NO: 560, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 375, the CDRL2 has the sequence of SEQ ID NO: 557, the CDRL3 has the sequence of SEQ ID NO: 377, the CDRH1 has the sequence of SEQ ID NO: 625, the CDRH2 has the sequence of SEQ ID NO: 626, and the CDRH3 has the sequence of SEQ ID NO: 560, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 690, the CDRL2 has the sequence of SEQ ID NO: 691 , the CDRL3 has the sequence of SEQ ID NO: 692, the CDRH1 has the sequence of SEQ ID NO: 693, the CDRH2 has the sequence of SEQ ID NO: 694, and the CDRH3 has the sequence of SEQ ID NO: 695, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 389, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 391 , the CDRH2 has the sequence of SEQ ID NO: 392, and the CDRH3 has the sequence of SEQ ID NO: 393, according to North; the CDRL1 has the sequence of SEQ ID NO: 492, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 493, the CDRH2 has the sequence of SEQ ID NO: 494, and the CDRH3 has the sequence of SEQ ID NO: 393, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 565, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 566, the CDRH2 has the sequence of SEQ ID NO: 567, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 387, the CDRL2 has the sequence of SEQ ID NO: 565, the CDRL3 has the sequence of SEQ ID NO: 390, the CDRH1 has the sequence of SEQ ID NO: 629, the CDRH2 has the sequence of SEQ ID NO: 630, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 702, the CDRL2 has the sequence of SEQ ID NO: 703, the CDRL3 has the sequence of SEQ ID NO: 704, the CDRH1 hasthe sequence of SEQ ID NO: 705, the CDRH2 has the sequence of SEQ ID NO: 706, and the CDRH3 has the sequence of SEQ ID NO: 707, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 397, the CDRH2 has the sequence of SEQ ID NO: 398, and the CDRH3 has the sequence of SEQ ID NO: 399, according to North; the CDRL1 has the sequence of SEQ ID NO: 495, the CDRL2 comprises the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 496, the CDRH2 has the sequence of SEQ ID NO: 497, and the CDRH3 has the sequence of SEQ ID NO: 399, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 570, the CDRH2 has the sequence of SEQ ID NO: 571 , and the CDRH3 has the sequence of SEQ ID NO: 572, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 394, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 631 , the CDRH2 has the sequence of SEQ ID NO: 632, and the CDRH3 has the sequence of SEQ ID NO: 572, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 708, the CDRL2 has the sequence of SEQ ID NO: 709, the CDRL3 has the sequence of SEQ ID NO: 710, the CDRH1 has the sequence of SEQ ID NO: 711 , the CDRH2 has the sequence of SEQ ID NO: 712, and the CDRH3 has the sequence of SEQ ID NO: 713, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 has the sequence of SEQ ID NO: 402, the CDRH2 has the sequence of SEQ ID NO: 403, and the CDRH3 has the sequence of SEQ ID NO: 404, according to North; the CDRL1 has the sequence of SEQ ID NO: 498, the CDRL2 comprises the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 has the sequence of SEQ ID NO: 499, the CDRH2 has the sequence of SEQ ID NO: 500, and the CDRH3 has the sequence of SEQ ID NO: 404, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 has the sequence of SEQ ID NO: 570, the CDRH2 has the sequence of SEQ ID NO: 573, and the CDRH3 has the sequence of SEQ ID NO: 574, according to Kabat;the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 401 , the CDRH1 has the sequence of SEQ ID NO: 633, the CDRH2 has the sequence of SEQ ID NO: 634, and the CDRH3 has the sequence of SEQ ID NO: 574, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 708, the CDRL2 has the sequence of SEQ ID NO: 709, the CDRL3 has the sequence of SEQ ID NO: 714, the CDRH1 has the sequence of SEQ ID NO: 711 , the CDRH2 has the sequence of SEQ ID NO: 715, and the CDRH3 has the sequence of SEQ ID NO: 716, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 405, the CDRH2 has the sequence of SEQ ID NO: 403, and the CDRH3 has the sequence of SEQ ID NO: 399, according to North; the CDRL1 has the sequence of SEQ ID NO: 498, the CDRL2 comprises the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 501 , the CDRH2 has the sequence of SEQ ID NO: 500, and the CDRH3 has the sequence of SEQ ID NO: 399, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 575, the CDRH2 has the sequence of SEQ ID NO: 573, and the CDRH3 has the sequence of SEQ ID NO: 572, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 635, the CDRH2 has the sequence of SEQ ID NO: 634, and the CDRH3 has the sequence of SEQ ID NO: 572, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 708, the CDRL2 has the sequence of SEQ ID NO: 709, the CDRL3 has the sequence of SEQ ID NO: 710, the CDRH1 has the sequence of SEQ ID NO: 717, the CDRH2 has the sequence of SEQ ID NO: 715, and the CDRH3 has the sequence of SEQ ID NO: 713, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 395, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 406, the CDRH2 has the sequence of SEQ ID NO: 398, and the CDRH3 has the sequence of SEQ ID NO: 407, according to North; the CDRL1 has the sequence of SEQ ID NO: 498, the CDRL2 comprises the sequence WAS, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has thesequence of SEQ ID NO: 502, the CDRH2 has the sequence of SEQ ID NO: 497, and the CDRH3 has the sequence of SEQ ID NO: 407, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 570, the CDRH2 has the sequence of SEQ ID NO: 571 , and the CDRH3 has the sequence of SEQ ID NO: 576, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 400, the CDRL2 has the sequence of SEQ ID NO: 569, the CDRL3 has the sequence of SEQ ID NO: 396, the CDRH1 has the sequence of SEQ ID NO: 636, the CDRH2 has the sequence of SEQ ID NO: 632, and the CDRH3 has the sequence of SEQ ID NO: 576, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 708, the CDRL2 has the sequence of SEQ ID NO: 709, the CDRL3 has the sequence of SEQ ID NO: 710, the CDRH1 has the sequence of SEQ ID NO: 718, the CDRH2 has the sequence of SEQ ID NO: 712, and the CDRH3 has the sequence of SEQ ID NO: 719, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 408, the CDRL2 has the sequence of SEQ ID NO: 409, the CDRL3 has the sequence of SEQ ID NO: 410, the CDRH1 has the sequence of SEQ ID NO: 411 , the CDRH2 has the sequence of SEQ ID NO: 412, and the CDRH3 has the sequence of SEQ ID NO: 413, according to North; the CDRL1 has the sequence of SEQ ID NO: 503, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 410, the CDRH1 has the sequence of SEQ ID NO: 504, the CDRH2 has the sequence of SEQ ID NO: 505, and the CDRH3 has the sequence of SEQ ID NO: 413, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 408, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 410, the CDRH1 has the sequence of SEQ ID NO: 578, the CDRH2 has the sequence of SEQ ID NO: 579, and the CDRH3 has the sequence of SEQ ID NO: 580, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 408, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 410, the CDRH1 has the sequence of SEQ ID NO: 637, the CDRH2 has the sequence of SEQ ID NO: 638, and the CDRH3 has the sequence of SEQ ID NO: 580, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 720, the CDRL2 has the sequence of SEQ ID NO: 721 , the CDRL3 has the sequence of SEQ ID NO: 722, the CDRH1 has the sequence of SEQ ID NO: 723, the CDRH2 has the sequence of SEQ ID NO: 724, and the CDRH3 has the sequence of SEQ ID NO: 725, according to Contact;the CDRL1 has the sequence of SEQ ID NO: 414, the CDRL2 has the sequence of SEQ ID NO: 415, the CDRL3 has the sequence of SEQ ID NO: 416, the CDRH1 has the sequence of SEQ ID NO: 417, the CDRH2 has the sequence of SEQ ID NO: 418, and the CDRH3 has the sequence of SEQ ID NO: 419, according to North; the CDRL1 has the sequence of SEQ ID NO: 506, the CDRL2 comprises the sequence KIS, the CDRL3 has the sequence of SEQ ID NO: 416, the CDRH1 has the sequence of SEQ ID NO: 507, the CDRH2 has the sequence of SEQ ID NO: 508, and the CDRH3 has the sequence of SEQ ID NO: 419, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 414, the CDRL2 has the sequence of SEQ ID NO: 581 , the CDRL3 has the sequence of SEQ ID NO: 416, the CDRH1 has the sequence of SEQ ID NO: 566, the CDRH2 has the sequence of SEQ ID NO: 582, and the CDRH3 has the sequence of SEQ ID NO: 583, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 414, the CDRL2 has the sequence of SEQ ID NO: 581 , the CDRL3 has the sequence of SEQ ID NO: 416, the CDRH1 has the sequence of SEQ ID NO: 639, the CDRH2 has the sequence of SEQ ID NO: 640, and the CDRH3 has the sequence of SEQ ID NO: 583, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 726, the CDRL2 has the sequence of SEQ ID NO: 727, the CDRL3 has the sequence of SEQ ID NO: 728, the CDRH1 has the sequence of SEQ ID NO: 705, the CDRH2 has the sequence of SEQ ID NO: 729, and the CDRH3 has the sequence of SEQ ID NO: 730, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 420, the CDRL2 has the sequence of SEQ ID NO: 421 , the CDRL3 has the sequence of SEQ ID NO: 422, the CDRH1 has the sequence of SEQ ID NO: 423, the CDRH2 has the sequence of SEQ ID NO: 424, and the CDRH3 has the sequence of SEQ ID NO: 425, according to North; the CDRL1 has the sequence of SEQ ID NO: 509, the CDRL2 comprises the sequence DAS, the CDRL3 has the sequence of SEQ ID NO: 422, the CDRH1 has the sequence of SEQ ID NO: 510, the CDRH2 has the sequence of SEQ ID NO: 511 , and the CDRH3 has the sequence of SEQ ID NO: 425, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 420, the CDRL2 has the sequence of SEQ ID NO: 584, the CDRL3 has the sequence of SEQ ID NO: 422, the CDRH1 has the sequence of SEQ ID NO: 585, the CDRH2 has the sequence of SEQ ID NO: 586, and the CDRH3 has the sequence of SEQ ID NO: 587, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 420, the CDRL2 has the sequence of SEQ ID NO: 584, the CDRL3 has the sequence of SEQ ID NO: 422, the CDRH1 hasthe sequence of SEQ ID NO: 641 , the CDRH2 has the sequence of SEQ ID NO: 642, and the CDRH3 has the sequence of SEQ ID NO: 587, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 731 , the CDRL2 has the sequence of SEQ ID NO: 732, the CDRL3 has the sequence of SEQ ID NO: 733, the CDRH1 has the sequence of SEQ ID NO: 734, the CDRH2 has the sequence of SEQ ID NO: 735, and the CDRH3 has the sequence of SEQ ID NO: 736, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 426, the CDRL2 has the sequence of SEQ ID NO: 409, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 391 , the CDRH2 has the sequence of SEQ ID NO: 392, and the CDRH3 has the sequence of SEQ ID NO: 393, according to North; the CDRL1 has the sequence of SEQ ID NO: 512, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 493, the CDRH2 has the sequence of SEQ ID NO: 494, and the CDRH3 has the sequence of SEQ ID NO: 393, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 426, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 566, the CDRH2 has the sequence of SEQ ID NO: 588, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 643, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 629, the CDRH2 has the sequence of SEQ ID NO: 630, and the CDRH3 has the sequence of SEQ ID NO: 568, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 737, the CDRL2 has the sequence of SEQ ID NO: 721 , the CDRL3 has the sequence of SEQ ID NO: 738, the CDRH1 has the sequence of SEQ ID NO: 705, the CDRH2 has the sequence of SEQ ID NO: 706, and the CDRH3 has the sequence of SEQ ID NO: 707, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 428, the CDRL2 has the sequence of SEQ ID NO: 429, the CDRL3 has the sequence of SEQ ID NO: 430, the CDRH1 has the sequence of SEQ ID NO: 431 , the CDRH2 has the sequence of SEQ ID NO: 432, and the CDRH3 has the sequence of SEQ ID NO: 433, according to North; the CDRL1 has the sequence of SEQ ID NO: 513, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 430, the CDRH1 has the sequence of SEQ ID NO: 514, the CDRH2 has the sequence of SEQ ID NO: 515, and the CDRH3 has the sequence of SEQ ID NO: 433, according to IMGT;the CDRL1 has the sequence of SEQ ID NO: 428, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 430, the CDRH1 has the sequence of SEQ ID NO: 589, the CDRH2 has the sequence of SEQ ID NO: 590, and the CDRH3 has the sequence of SEQ ID NO: 591 , according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 428, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 430, the CDRH1 has the sequence of SEQ ID NO: 644, the CDRH2 has the sequence of SEQ ID NO: 645, and the CDRH3 has the sequence of SEQ ID NO: 591 , according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 739, the CDRL2 has the sequence of SEQ ID NO: 740, the CDRL3 has the sequence of SEQ ID NO: 741 , the CDRH1 has the sequence of SEQ ID NO: 742, the CDRH2 has the sequence of SEQ ID NO: 743, and the CDRH3 has the sequence of SEQ ID NO: 744, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 434, the CDRL2 has the sequence of SEQ ID NO: 435, the CDRL3 has the sequence of SEQ ID NO: 436, the CDRH1 has the sequence of SEQ ID NO: 437, the CDRH2 has the sequence of SEQ ID NO: 438, and the CDRH3 has the sequence of SEQ ID NO: 439, according to North; the CDRL1 has the sequence of SEQ ID NO: 516, the CDRL2 comprises the sequence RVS, the CDRL3 has the sequence of SEQ ID NO: 436, the CDRH1 has the sequence of SEQ ID NO: 517, the CDRH2 has the sequence of SEQ ID NO: 518, and the CDRH3 has the sequence of SEQ ID NO: 439, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 434, the CDRL2 has the sequence of SEQ ID NO: 592, the CDRL3 has the sequence of SEQ ID NO: 436, the CDRH1 has the sequence of SEQ ID NO: 593, the CDRH2 has the sequence of SEQ ID NO: 594, and the CDRH3 has the sequence of SEQ ID NO: 595, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 434, the CDRL2 has the sequence of SEQ ID NO: 646, the CDRL3 has the sequence of SEQ ID NO: 436, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 647, and the CDRH3 has the sequence of SEQ ID NO: 595, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 690, the CDRL2 has the sequence of SEQ ID NO: 745, the CDRL3 has the sequence of SEQ ID NO: 746, the CDRH1 has the sequence of SEQ ID NO: 747, the CDRH2 has the sequence of SEQ ID NO: 748, and the CDRH3 has the sequence of SEQ ID NO: 749, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 444, the CDRL2 has the sequence of SEQ ID NO: 445, the CDRL3 has the sequence of SEQ ID NO: 446, the CDRH1 hasthe sequence of SEQ ID NO: 447, the CDRH2 has the sequence of SEQ ID NO: 448, and the CDRH3 has the sequence of SEQ ID NO: 449, according to North; the CDRL1 has the sequence of SEQ ID NO: 489, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 446, the CDRH1 has the sequence of SEQ ID NO: 522, the CDRH2 has the sequence of SEQ ID NO: 523, and the CDRH3 has the sequence of SEQ ID NO: 449, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 444, the CDRL2 has the sequence of SEQ ID NO: 599, the CDRL3 has the sequence of SEQ ID NO: 446, the CDRH1 has the sequence of SEQ ID NO: 600, the CDRH2 has the sequence of SEQ ID NO: 601 , and the CDRH3 has the sequence of SEQ ID NO: 602, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 444, the CDRL2 has the sequence of SEQ ID NO: 599, the CDRL3 has the sequence of SEQ ID NO: 446, the CDRH1 has the sequence of SEQ ID NO: 650, the CDRH2 has the sequence of SEQ ID NO: 651 , and the CDRH3 has the sequence of SEQ ID NO: 602, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 754, the CDRL2 has the sequence of SEQ ID NO: 755, the CDRL3 has the sequence of SEQ ID NO: 756, the CDRH1 has the sequence of SEQ ID NO: 757, the CDRH2 has the sequence of SEQ ID NO: 758, and the CDRH3 has the sequence of SEQ ID NO: 759, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 450, the CDRL2 has the sequence of SEQ ID NO: 409, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 451 , the CDRH2 has the sequence of SEQ ID NO: 452, and the CDRH3 has the sequence of SEQ ID NO: 453, according to North; the CDRL1 has the sequence of SEQ ID NO: 524, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 525, the CDRH2 has the sequence of SEQ ID NO: 526, and the CDRH3 has the sequence of SEQ ID NO: 453, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 450, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 566, the CDRH2 has the sequence of SEQ ID NO: 603, and the CDRH3 has the sequence of SEQ ID NO: 604, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 450, the CDRL2 has the sequence of SEQ ID NO: 577, the CDRL3 has the sequence of SEQ ID NO: 427, the CDRH1 has the sequence of SEQ ID NO: 652, the CDRH2 has the sequence of SEQ ID NO: 653, and the CDRH3 has the sequence of SEQ ID NO: 604, according to Chothia;the CDRL1 has the sequence of SEQ ID NO: 760, the CDRL2 has the sequence of SEQ ID NO: 721 , the CDRL3 has the sequence of SEQ ID NO: 738, the CDRH1 has the sequence of SEQ ID NO: 705, the CDRH2 has the sequence of SEQ ID NO: 761 , and the CDRH3 has the sequence of SEQ ID NO: 762, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 467, the CDRL2 has the sequence of SEQ ID NO: 468, the CDRL3 has the sequence of SEQ ID NO: 469, the CDRH1 has the sequence of SEQ ID NO: 470, the CDRH2 has the sequence of SEQ ID NO: 471 , and the CDRH3 has the sequence of SEQ ID NO: 472, according to North; the CDRL1 has the sequence of SEQ ID NO: 534, the CDRL2 comprises the sequence AAS, the CDRL3 has the sequence of SEQ ID NO: 469, the CDRH1 has the sequence of SEQ ID NO: 535, the CDRH2 has the sequence of SEQ ID NO: 536, and the CDRH3 has the sequence of SEQ ID NO: 472, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 467, the CDRL2 has the sequence of SEQ ID NO: 612, the CDRL3 has the sequence of SEQ ID NO: 469, the CDRH1 has the sequence of SEQ ID NO: 613, the CDRH2 has the sequence of SEQ ID NO: 614, and the CDRH3 has the sequence of SEQ ID NO: 615, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 467, the CDRL2 has the sequence of SEQ ID NO: 612, the CDRL3 has the sequence of SEQ ID NO: 469, the CDRH1 has the sequence of SEQ ID NO: 658, the CDRH2 has the sequence of SEQ ID NO: 659, and the CDRH3 has the sequence of SEQ ID NO: 615, according to Chothia; the CDRL1 has the sequence of SEQ ID NO: 777, the CDRL2 has the sequence of SEQ ID NO: 778, the CDRL3 has the sequence of SEQ ID NO: 779, the CDRH1 has the sequence of SEQ ID NO: 780, the CDRH2 has the sequence of SEQ ID NO: 781 , and the CDRH3 has the sequence of SEQ ID NO: 782, according to Contact; the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 347, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 360, the CDRH2 has the sequence of SEQ ID NO: 473, and the CDRH3 has the sequence of SEQ ID NO: 474, according to North; the CDRL1 has the sequence of SEQ ID NO: 519, the CDRL2 comprises the sequence GAS, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 482, the CDRH2 has the sequence of SEQ ID NO: 537, and the CDRH3 has the sequence of SEQ ID NO: 474, according to IMGT; the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 hasthe sequence of SEQ ID NO: 546, the CDRH2 has the sequence of SEQ ID NO: 616, and the CDRH3 has the sequence of SEQ ID NO: 617, according to Kabat; the CDRL1 has the sequence of SEQ ID NO: 440, the CDRL2 has the sequence of SEQ ID NO: 538, the CDRL3 has the sequence of SEQ ID NO: 348, the CDRH1 has the sequence of SEQ ID NO: 622, the CDRH2 has the sequence of SEQ ID NO: 660, and the CDRH3 has the sequence of SEQ ID NO: 617, according to Chothia; or the CDRL1 has the sequence of SEQ ID NO: 667, the CDRL2 has the sequence of SEQ ID NO: 750, the CDRL3 has the sequence of SEQ ID NO: 663, the CDRH1 has the sequence of SEQ ID NO: 675, the CDRH2 has the sequence of SEQ ID NO: 783, and the CDRH3 has the sequence of SEQ ID NO: 784, according to Contact.

2. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof comprises human variable framework regions.

3. The antibody or fragment thereof of claim 1 , wherein: the variable light chain comprises the sequence of SEQ ID NO: 245 or a sequence having at least 90% sequence identity to SEQ ID NO: 245, and the variable heavy chain comprises the sequence of SEQ ID NO: 246 or a sequence having at least 90% sequence identity to SEQ ID NO: 246; the variable light chain comprises the sequence of SEQ ID NO: 209 or a sequence having at least 90% sequence identity to SEQ ID NO: 209, and the variable heavy chain comprises the sequence of SEQ ID NO: 210 or a sequence having at least 90% sequence identity to SEQ ID NO: 210; the variable light chain comprises the sequence of SEQ ID NO: 221 or a sequence having at least 90% sequence identity to SEQ ID NO: 221 , and the variable heavy chain comprises the sequence of SEQ ID NO: 222 or a sequence having at least 90% sequence identity to SEQ ID NO: 222; the variable light chain comprises the sequence of SEQ ID NO: 207 or a sequence having at least 90% sequence identity to SEQ ID NO: 207, and the variable heavy chain comprises the sequence of SEQ ID NO: 208 or a sequence having at least 90% sequence identity to SEQ ID NO: 208; the variable light chain comprises the sequence of SEQ ID NO: 211 or a sequence having at least 90% sequence identity to SEQ ID NO: 211 , and the variable heavy chain comprises the sequence of SEQ ID NO: 212 or a sequence having at least 90% sequence identity to SEQ ID NO: 212; the variable light chain comprises the sequence of SEQ ID NO: 213 or a sequencehaving at least 90% sequence identity to SEQ ID NO: 213, and the variable heavy chain comprises the sequence of SEQ ID NO: 214 or a sequence having at least 90% sequence identity to SEQ ID NO: 214; the variable light chain comprises the sequence of SEQ ID NO: 215 or a sequence having at least 90% sequence identity to SEQ ID NO: 215, and the variable heavy chain comprises the sequence of SEQ ID NO: 216 or a sequence having at least 90% sequence identity to SEQ ID NO: 216; the variable light chain comprises the sequence of SEQ ID NO: 217 or a sequence having at least 90% sequence identity to SEQ ID NO: 217, and the variable heavy chain comprises the sequence of SEQ ID NO: 218 or a sequence having at least 90% sequence identity to SEQ ID NO: 218; the variable light chain comprises the sequence of SEQ ID NO: 219 or a sequence having at least 90% sequence identity to SEQ ID NO: 219, and the variable heavy chain comprises the sequence of SEQ ID NO: 220 or a sequence having at least 90% sequence identity to SEQ ID NO: 220; the variable light chain comprises the sequence of SEQ ID NO: 223 or a sequence having at least 90% sequence identity to SEQ ID NO: 223, and the variable heavy chain comprises the sequence of SEQ ID NO: 224 or a sequence having at least 90% sequence identity to SEQ ID NO: 224; the variable light chain comprises the sequence of SEQ ID NO: 225 or a sequence having at least 90% sequence identity to SEQ ID NO: 225, and the variable heavy chain comprises the sequence of SEQ ID NO: 226 or a sequence having at least 90% sequence identity to SEQ ID NO: 226; the variable light chain comprises the sequence of SEQ ID NO: 227 or a sequence having at least 90% sequence identity to SEQ ID NO: 227, and the variable heavy chain comprises the sequence of SEQ ID NO: 228 or a sequence having at least 90% sequence identity to SEQ ID NO: 228; the variable light chain comprises the sequence of SEQ ID NO: 229 or a sequence having at least 90% sequence identity to SEQ ID NO: 229, and the variable heavy chain comprises the sequence of SEQ ID NO: 230 or a sequence having at least 90% sequence identity to SEQ ID NO: 230; the variable light chain comprises the sequence of SEQ ID NO: 231 or a sequence having at least 90% sequence identity to SEQ ID NO: 231 , and the variable heavy chain comprises the sequence of SEQ ID NO: 232 or a sequence having at least 90% sequenceidentity to SEQ ID NO: 232; the variable light chain comprises the sequence of SEQ ID NO: 233 or a sequence having at least 90% sequence identity to SEQ ID NO: 233, and the variable heavy chain comprises the sequence of SEQ ID NO: 234 or a sequence having at least 90% sequence identity to SEQ ID NO: 234; the variable light chain comprises the sequence of SEQ ID NO: 235 or a sequence having at least 90% sequence identity to SEQ ID NO: 235, and the variable heavy chain comprises the sequence of SEQ ID NO: 236 or a sequence having at least 90% sequence identity to SEQ ID NO: 236; the variable light chain comprises the sequence of SEQ ID NO: 237 or a sequence having at least 90% sequence identity to SEQ ID NO: 237, and the variable heavy chain comprises the sequence of SEQ ID NO: 238 or a sequence having at least 90% sequence identity to SEQ ID NO: 238; the variable light chain comprises the sequence of SEQ ID NO: 239 or a sequence having at least 90% sequence identity to SEQ ID NO: 239, and the variable heavy chain comprises the sequence of SEQ ID NO: 240 or a sequence having at least 90% sequence identity to SEQ ID NO: 240; the variable light chain comprises the sequence of SEQ ID NO: 241 or a sequence having at least 90% sequence identity to SEQ ID NO: 241 , and the variable heavy chain comprises the sequence of SEQ ID NO: 242 or a sequence having at least 90% sequence identity to SEQ ID NO: 242; the variable light chain comprises the sequence of SEQ ID NO: 243 or a sequence having at least 90% sequence identity to SEQ ID NO: 243, and the variable heavy chain comprises the sequence of SEQ ID NO: 244 or a sequence having at least 90% sequence identity to SEQ ID NO: 244; the variable light chain comprises the sequence of SEQ ID NO: 247 or a sequence having at least 90% sequence identity to SEQ ID NO: 247, and the variable heavy chain comprises the sequence of SEQ ID NO: 248 or a sequence having at least 90% sequence identity to SEQ ID NO: 248; the variable light chain comprises the sequence of SEQ ID NO: 249 or a sequence having at least 90% sequence identity to SEQ ID NO: 249, and the variable heavy chain comprises the sequence of SEQ ID NO: 250 or a sequence having at least 90% sequence identity to SEQ ID NO: 250; the variable light chain comprises the sequence of SEQ ID NO: 256 or a sequencehaving at least 90% sequence identity to SEQ ID NO: 256, and the variable heavy chain comprises the sequence of SEQ ID NO: 257 or a sequence having at least 90% sequence identity to SEQ ID NO: 257; or the variable light chain comprises the sequence of SEQ ID NO: 245 or a sequence having at least 90% sequence identity to SEQ ID NO: 245, and the variable heavy chain comprises the sequence of SEQ ID NO: 258 or a sequence having at least 90% sequence identity to SEQ ID NO: 258.

4. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof comprises a human constant region.

5. The antibody or fragment thereof of claim 4, wherein the human constant region comprises a human light chain constant region and / or a human heavy chain constant region.

6. The antibody or fragment thereof of claim 5, wherein the human light chain constant region comprises a human IgK light chain constant region or a human IgA light chain constant region.

7. The antibody or fragment thereof of claim 5, wherein the human light chain constant region comprises a human IgK light chain constant region.

8. The antibody or fragment thereof of claim 5, wherein the human heavy chain constant region comprises a human I gG 1 heavy chain constant region, a human lgG2 heavy chain constant region, a human lgG3 heavy chain constant region, or a human lgG4 heavy chain constant region.

9. The antibody or fragment thereof of claim 8, wherein the human lgG4 heavy chain constant region comprises a human lgG4_S228P heavy chain constant region.

10. The antibody or fragment thereof of claim 5, wherein the human heavy chain constant region comprises a human I gG 1 heavy chain constant region.

11. The antibody or fragment thereof of claim 5, wherein the human heavy chain constant region comprises a human lgG4_S228P heavy chain constant region.

12. The antibody or fragment thereof of claim 1 , comprising: a light chain having at least 95% sequence identity to SEQ ID NO: 785 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 786 or SEQ ID NO: 787; a light chain having at least 95% sequence identity to SEQ ID NO: 788 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 789 or SEQ ID NO: 790; a light chain having at least 95% sequence identity to SEQ ID NO: 791 a heavy chain having at least 95% sequence identity to SEQ ID NO: 792 or SEQ ID NO: 793; a light chain having at least 95% sequence identity to SEQ ID NO: 794 and a heavychain having at least 95% sequence identity to SEQ ID NO: 795 or SEQ ID NO: 796; a light chain having at least 95% sequence identity to SEQ ID NO: 797 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 798 or SEQ ID NO: 799; a light chain having at least 95% sequence identity to SEQ ID NO: 800 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 801 or SEQ ID NO: 802; a light chain having at least 95% sequence identity to SEQ ID NO: 803 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 804 or SEQ ID NO: 805; a light chain having at least 95% sequence identity to SEQ ID NO: 806 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 807 or SEQ ID NO: 808; a light chain having at least 95% sequence identity to SEQ ID NO: 809 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 810 or SEQ ID NO: 811 ; a light chain having at least 95% sequence identity to SEQ ID NO: 812 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 813 or SEQ ID NO: 814; a light chain having at least 95% sequence identity to SEQ ID NO: 815 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 816 or SEQ ID NO: 817; a light chain having at least 95% sequence identity to SEQ ID NO: 818 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 819 or SEQ ID NO: 820; a light chain having at least 95% sequence identity to SEQ ID NO: 821 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 822 or SEQ ID NO: 823; a light chain having at least 95% sequence identity to SEQ ID NO: 824 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 825 or SEQ ID NO: 826; a light chain having at least 95% sequence identity to SEQ ID NO: 827 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 828 or SEQ ID NO: 829; a light chain having at least 95% sequence identity to SEQ ID NO: 830 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 831 or SEQ ID NO: 832; a light chain having at least 95% sequence identity to SEQ ID NO: 833 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 834 or SEQ ID NO: 835; a light chain having at least 95% sequence identity to SEQ ID NO: 836 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 837 or SEQ ID NO: 838; a light chain having at least 95% sequence identity to SEQ ID NO: 839 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 840 or SEQ ID NO: 841 ; a light chain having at least 95% sequence identity to SEQ ID NO: 842 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 843 or SEQ ID NO: 844; a light chain having at least 95% sequence identity to SEQ ID NO: 845 and a heavychain having at least 95% sequence identity to SEQ ID NO: 846 or SEQ ID NO: 847; a light chain having at least 95% sequence identity to SEQ ID NO: 848 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 849 or SEQ ID NO: 850; a light chain having at least 95% sequence identity to SEQ ID NO: 851 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 852 or SEQ ID NO: 853; a light chain having at least 95% sequence identity to SEQ ID NO: 854 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 855 or SEQ ID NO: 856; a light chain having the sequence of SEQ ID NO: 785 and a heavy chain having the sequence of SEQ ID NO: 786 or SEQ ID NO: 787; a light chain having the sequence of SEQ ID NO: 788 and a heavy chain having the sequence of SEQ ID NO: 789 or SEQ ID NO: 790; a light chain having the sequence of SEQ ID NO: 791 a heavy chain having the sequence of SEQ ID NO: 792 or SEQ ID NO: 793; a light chain having the sequence of SEQ ID NO: 794 and a heavy chain having the sequence of SEQ ID NO: 795 or SEQ ID NO: 796; a light chain having the sequence of SEQ ID NO: 797 and a heavy chain having the sequence of SEQ ID NO: 798 or SEQ ID NO: 799; a light chain having the sequence of SEQ ID NO: 800 and a heavy chain having the sequence of SEQ ID NO: 801 or SEQ ID NO: 802; a light chain having the sequence of SEQ ID NO: 803 and a heavy chain having the sequence of SEQ ID NO: 804 or SEQ ID NO: 805; a light chain having the sequence of SEQ ID NO: 806 and a heavy chain having the sequence of SEQ ID NO: 807 or SEQ ID NO: 808; a light chain having the sequence of SEQ ID NO: 809 and a heavy chain having the sequence of SEQ ID NO: 810 or SEQ ID NO: 811 ; a light chain having the sequence of SEQ ID NO: 812 and a heavy chain having the sequence of SEQ ID NO: 813 or SEQ ID NO: 814; a light chain having the sequence of SEQ ID NO: 815 and a heavy chain having the sequence of SEQ ID NO: 816 or SEQ ID NO: 817; a light chain having the sequence of SEQ ID NO: 818 and a heavy chain having the sequence of SEQ ID NO: 819 or SEQ ID NO: 820; a light chain having the sequence of SEQ ID NO: 821 and a heavy chain having the sequence of SEQ ID NO: 822 or SEQ ID NO: 823; a light chain having the sequence of SEQ ID NO: 824 and a heavy chain havingthe sequence of SEQ ID NO: 825 or SEQ ID NO: 826; a light chain having the sequence of SEQ ID NO: 827 and a heavy chain having the sequence of SEQ ID NO: 828 or SEQ ID NO: 829; a light chain having the sequence of SEQ ID NO: 830 and a heavy chain having the sequence of SEQ ID NO: 831 or SEQ ID NO: 832; a light chain having the sequence of SEQ ID NO: 833 and a heavy chain having the sequence of SEQ ID NO: 834 or SEQ ID NO: 835; a light chain having the sequence of SEQ ID NO: 836 and a heavy chain having the sequence of SEQ ID NO: 837 or SEQ ID NO: 838; a light chain having the sequence of SEQ ID NO: 839 and a heavy chain having the sequence of SEQ ID NO: 840 or SEQ ID NO: 841 ; a light chain having the sequence of SEQ ID NO: 842 and a heavy chain having the sequence of SEQ ID NO: 843 or SEQ ID NO: 844; a light chain having the sequence of SEQ ID NO: 845 and a heavy chain having the sequence of SEQ ID NO: 846 or SEQ ID NO: 847; a light chain having the sequence of SEQ ID NO: 848 and a heavy chain having the sequence of SEQ ID NO: 849 or SEQ ID NO: 850; a light chain having the sequence of SEQ ID NO: 851 and a heavy chain having the sequence of SEQ ID NO: 852 or SEQ ID NO: 853; or a light chain having the sequence of SEQ ID NO: 854 and a heavy chain having the sequence of SEQ ID NO: 855 or SEQ ID NO: 856; wherein the antibody or fragment thereof retains its ability to bind human CD45.

13. The antibody or fragment thereof of claim 1 , wherein the variable light chain further comprises a signal peptide.

14. The antibody or fragment thereof of claim 13, wherein the signal peptide comprises SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 13, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , SEQ ID NO: 22, or SEQ ID NO: 23.

15. The antibody or fragment thereof of claim 1 , wherein the variable heavy chain further comprises a signal peptide.

16. The antibody or fragment thereof of claim 15, wherein the signal peptide comprises SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 30, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37,SEQ ID NO: 38, SEQ ID NO: 393, SEQ ID NO: 40, or SEQ ID NO: 41.

17. The antibody or fragment thereof of claim 1, comprising: a light chain having at least 95% sequence identity to SEQ ID NO: 102 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 103 or SEQ ID NO: 104; a light chain having at least 95% sequence identity to SEQ ID NO: 48 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 49 or SEQ ID NO: 50; a light chain having at least 95% sequence identity to SEQ ID NO: 66 a heavy chain having at least 95% sequence identity to SEQ ID NO: 67 or SEQ ID NO: 68; a light chain having at least 95% sequence identity to SEQ ID NO:45 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 46 or SEQ ID NO: 47; a light chain having at least 95% sequence identity to SEQ ID NO: 51 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 52 or SEQ ID NO: 53; a light chain having at least 95% sequence identity to SEQ ID NO: 54 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 55 or SEQ ID NO: 56; a light chain having at least 95% sequence identity to SEQ ID NO: 57 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 58 or SEQ ID NO: 59; a light chain having at least 95% sequence identity to SEQ ID NO: 60 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 61 or SEQ ID NO: 62; a light chain having at least 95% sequence identity to SEQ ID NO: 63 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 64 or SEQ ID NO: 65; a light chain having at least 95% sequence identity to SEQ ID NO: 69 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 70 or SEQ ID NO: 71 ; a light chain having at least 95% sequence identity to SEQ ID NO: 72 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 73 or SEQ ID NO: 74; a light chain having at least 95% sequence identity to SEQ ID NO: 75 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 76 or SEQ ID NO: 77; a light chain having at least 95% sequence identity to SEQ ID NO: 78 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 79 or SEQ ID NO: 80; a light chain having at least 95% sequence identity to SEQ ID NO: 81 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 82 or SEQ ID NO: 83; a light chain having at least 95% sequence identity to SEQ ID NO: 84 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 85 or SEQ ID NO: 86; a light chain having at least 95% sequence identity to SEQ ID NO: 87 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 88 or SEQ ID NO: 89;a light chain having at least 95% sequence identity to SEQ ID NO: 90 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 91 or SEQ ID NO: 92; a light chain having at least 95% sequence identity to SEQ ID NO: 93 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 94 or SEQ ID NO: 95; a light chain having at least 95% sequence identity to SEQ ID NO: 96 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 97 or SEQ ID NO: 98; a light chain having at least 95% sequence identity to SEQ ID NO: 99 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 100 or SEQ ID NO: 101 ; a light chain having at least 95% sequence identity to SEQ ID NO: 105 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 106 or SEQ ID NO: 107; a light chain having at least 95% sequence identity to SEQ ID NO: 108 and a heavy chain having at least 95% sequence identity to SEQ I D NO: 109 or SEQ I D NO: 110; a light chain having at least 95% sequence identity to SEQ ID NO: 118 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 119 or SEQ ID NO: 120; a light chain having at least 95% sequence identity to SEQ ID NO: 121 and a heavy chain having at least 95% sequence identity to SEQ ID NO: 122 or SEQ ID NO: 123; a light chain having the sequence of SEQ ID NO: 102 and a heavy chain having the sequence of SEQ ID NO: 103 or SEQ ID NO: 104; a light chain having the sequence of SEQ ID NO: 48 and a heavy chain having the sequence of SEQ ID NO: 49 or SEQ ID NO: 50; a light chain having the sequence of SEQ ID NO: 66 and a heavy chain having the sequence of SEQ ID NO: 67 or SEQ ID NO: 68; a light chain having the sequence of SEQ ID NO:45 and a heavy chain having the sequence of SEQ ID NO: 46 or SEQ ID NO: 47; a light chain having the sequence of SEQ I D NO: 51 and a heavy chain having the sequence of SEQ ID NO: 52 or SEQ ID NO: 53; a light chain having the sequence of SEQ ID NO: 54 and a heavy chain having the sequence of SEQ ID NO: 55 or SEQ ID NO: 56; a light chain having the sequence of SEQ I D NO: 57 and a heavy chain having the sequence of SEQ ID NO: 58 or SEQ ID NO: 59; a light chain having the sequence of SEQ ID NO: 60 and a heavy chain having the sequence of SEQ ID NO: 61 or SEQ ID NO: 62; a light chain having the sequence of SEQ ID NO: 63 and a heavy chain having the sequence of SEQ ID NO: 64 or SEQ ID NO: 65;a light chain having the sequence of SEQ ID NO: 69 and a heavy chain having the sequence of SEQ ID NO: 70 or SEQ ID NO: 71; a light chain having the sequence of SEQ ID NO: 72 and a heavy chain having the sequence of SEQ ID NO: 73 or SEQ ID NO: 74; a light chain having the sequence of SEQ I D NO: 75 and a heavy chain having the sequence of SEQ ID NO: 76 or SEQ ID NO: 77; a light chain having the sequence of SEQ I D NO: 78 and a heavy chain having the sequence of SEQ ID NO: 79 or SEQ ID NO: 80; a light chain having the sequence of SEQ I D NO: 81 and a heavy chain having the sequence of SEQ ID NO: 82 or SEQ ID NO: 83; a light chain having the sequence of SEQ I D NO: 84 and a heavy chain having the sequence of SEQ ID NO: 85 or SEQ ID NO: 86; a light chain having the sequence of SEQ ID NO: 87 and a heavy chain having the sequence of SEQ ID NO: 88 or SEQ ID NO: 89; a light chain having the sequence of SEQ ID NO: 95 and a heavy chain having the sequence of SEQ ID NO: 91 or SEQ ID NO: 92; a light chain having the sequence of SEQ I D NO: 93 and a heavy chain having the sequence of SEQ ID NO: 94 or SEQ ID NO: 95; a light chain having the sequence of SEQ ID NO: 96 and a heavy chain having the sequence of SEQ ID NO: 97 or SEQ ID NO: 98; a light chain having the sequence of SEQ ID NO: 99 and a heavy chain having the sequence of SEQ ID NO: 100 or SEQ ID NO: 101 ; a light chain having the sequence of SEQ ID NO: 105 and a heavy chain having the sequence of SEQ ID NO: 106 or SEQ ID NO: 107; a light chain having the sequence of SEQ ID NO: 108 and a heavy chain having the sequence of SEQ ID NO: 109 or SEQ ID NO: 110; a light chain having the sequence of SEQ ID NO: 118 and a heavy chain having the sequence of SEQ ID NO: 119 or SEQ ID NO: 120; or a light chain having the sequence of SEQ ID NO: 121 and a heavy chain having the sequence of SEQ ID NO: 122 or SEQ ID NO: 123; wherein the antibody or fragment thereof retains its ability to bind human CD45.

18. A multi-domain binding molecule comprising at least two binding domains wherein at least one binding domain comprises the antibody or fragment thereof of claim 1 .

19. The multi-domain binding molecule of claim 18, wherein the multi-domain bindingmolecule comprises an immune cell engaging molecule.

20. The multi-domain binding molecule of claim 19, wherein the immune cell engaging molecule activates a B cell, T cell, natural killer (NK) cell, or macrophage.

21. The multi-domain binding molecule of claim 20, wherein the T cell is a CD3 T cell, a CD4 T cell, a CD8 T cell, a central memory T cell, an effector memory T cell, and / or a naive T cell.

22. The multi-domain binding molecule of claim 19, wherein a binding domain of the immune cell engaging molecule binds CD3, CD28, CD8, NKG2D, CD8, CD16, KIR2DL4, KIR2DS1, KIR2DS2, KIR3DS1 , NKG2C, NKG2E, NKG2D, NKp30, NKp44, NKp46, NKp80, DNAM-1 , CD11b, CD11c, CD64, CD68, CD119, CD163, CD206, CD209, F4 / 80, IFGR2, Toll-like receptors 1-9, IL-4Ra, or MARCO.

23. The multi-domain binding molecule of claim 18, wherein the at least two binding domains comprise at least two copies of the antibody or fragment thereof of claim 1.

24. The multi-domain binding molecule of claim 23, wherein the at least two copies are joined by a protein linker.

25. The multi-domain binding molecule of claim 24, wherein the protein linker is a Gly-Ser linker.

26. The multi-domain binding molecule of claim 25, wherein the Gly-Ser linker is (GlyxSery)nwherein x and y are independently an integer from 0 to 10 provided that x and y are not both 0 and wherein n is an integer of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10.

27. The multi-domain binding molecule of claim 18, comprising 2, 3, 4, 5, 6, 7, 8, 9, or 10 copies of the antibody or fragment thereof of claim 1.

28. The multi-domain binding molecule of claim 18, wherein the multi-domain binding molecule is a dimer, trimer, tetramer, pentamer, hexamer, or heptamer.

29. The multi-domain binding molecule of claim 23, wherein the at least two copies are linked to an Fc region of an antibody.

30. The multi-domain binding molecule of claim 29, wherein the Fc region is an IgA Fc region or an IgM Fc region.

31. The multi-domain binding molecule of claim 29, wherein the Fc region is an IgA Fc region having the sequence of SEQ I D NO: 312 or SEQ I D NO: 313.

32. The multi-domain binding molecule of claim 29, wherein the Fc region is an IgM Fc region having the sequence of any one of SEQ ID NOs: 314-324.

33. The multi-domain binding molecule of claim 29, wherein the Fc region comprises a multimerizing fragment of an IgA Fc region or a multimerizing fragment of an IgM Fcregion.

34. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgA Fc region comprises an IgA tailpiece.

35. The multi-domain binding molecule of claim 34, wherein the IgA tailpiece has residues 331-352 of SEQ ID NO: 312 or residues 318-340 of SEQ ID NO: 313.

36. The multi-domain binding molecule of claim 34, wherein the multimerizing fragment of the IgA Fc region comprises an IgA CA3 domain and the IgA tailpiece.

37. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgA Fc region comprises an IgA CA2 domain, an IgA CA3 domain, and an IgA tailpiece.

38. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgA Fc region comprises an IgA CA1 domain, an IgA CA2 domain, an IgA CA3 domain, and an IgA tailpiece.

39. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region comprises an IgM tailpiece.

40. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region comprises a Cp4 domain and an IgM tailpiece.

41. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region comprises a Cp3 domain, a Cp4 domain, and an IgM tailpiece.

42. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region comprises a Cp2 domain, a Cp3 domain, a Cp4 domain, and an IgM tailpiece.

43. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region comprises a Cp1 domain, a Cp2 domain, a Cp3 domain, a Cp4 domain, and an IgM tailpiece.

44. The multi-domain binding molecule of claim 33, wherein the multimerizing fragment of the IgM Fc region has the sequence of SEQ ID NO: 317.

45. A single-chain variable fragment (scFv) comprising the antibody fragment of claim 1 , wherein the antibody fragment comprises a human light chain variable region and a human heavy chain variable region and lacks a constant region.

46. A conjugate comprising the antibody or fragment thereof of claim 1 linked to a radioactive isotope, an immunotoxin, a drug, a detectable label, or a particle.

47. The conjugate of claim 46, wherein the radioactive isotope comprises228Ac,111Ag,124Am, 74As,211At,209At,194Au,128Ba,7Be,206Bi,245Bk,246Bk,76Br,11C,14C,47Ca,254Cf,242Cm,51Cr, 67Cu,153Dy,157Dy,159Dy,165Dy,166Dy,171Er,250Es,254Es,147Eu,157Eu,52Fe,59Fe,251Fm,260Md,28Mg,52Mn,90Mo,24Na,95Nb,138Nd,57Ni,66Ni,234Np,15O,1820s,189mOs,1910s,32P, 201Pb,101Pd,143Pr,191Pt,243Pu,225Ra,81Rb,188Re,105Rh,211Rn,103Ru,35S,44Sc,72Se, 153Sm,125Sn,91Sr,173Ta,154Tb,127Te,234Th,45Ti,166Tm,230U,237U,240U,48V,178W,181W, 188W,125Xe,127Xe,133Xe,133mXe,135Xe,85mY,86Y,90Y,93Y,169Yb,175Yb,65Zn,71mZn,86Zr, 95Zr, or97Zr.

48. The conjugate of claim 46, wherein the radioactive isotope comprises an a-emitter or a [3- emitter.

49. The conjugate of claim 46, wherein the radioactive isotope comprises131l,90Y, or211At.

50. The conjugate of claim 46, wherein the radioactive isotope does not emit daughter radionuclides.

51. The conjugate of claim 46, wherein the immunotoxin comprises a plant toxin or bacterial toxin.

52. The conjugate of claim 51 , wherein the plant toxin comprises ricin, abrin, mistletoe lectin, modeccin, pokeweed antiviral protein, saporin, Bryodin 1 , bouganin, or gelonin.

53. The conjugate of claim 51 , wherein the bacterial toxin comprises diphtheria toxin or Pseudomonas exotoxin.

54. The conjugate of claim 46, wherein the drug comprises a cytotoxic drug.

55. The conjugate of claim 54, wherein the cytotoxic drug comprises actinomycin D, anthracycline, auristatin, calicheamicin, camptothecin, CC1065, colchicin, cytochalasin B, daunorubicin, 1 -dehydrotestosterone, dihydroxy anthracinedione, dolastatin, doxorubicin, duocarmycin, elinafide, emetine, ethidium bromide, etoposide, gramicidin D, glucocorticoids, lidocaine, maytansinoid, mithramycin, mitomycin, mitoxantrone, nemorubicin, PNU-159682, procaine, propranolol, puromycin, pyrrolobenzodiazepine, taxane, taxol, tenoposide, tetracaine, trichothecene, vinblastine, vinca alkaloid, or vincristine.

56. The conjugate of claim 46, wherein the detectable label comprises a fluorescent label, a chemiluminescent label, a spectral colorimetric label, an enzymatic label, or an affinity tag.

57. The conjugate of claim 56, wherein the fluorescent label comprises blue fluorescent protein, cyan fluorescent protein, green fluorescent protein, luciferase, orange fluorescent protein, red fluorescent protein, far red fluorescent protein, or yellow fluorescent protein.

58. The conjugate of claim 56, wherein the chemiluminescent label comprises lucigenin, luminol, luciferin, isoluminol, theromatic acridinium ester, imidazole, acridinium salt, oroxalate ester.

59. The conjugate of claim 56, wherein the spectral colorimetric label comprises colloidal gold.

60. The conjugate of claim 56, wherein the enzymatic label comprises malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alphaglycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI-phosphate dehydrogenase, glucoamylase, or acetylcholinesterase.

61. A recombinant receptor that, when expressed by a cell, comprises an extracellular component comprising the scFv of claim 45.

62. The recombinant receptor of claim 61 , wherein the recombinant receptor comprises a chimeric antigen receptor (CAR) or an engineered T cell receptor (eTCR).

63. The recombinant receptor of claim 62, wherein the CAR comprises an intracellular component linked to the extracellular component by a transmembrane domain.

64. The recombinant receptor of claim 63, wherein the intracellular component comprises an effector domain comprising: 4-1 BB (CD137), CD3y, CD36, CD3s, CD3 , CD27, CD28, DAP10, ICOS, LAG3, NKG2D, NOTCH1 , 0X40, ROR2, SLAMF1 , TCRa, TCR , TRIM, Wnt, Zap70, or a combination thereof.

65. The recombinant receptor of claim 63, wherein the transmembrane domain comprises a transmembrane region of: an a, p or chain of a T-cell receptor; CD28; CD27; CD3; CD45; CD4; CD5; CD8; CD9; CD16; CD22; CD33; CD37; CD64; CD80; CD86; CD134; CD137; CD154; or a combination thereof.

66. The recombinant receptor of claim 62, wherein the CAR further comprises a spacer region.

67. The recombinant receptor of claim 62, wherein the eTCR comprises a constant alpha domain (Ca), and a constant beta domain (Cp).

68. The recombinant receptor of claim 67, wherein the scFv of claim 45 is linked to the Cadomain.

69. The recombinant receptor of claim 67, wherein the scFv of claim 45 is linked to the Cp domain.

70. The recombinant receptor of claim 67, wherein one scFv of claim 45 is linked to the Cadomain and one scFv of claim 45 is linked to the Cp domain.

71. A nucleic acid encoding the antibody or fragment thereof of claim 1, the multi-domain binding molecule of claim 18, the scFv of claim 45, or the recombinant receptor of claim 61.

2. The nucleic acid of claim 71 , wherein the antibody or fragment thereof comprises a light chain and a heavy chain, wherein: the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 183 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 184; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 183 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 185; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 129 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 130; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 129 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 131 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 147 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 148; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 147 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 149; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 126 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 127; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 126 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 128; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 132 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 133; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 132 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 134; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 135 and the heavy chain is encoded by a sequence having at least 95%sequence identity to SEQ ID NO: 136; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 135 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 137; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 138 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 139; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 138 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 140; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 141 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 142; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 141 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 143; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 144 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 145; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 144 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 146; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 150 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 151 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 150 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 152; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 153 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 154; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 153 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 155;the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 156 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 157; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 156 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 158; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 159 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 160; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 159 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 161 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 162 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 163; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 162 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 164; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 165 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 166; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 165 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 167; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 168 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 169; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 168 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 170; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 171 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 172; the light chain is encoded by a sequence having at least 95% sequence identity toSEQ ID NO: 171 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 173; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 174 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 175; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 174 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 176; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 177 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 178; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 177 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 179; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 180 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 181 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 180 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 182; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 186 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 187; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 186 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 188; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 189 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 190; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 189 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 191 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 199 and the heavy chain is encoded by a sequence having at least 95%sequence identity to SEQ ID NO: 200; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 199 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 201 ; the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 202 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 203; or the light chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 202 and the heavy chain is encoded by a sequence having at least 95% sequence identity to SEQ ID NO: 204, wherein the encoded antibody or fragment retains its ability to bind human CD45.

73. The nucleic acid of claim 71 , wherein the antibody or fragment thereof comprises a light chain and a heavy chain, wherein: the light chain is encoded by the sequence of SEQ ID NO: 183 and the heavy chain is encoded by the sequence of SEQ ID NO: 184; the light chain is encoded by the sequence of SEQ ID NO: 183 and the heavy chain is encoded by the sequence of SEQ ID NO: 185; the light chain is encoded by the sequence of SEQ ID NO: 129 and the heavy chain is encoded by the sequence of SEQ ID NO: 130; the light chain is encoded by the sequence of SEQ ID NO: 129 and the heavy chain is encoded by the sequence of SEQ ID NO: 131 ; the light chain is encoded by the sequence of SEQ ID NO: 147 and the heavy chain is encoded by the sequence of SEQ ID NO: 148; the light chain is encoded by the sequence of SEQ ID NO: 147 and the heavy chain is encoded by the sequence of SEQ ID NO: 149; the light chain is encoded by the sequence of SEQ ID NO: 126 and the heavy chain is encoded by the sequence of SEQ ID NO: 127; the light chain is encoded by the sequence of SEQ ID NO: 126 and the heavy chain is encoded by the sequence of SEQ ID NO: 128; the light chain is encoded by the sequence of SEQ ID NO: 132 and the heavy chain is encoded by the sequence of SEQ ID NO: 133; the light chain is encoded by the sequence of SEQ ID NO: 132 and the heavy chain is encoded by the sequence of SEQ ID NO: 134; the light chain is encoded by the sequence of SEQ ID NO: 135 and the heavy chainded by the sequence of SEQ ID NO: 136; the light chain is encoded by the sequence of SEQ ID NO: 135 and the heavy chainded by the sequence of SEQ ID NO: 137; the light chain is encoded by the sequence of SEQ ID NO: 138 and the heavy chainded by the sequence of SEQ ID NO: 139; the light chain is encoded by the sequence of SEQ ID NO: 138 and the heavy chainded by the sequence of SEQ ID NO: 140; the light chain is encoded by the sequence of SEQ ID NO: 141 and the heavy chainded by the sequence of SEQ ID NO: 142; the light chain is encoded by the sequence of SEQ ID NO: 141 and the heavy chainded by the sequence of SEQ ID NO: 143; the light chain is encoded by the sequence of SEQ ID NO: 144 and the heavy chainded by the sequence of SEQ ID NO: 145; the light chain is encoded by the sequence of SEQ ID NO: 144 and the heavy chainded by the sequence of SEQ ID NO: 146; the light chain is encoded by the sequence of SEQ ID NO: 150 and the heavy chainded by the sequence of SEQ ID NO: 151 ; the light chain is encoded by the sequence of SEQ ID NO: 150 and the heavy chainded by the sequence of SEQ ID NO: 152; the light chain is encoded by the sequence of SEQ ID NO: 153 and the heavy chainded by the sequence of SEQ ID NO: 154; the light chain is encoded by the sequence of SEQ ID NO: 153 and the heavy chainded by the sequence of SEQ ID NO: 155; the light chain is encoded by the sequence of SEQ ID NO: 156 and the heavy chainded by the sequence of SEQ ID NO: 157; the light chain is encoded by the sequence of SEQ ID NO: 156 and the heavy chainded by the sequence of SEQ ID NO: 158; the light chain is encoded by the sequence of SEQ ID NO: 159 and the heavy chainded by the sequence of SEQ ID NO: 160; the light chain is encoded by the sequence of SEQ ID NO: 159 and the heavy chainded by the sequence of SEQ ID NO: 161 ; the light chain is encoded by the sequence of SEQ ID NO: 162 and the heavy chainded by the sequence of SEQ ID NO: 163; the light chain is encoded by the sequence of SEQ ID NO: 162 and the heavy chainded by the sequence of SEQ ID NO: 164; the light chain is encoded by the sequence of SEQ ID NO: 165 and the heavy chainded by the sequence of SEQ ID NO: 166; the light chain is encoded by the sequence of SEQ ID NO: 165 and the heavy chainded by the sequence of SEQ ID NO: 167; the light chain is encoded by the sequence of SEQ ID NO: 168 and the heavy chainded by the sequence of SEQ ID NO: 169; the light chain is encoded by the sequence of SEQ ID NO: 168 and the heavy chainded by the sequence of SEQ ID NO: 170; the light chain is encoded by the sequence of SEQ ID NO: 171 and the heavy chainded by the sequence of SEQ ID NO: 172; the light chain is encoded by the sequence of SEQ ID NO: 171 and the heavy chainded by the sequence of SEQ ID NO: 173; the light chain is encoded by the sequence of SEQ ID NO: 174 and the heavy chainded by the sequence of SEQ ID NO: 175; the light chain is encoded by the sequence of SEQ ID NO: 174 and the heavy chainded by the sequence of SEQ ID NO: 176; the light chain is encoded by the sequence of SEQ ID NO: 177 and the heavy chainded by the sequence of SEQ ID NO: 178; the light chain is encoded by the sequence of SEQ ID NO: 177 and the heavy chainded by the sequence of SEQ ID NO: 179; the light chain is encoded by the sequence of SEQ ID NO: 180 and the heavy chainded by the sequence of SEQ ID NO: 181 ; the light chain is encoded by the sequence of SEQ ID NO: 180 and the heavy chainded by the sequence of SEQ ID NO: 182; the light chain is encoded by the sequence of SEQ ID NO: 186 and the heavy chainded by the sequence of SEQ ID NO: 187; the light chain is encoded by the sequence of SEQ ID NO: 186 and the heavy chainded by the sequence of SEQ ID NO: 188; the light chain is encoded by the sequence of SEQ ID NO: 189 and the heavy chainded by the sequence of SEQ ID NO: 190; the light chain is encoded by the sequence of SEQ ID NO: 189 and the heavy chainded by the sequence of SEQ ID NO: 191 ; the light chain is encoded by the sequence of SEQ ID NO: 199 and the heavy chainis encoded by the sequence of SEQ ID NO: 200; the light chain is encoded by the sequence of SEQ ID NO: 199 and the heavy chain is encoded by the sequence of SEQ ID NO: 201 ; the light chain is encoded by the sequence of SEQ ID NO: 202 and the heavy chain is encoded by the sequence of SEQ ID NO: 203; or the light chain is encoded by the sequence of SEQ ID NO: 202 and the heavy chain is encoded by the sequence of SEQ ID NO: 204, wherein the encoded antibody or fragment thereof retains its ability to bind human CD45.

74. A cell genetically modified to express the antibody or fragment thereof of claim 1 , or the recombinant receptor of claim 61.

75. The cell of claim 74, wherein the cell is an immune cell.

76. The cell of claim 75, wherein the immune cell is a T cell, B cell, natural killer cell, or macrophage.

77. A composition comprising the antibody or fragment thereof of claim 1, the multi-domain binding molecule of claim 18, the scFv of claim 45, the conjugate of claim 46, or the nucleic acid of claim 71 , and a pharmaceutically acceptable carrier.

78. A formulation comprising the cell of claim 74 and a pharmaceutically acceptable carrier.

79. A kit comprising the antibody or fragment thereof of claim 1 , the multi-domain binding molecule of claim 18, the scFv of claim 45, the conjugate of claim 46, the recombinant receptor of claim 61 , and / or the nucleic acid of claim 71 .

80. A method of treating a subject in need thereof comprising administering a therapeutically effective amount of the composition of claim 77 and / or the formulation of claim 78, thereby treating the subject in need thereof.

81. The method of claim 80, wherein the therapeutically effective amount provides a prophylactic or a therapeutic treatment against a pathology.

82. The method of claim 81 , wherein the pathology comprises a stem cell disorder, cancer, inherited blood disorder, autoimmune disease, metabolic storage disorder, immunodeficiency.

83. The method of claim 82, wherein the stem cell disorder comprises a hematopoietic malignancy.

84. The method of claim 82, wherein the cancer comprises leukemia, lymphoma, or myeloma.

85. The method of claim 84, wherein the leukemia comprises acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML).

86. The method of claim 85, wherein the AML comprises relapsed or refractory AML.

87. The method of claim 82, wherein the inherited blood disorder comprises sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, or Diamond-Blackfan anemia.

88. The method of claim 82, wherein the autoimmune disease comprises scleroderma, multiple sclerosis, ulcerative colitis, Crohn's disease, Type 1 diabetes, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, or juvenile rheumatoid arthritis.

89. The method of claim 82, wherein the metabolic storage disorder comprises a glycogen storage disease, a lysosomal storage disease, or a lipid storage disease.

90. The method of claim 82, wherein the immunodeficiency comprises severe combined immunodeficiency (SCID), adenosine deaminase severe combined immunodeficiency (ADA SCID), acquired immunodeficiency syndrome (AIDS), Wiscott-Aldrich syndrome, hyper immunoglobin M (IgM) syndrome, or Chediak-Higashi disease.

91. The method of claim 80, wherein the therapeutically effective amount provides a conditioning treatment for the subject before the subject receives a hematopoietic cell transplant.

92. The method of claim 91 , wherein the hematopoietic cell transplant comprises an allogeneic hematopoietic cell transplant or an autologous hematopoietic cell transplant.

93. The method of claim 91 , wherein the hematopoietic cell transplant comprises gene-edited cells.

94. The method of claim 93, wherein the gene-edited cells comprise a recombinant receptor.

95. The method of claim 93, wherein the gene-edited cells do not express CD45.

96. The method of claim 80, wherein the administering is through intravenous, intradermal, intraarterial, intranodal, intravesicular, intrathecal, intraperitoneal, intraparenteral, intranasal, intralesional, intramuscular, oral, intrapulmonary, subcutaneous, or sublingual administering.

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