Biparatopic Anti-CD38 antibodies and antibody drug conjugates

Abstract

Provided herein are, inter alia, antibodies (e.g., humanized antibodies, chimeric antibodies, monoclonal antibodies, biparatopic antibodies, antibody fragments (e.g., Fab')), which bind CD38 with high efficiency and specificity. Inter alia, are provided biparatopic antibodies that bind CD38 specifically and effectively. The biparatopic antibodies provided herein may have an increased binding avidity relative to the monoclonal antibodies they are derived from and are specifically useful for therapeutic and diagnostic purposes.

Description

Attorney Docket No.: 048440-849001 WOBIPARATOPIC ANTI-CD38 ANTIBODIES AND ANTIBODY DRUG CONJUGATESCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to US Application No. 63 / 706,519 filed October 11, 2024, the disclosures of which is incorporated by reference herein in its entirety.REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE

[0002] The Sequence Listing written in file 048440-84900 lWO_Sequence Listing_ST26.xml, created on October 9, 2025, 269,880 bytes, machine format IBM-PC, MS Windows operating system, is incorporated herein by reference.BACKGROUND

[0003] CD38 remains expressed on cancerous cells in patients with multiple myeloma, however, these patients fail to gain benefit from commercially available therapeutic antibodies targeting CD38. For example, daratumumab (Dara) is a humanized IgGl antibody against the highly expressed plasma cell (PC) receptor CD38 and approved for the treatment of relapsed multiple myeloma. Unfortunately, despite daratumumab ’s significant efficacy, relapse or resistance remain an issue. The compositions and methods provided herein, inter alia, address these and other problems in the art.BRIEF SUMMARY OF THE INVENTION

[0004] In an aspect is provided a biparatopic anti-CD38 antibody including a first antigen binding domain and a second antigen binding domain independently including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and wherein the light chain variable domain includes a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2.Attorney Docket No.: 048440-849001 WO

[0005] In another aspect is provided an anti-CD38 antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and wherein the light chain variable domain includes a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2.

[0006] In another aspect is provided a pharmaceutical composition including a therapeutically effective amount of an antibody as disclosed herein including embodiments thereof and a pharmaceutically acceptable excipient.

[0007] In another aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to a subject a therapeutically effective amount of an antibody as disclosed herein including embodiments thereof.

[0008] In an aspect is provided an anti-CD38 antibody including (i) a heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3, and (ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO:92, and a CDR L3 as set forth in SEQ ID NO: 93.

[0009] In another aspect is provided an anti-CD38 antibody including (i) a heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO:85, a CDR H2 as set forth in SEQ ID NO:86 and a CDR H3 as set forth in SEQ ID NO:87, and (ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177.

[0010] In an aspect is provided a nucleic acid composition including a sequence encoding the antibody provided herein including embodiments thereof.

[0011] In another aspect an expression vector including the nucleic acid provided herein including embodiments is provided.Attorney Docket No.: 048440-849001 WO

[0012] In an aspect is provided a pharmaceutical composition including a therapeutically effective amount of an antibody provided herein including embodiments thereof and a pharmaceutically acceptable excipient.

[0013] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to a subject a therapeutically effective amount of an antibody provided herein including embodiments thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGS. 1A-1C present graphs showing size exclusion chromatography of anti-CD38 antibodies provided herein.

[0015] FIG. 2 shows pictures of SDS-PAGE blots with anti-CD38 antibodies (NR-non- reduced and R-reduced) provided herein.

[0016] FIGS. 3A-3C present graphs demonstrating binding of anti-CD38 antibodies provided herein to human CD 38 on SPR.

[0017] FIGS. 4A-4C present graphs demonstrating binding of anti-CD38 antibodies provided herein to cyno CD 38 on SPR.

[0018] FIGS. 5A-5C present graphs demonstrating binding of anti-CD38 Fabs provided herein to human CD38 on SPR.

[0019] FIG. 6 illustrates thermal stability data for anti-CD38 Fabs provided herein.

[0020] FIGS. 7A-7B present graphs demonstrating dual binding of anti-CD38 Fabs provided herein to human CD38 on SPR.

[0021] FIGS. 8A-8B present exemplary data showing that anti-CD38 antibodies provided herein induced antibody-dependent cellular cytotoxicity (ADCC) in multiple myeloma (MM) cells with peripheral blood mononuclear cells (PBMCs) used as effector cells.

[0022] FIGS. 9A-9B present exemplary data showing that anti-CD38 antibodies provided herein induced ADCC in MM cells with Natural Killer (NK) cells used as effector cells.Attorney Docket No.: 048440-849001 WO

[0023] FIG. 10 shows pictures of SDS-PAGE blots with anti-CD38 antibodies (NR-non- reduced and R-reduced) provided herein.

[0024] FIG. 11 presents graphs showing size exclusion chromatography of anti-CD38 antibodies provided herein.

[0025] FIGS. 12A-12B present graphs demonstrating binding of anti-CD38 antibodies provided herein to CD38-Fc on SPR.

[0026] FIGS. 13A-13B present graphs demonstrating binding of anti-CD38 antibodies provided herein to FcyRI on SPR.

[0027] FIGS. 14A-14B present graphs demonstrating binding of anti-CD38 antibodies provided herein to Fey RIIIA on SPR.

[0028] FIG. 15 Simultaneous Fab Binding by SPR. Analysis if anti-CD38 Fab bind simultaneously to recombinant CD38 antigen by SPR. In various combinations, a Fab was immobilized on a CM5 chip, CD38 antigen was flowed over, then another Fab was flowed over. Increased signal observed after the second Fab was introduced indicates that dual binding to CD38 occurred.

[0029] FIG. 16A-FIG. 16H: Dual binding experiments with daratumumab and exemplary antidbodies provided herein including embodiments thereof. FIG. 16A anti-CD38 Fab Dara immobilized; Results from SPR dual -binding demonstrating which anti-CD38 Fabs bind nonoverlapping epitopes to Dara Fab. Section 1 shows the baseline of Dara Fab immobilized on a CM5 chip. Section 2 shows the response after addition of recombinant CD38. Section 3 shows the response after addition of another anti-CD38 Fab. Results indicate Fab 6, 27, and 40 (shown in solid lines) bind simultaneously with Fab Dara. FIG. 16B anti-CD38 Fab 6 immobilized; Results from SPR dual -binding demonstrating which anti-CD38 Fabs bind non-overlapping epitopes to Fab 6. Section 1 shows the baseline of Fab 6 immobilized on a CM5 chip. Section 2 shows the response after addition of recombinant CD38. Section 3 shows the response after addition of another anti-CD38 Fab. Results indicate Fab 1, 25, 27, 40, and Dara Fab (shown in solid lines) bind simultaneously with Fab 6. FIG. 16C anti-CD38 Fab 25 immobilized; Results from SPR dual -binding demonstrating which anti-CD38 Fabs bind non-overlapping epitopes to Fab 25. Section 1 shows the baseline of Fab 25 immobilized on a CM5 chip. Section 2 shows theAttorney Docket No.: 048440-849001 WO response after addition of recombinant CD38. Section 3 shows the response after addition of another anti-CD38 Fab. Results indicate Fab 1, 6, 23, 27, 40, and Dara Fab (shown in solid lines) bind simultaneously with Fab 25. FIG. 16D anti-CD38 Fab 48 immobilized; Results from SPR dual-binding demonstrating which anti-CD38 Fabs bind non-overlapping epitopes to Fab 48. Section 1 shows the baseline of Fab 48 immobilized on a CM5 chip. Section 2 shows the response after addition of recombinant CD38. Section 3 shows the response after addition of another anti-CD38 Fab. Results indicate Fab 1, 6, 27, and 40 (shown in solid lines) bind simultaneously with Fab 48. FIG. 16E SPR anti-CD38 Fab Binding anti-CD38 Fab Dara immobilized; FIG. 16F SPR anti-CD38 Fab Binding anti-CD38 Fab 25 immobilized; FIG. 16G SPR anti-CD38 Fab Binding anti-CD38 Fab 6 immobilized; FIG. 16H SPR anti-CD38 Fab Binding anti-CD38 Fab 48 immobilized.

[0030] FIG. 17A-FIG. 17C HPLC data (SEC) of exemplary antibodies provided herein including embodiments thereof are shown. Anti-CD38 Antibodies HPLC - TSKgel UP-SW Aggregate Column (size exclusion chromatography) -Buffer A: 0.1 M sodium phosphate, pH 6.7, 0.1 M sodium sullfate, 0.05% sodium azide, -Run sample 40 min at 0.35 mL / min, 100% A - 10 ug loaded. Size exclusion chromatography demonstrates binding of fabs to recombinant CD38 . High-performance liquid chromatography (HPLC) with a TSKgel UP-SW Aggregate Column was used to determine binding of fabs to recombinant CD38. Fab 1 alone or in complex with CD38 was loaded on the column, and a shift correlating to an increase in size for the complex compared to the fab alone was observed. Fab 48 alone or in complex with CD38 was loaded on the column, and a shift correlating to an increase in size for the complex compared to the fab alone was observed.

[0031] FIG. 18 HPLC data of exemplary antibodies provided herein including embodiments thereof are shown (biparatopics). HPLC - TSKgel Butyl-NPR Column (hydrophobic interaction) - antiCD38 biparatopic generation - 5ug loaded -goal to generate biparatopic Ab.

[0032] FIG. 19 HPLC data (hydrophobicity) of Anti-CD38 Antibodies: generation of biparatopic Ab and ADC simultaneously by conjugating to site-specific engineered cystine. HPLC-TSKgel Butyl-NPR Column (hydrophobic interaction) 5ug loaded ADC.Attorney Docket No.: 048440-849001 WO

[0033] FIG. 20 HPLC data of Anti-CD38 Antibodies TSKgel Butyl-NPR Column (hydrophobic interaction) antiCD38 Ab 6 Fc null CysMut 5ug loaded. Generation of biparatopic Ab and ADC simultaneously by conjugating to site-specific engineered cystine. Examine conjugation efficiency using different concentrations of Ab 10 mg / mL (6.66 nmol) 5 mg / mL (3.33 nmol) 1 mg / mL (0.66 nmol) ADC.

[0034] FIG. 21 Crystal Structures of anti-CD38 Fabs Binding Epitopes. CD38, Fab Dara, Fab 27, Fab 40, Fab 48 A. Cartoon display of anti-CD38 Fabs in complex with CD38. B. Mesh display of anti-CD38 Fabs in complex with CD38.

[0035] FIG. 22A-FIG.22I SPR analysis of anti-CD38 antibodies in the presence of immobilized CD38. Binding kinetics of anti-CD38 Fab 1. Recombinant CD38 antigen was immobilized on a CM5 chip, then fab was flowed over the chip at various concentrations to measure binding affinities by SPR.

[0036] FIG. 23A-FIG. 23B Anti-CD38 Fab SPR data. FIG. 23 A Meditope enabled Dara Fab binding to the immobilized meditope. FIG. 23B Meditope enabled Dara Fab binding to the immobilized His-Tev-CD38.

[0037] FIG. 24 Schematic and data of affinity maturation of exemplary anti-CD38 scFv antibodies.

[0038] FIG. 25 Immunofluorescence of affinity maturation of exemplary humanized anti- CD38 scFv antibodies (Yeast display huscFv 48 Target - 0.5 nM Fc-CD38).

[0039] FIG. 26A-FIG. 26C: FIG. 26A Humanized Fab 48 affinity maturation mutations. FIG. 26B and FIG. 26C: 12 unique sequences identified from the 20 selected clones.

[0040] FIG. 27A-FIG. 27B FIG. Humanized Fab 48 affinity maturation mutations. FIG. 27A immunofluoerecence of selected clones. FIG. 27B: Alignments of unique sequences identified from selected clones.

[0041] FIG. 28 Molecular modeling of mutations for affinity maturation.

[0042] FIG. 29 Meditope enabled antibody clones.

[0043] FIG. 30 Amino acid substitutions in meditope-enabled antibody clones.Attorney Docket No.: 048440-849001 WO

[0044] FIG. 31A-31B. SPR results of affinity maturation mutations. His-Tev-CD38 was immobilized on CM5 chip. FIG. 31A Affinity maturation of humanized Fab 48. SPR results showing binding kinetics of the chimeric fab 48, the humanized fab 48, and the meditope enabled humanized affinity maturated fab 48. FIG. 3 IB SPR-anti-CD38 Dara Fab Meditope Binding. Humanized Fab 48 is meditope enabled. SPR results showing binding kinetics of the meditope enabled humanized fab 48 and meditope enabled Dara.

[0045] FIG. 32 SPR - anti-CD38 Fab Binding. CD38-TEV-His immobilized

[0046] FIG. 33A-33B Affinity maturation of Fab 1. FIG. 33 A. Flow cytometry data showing binding of the wild type (WT) chimeric scFv 1 sequence binding to increasing concentration of recombinant CD38 with an N-terminal Fc tag. FIG. 33B. Flow cytometry showing the binding of the scFv 1 library to recombinant CD38 with an N-terminal Fc tag. Gates represent sorted population. Over 4 rounds of sorting, the concentration of CD38 used was decreased to select for high affinity clones.

[0047] FIG. 34. Schematic representation of yeast surface display.

[0048] FIG. 35A-35B. FIG. 35 A: Affinity maturation of clones. 7 unique sequences were identified from the 20 selected clones. FIG. 35B Several mutations appear in the CDR loops based off an AlphaFold generated structure of Fab 1.

[0049] FIG. 36 Mutation decisions for affinity maturated Ab 1. From clone 1 heavy chain Y27D. From clone 12 heavy chain Y27S. From clone 2, 3, and 4 heavy chain F29S. From clone 3 light chain N50K.

[0050] FIG. 37 SPR results of affinity maturation mutations. His-Tev-CD38 immobilized on CM5 chip.

[0051] FIG. 38 SPR results of affinity maturation mutations.

[0052] FIG. 39 DSF results of affinity maturation mutations.

[0053] FIG. 40 Flow cytometry of antibodies binding to cells. Cell lines were washed, then treated with 10 ug of indicated anti-CD38 Abs for 30 minutes at 4 ° C. Cells were washed twice,Attorney Docket No.: 048440-849001 WO then stained with Goat anti -Human IgG Fc Secondary Antibody, PE for 30 minutes at 4 ° C. Cells were washed twice, then analyzed by flow cytometry.

[0054] FIG. 41 Anti-CD38 Ab Binding. Cells were stained with primary anti-CD38 Abs, then secondary anti-Fc-PE was used for detection by flow; Normalized to unstained.

[0055] FIG. 42 SPR, DSF, X-ray crystallography, and flow cytometry demonstrate improved properties of our affinity maturated anti-CD38 antibody. Panel A. Recombinant CD38 protein was immobilized on a CM5 chip, then fabs were measured for binding affinities by surface plasmon resonance (SPR). Panel B. Crystal structure of affinity maturated fab 1. Panel C. Differential scanning fluorimetry (DSF) shows increased thermal stability of fab 1 AM. Panel D. Flow cytometry results show binding to CD38+ cells is enhanced after affinity maturation.

[0056] FIG. 43A-43B . FIG. 43 A diagram depicting how biparatopic antibodies are generated using fab-arm-exchange technology. FIG. 43B. Top Panel: Size exclusion chromatography demonstrates Fab 1 and Fab 48 bind CD38 at non-overlapping epitopes. Bottom Panel: Biparatopic antibody formation is demonstrated by the differential interaction on a TSKgel Butyl-NPR column of two parental mAbs and the combination biparatopic antibody.

[0057] FIG. 44 Flow cytometry of biparatopic antibodies binding to CD38+ cells. Flow cytometry results show parental and biparatopic antibodies bind strongly to CD38+ H929 cell line. H929 cells were washed with PBS 2% BSA. 0.2*106 cells were treated with Ab in 100 uL volume. Cells were incubated at 4°C for 20 minutes. Cells were washed twice, then stained with anti-Fc PE at 4°C for 20 min. Cells were washed twice, then acquired by flow. Data is normalized to unstained.

[0058] FIG. 45 Exemplary embodiment for conjugation of therapeutic moiety to the antibody compositions provided herein using click chemistry. Shown is a schematic of the antibody conjugation using Invitrogen SiteClick™ Antibody Azido Modification Kit.

[0059] FIG. 46 Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. ADC generation is demonstrated by the different interactions on a TSKgel Butyl-NPR column before and after conjugation to DBCO-MMAF. TSKgel Butyl-NPR Column (hydrophobic interaction) Buffer A: 1.5 M ammonium sulfate, 25 mM phosphate pH 7.0Attorney Docket No.: 048440-849001 WOBuffer B: 25% isopropanol, 25 mM phosphate pH 7.0 Run sample 60 min at 0.5 mL / min, 0 to 100% 5 ug loaded.

[0060] FIG. 47 Mini-PROTEAN TGX Stain-Free Precast Gel 150V for 45 min lug protein loaded. Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. SDS-PAGE gel of antibodies before and after conjugation to MMAF.

[0061] FIG. 48 Ab 1 AM potently and selectively kills CD38+ cells in vitro when conjugated to MMAF CD38+ MM.1 S cell line was treated with ADCs, then cell viability was measured after 42 and 66 hours using a RealTime-Glo™ MT Cell Viability Assay. Results demonstrate Ab 1 AM alone or as a biparatopic demonstrates potent killing activity. Real-time gio MT cell viability assay: MM1S-GFP cells were seeded in 96 well plates at 5,000 cells per well. Cells were incubated with MT cell viability substrate and NanoLuc enzyme. Cells were treated in triplicate with ADC at indicated concentrations. Luminescence was measured over time in a plate reader.

[0062] FIG. 49 Ab 1 AM potently and selectively kills CD38+ cells in vitro when conjugated to MMAF CD38+ MM.1 S cell line was treated with ADCs, then cell viability was measured after 72 hours by flow cytometry. Results demonstrate Ab 1 AM alone or as a biparatopic demonstrates potent killing activity. Flow cytometry ADC killing assay: MM1S-GFP cells were seeded in a 24 well plate at 0.1*106 cells / mL in 500 uL volume. Cells were treated indicated concentration of ADC. Cells were incubated at 37 °C for 72 hours. Cells were washed twice with PBS 2% BSA, then stained with 7-AAD for 10 min. Cells were acquired by flow. Performed in duplicate.

[0063] FIG. 50 CD38 expression on MM cells. Dara (positive control), Ab 1 AM, and Tras (negative control) were conjugated to AF647 using the glycan modification strategy, then flow cytometry was used to evaluate binding to various cell lines. Flow cytometry Ab binding. Antibodies were labeled with AF647 through glycan modification. Cells were stained with 30 nM of Ab.

[0064] FIG. 51 Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. ADC generation is demonstrated by the different interactions on a TSKgel Butyl-NPR column before and after conjugation to DBCO-MMAF. ADC conjugationAttorney Docket No.: 048440-849001 WO evaluation. TSKgel Butyl -NPR Column (hydrophobic interaction) Buffer A: 1.5 M ammonium sulfate, 25 mM phosphate pH 7.0 Buffer B: 25% isopropanol, 25 mM phosphate pH 7.0 Run sample 60 min at 0.5 mL / min, 0 - 100% 10 ug loaded.

[0065] FIG. 52 Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. Left panel. A diagram depicting the conjugation strategy. Right panel. ADC generation is demonstrated by the different interactions on a TSKgel Butyl-NPR column before and after conjugation to DBCO-MMAF.

[0066] FIG. 53 Ab 1 AM potently and selectively kills CD38+ cells in vitro when conjugated to MMAF. Panel A. MM cell lines were treated with ADCs, then cell viability was measured after 48 hours using a RealTime-Glo™ MT Cell Viability Assay. Panel B. Killing analysis by flow cytometry of CD38+ or CD38- MM.1S-GFP cells. Representative dot plots display cells treated with 10 nM of drug. Total cell death is graphed as a % of DAPI+ and Annexin+ cells.

[0067] FIG. 54 Serum stability of Ab 1 AM conjugated to MMAF. Western blot demonstrating serum stability of Ab 1 AM conjugated to MMAF. 1000 ng of ADC was incubated in Rat serum at 37 °C for the indicated time point. After incubation, Samples were frozen and stored at -80 °C. Samples were then thawed, diluted to 20 % serum, and ran on an SDS-PAGE gel. Invitrogen MMAF Monoclonal Antibody was used for primary detection of the conjugated toxin, then a Goat Anti -Mouse IgGl-HRP was used for secondary detection. Mini- PROTEAN TGX Stain-Free Precast 15 well Gel. 170V for 40 min. Primary Ab: Invitrogen MMAF Monoclonal Antibody. Secondary Ab: Goat Anti -Mouse IgGl-HRP.

[0068] FIG. 55 Binding epitopes of anti-CD38 Fabs. Overlay of crystal structures of Dara Fab (left) bound to CD38 (bottom) and Fab 1 AM (right) bound to CD38 (bottom). Fabs bind unique epitopes on the CD38 molecule, however, steric hindrance prevents simultaneous binding.

[0069] FIG. 56 Humanization of affinity maturated of Fab 1. SPR results showing binding kinetics of the chimeric fab 1, the affinity maturated fab 1, and two humanized Fab 1 AM fabs to immobilized recombinant His-Tev-CD38. Both humanized sequences show binding kinetics are retained.Attorney Docket No.: 048440-849001 WO

[0070] FIG. 57 Humanization of affinity maturated of Fab 1. DSF results showing thermal stability of the chimeric fab 1, the affinity maturated fab 1, and two humanized Fab 1 AM fabs. Both humanized sequences show improved melting temperatures.

[0071] FIG. 58 Affinity de-tuning of Dara. SPR results showing binding kinetics of meditope enabled Dara to immobilized recombinant His-Tev-CD38. Results show the kinetics of the original Dara as well as four variations with mutations to adjust the binding kinetics.

[0072] FIG. 59 CD38 expression on MM.1 S cells. Indicated antibodies were conjugated to AF647 using the glycan modification strategy, then flow cytometry was used to evaluate binding to MM. IS cells. Flow cytometry Ab binding to MM. IS cells. Cells were washed with PBS 2% BSA. 0.1*106 cells were treated with Ab-AF647 (either 100 nM, 10 nM, or 1 nM concentration) in 100 uL volume. Cells were incubated at 4°C for 30 minutes. Cells were washed twice, then acquired by flow.

[0073] FIG. 60 CD38 expression on H929 cells. Indicated antibodies were conjugated to AF647 using the glycan modification strategy, then flow cytometry was used to evaluate binding to H929 cells. Flow cytometry Ab binding to H929 cells: Cells were washed with PBS 2% BSA. 0.1*106 cells were treated with Ab-AF647 (either 100 nM, 10 nM, or 1 nM concentration) in 100 uL volume. Cells were incubated at 4°C for 30 minutes. Cells were washed twice, then acquired by flow.

[0074] FIG. 61A-61B Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. ADC generation is demonstrated by the different interactions on a TSKgel Butyl-NPR column before and after conjugation to a DBCO containing molecule. Graphs show nonconjugated antibody compared to antibody conjugated with either DBCO- PEG4-Val-Cit-PAB-MMAF (cleavable linker) or DBCO-PEG4-MMAF (non-cleavable linker). (vcMMAF indicates a cleavable linker). HPLC ADC conjugation evaluation: TSKgel Butyl-NPR Column (hydrophobic interaction). Buffer A: 1.5 M ammonium sulfate, 25 mM phosphate pH 7.0. Buffer B: 25% isopropanol, 25 mM phosphate pH 7.0. Run sample 80 min at 0.5 mL / min, 0 - 100%. 15 ug loaded.

[0075] FIG. 62 Comparison of ADC in vitro killing activity with different linkers. MM.1 S cell line was treated with ADCs, then cell viability was measured after 48 and 72 hours using aAttorney Docket No.: 048440-849001 WORealTime-Glo™ MT Cell Viability Assay. Results show humanized Ab 1 AM has similar activity to the chimeric version. The non-cleavable MMAF did not show killing activity.

[0076] FIG. 63A-63B Comparison of ADC in vitro killing activity with different affinities and binding epitopes. MM. IS and H929 cell lines were treated with ADCs, then cell viability was measured after 48 and 72 hours using a RealTime-Glo™ MT Cell Viability Assay. Results show humanized Ab 1 AM has similar activity to the chimeric version. FTL004 has ADC activity, however it is not as potent as Ab 1. Detuning Dara seems to increase its activity as an ADC.

[0077] FIG. 64 Comparison of ADC in vitro killing activity with different affinities and binding epitopes. H929 cell line was treated with ADCs, then cell viability was measured after 48 hours using a RealTime-Glo™ MT Cell Viability Assay. Results show humanized Ab 1 AM has similar activity to the chimeric version. FTL004 has ADC activity, however it is not as potent as Ab 1. Detuning Dara increases its activity as an ADC at concentrations 10 nM and 30 nM.

[0078] FIG. 65 Comparison of ADC in vitro killing activity with different affinities and binding epitopes. Antibodies were conjugated to AF647 using the glycan modification strategy, then flow cytometry was used to evaluate binding to healthy donor PBMCs (n=3). Results show the percentage of binding of antibodies to CD45+ CD3+ T cells, CD3+ CD4+ T cells, CD3+ CD8+ T cells, CD3-CD56+NK cells, CD45+ CD19+ B cells and CD45+ CD33+ myeloid cells. Ab binding to healthy donor PBMCs: PBMCs from healthy donors Fl 8, F60, and F63. Cells were washed with PBS 2% BSA. 0.5 million cells per tube. Cells stained for markers. Flow cytometry was performed.

[0079] FIG. 66 Comparison of ADC in vitro killing activity against MM cell lines and healthy donor PBMCs. Antibodies were conjugated to MMAF using the glycan modification strategy, then cells were treated with 10 nM of unconjugated antibody or ADC for 48 hours. Cells were then washed and stained with Dapi and Annexin-V-APC to evaluate cell viability by flow cytometry. Percentage of cell death normalized to untreated controls is shown with CD38+ MM cell lines (MM.1 S and H929) and healthy PBMCs (n=2).

[0080] FIG. 67 ADC in vivo activity. Mice were engrafted with MM.1 S Luc+ cells, then randomized into 5 treatment groups. Mice were treated once per week for 3 weeks. TumorAttorney Docket No.: 048440-849001 WO progression was monitored weekly by bioluminescence imaging and weight was monitored weekly.DETAILED DESCRIPTIONDEFINITIONS

[0081] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means the specified value.

[0082] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about means the specified value.

[0083] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0084] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higherAttorney Docket No.: 048440-849001 WO homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkenyl includes one or more double bonds. An alkynyl includes one or more triple bonds.

[0085] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds.

[0086] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietyAttorney Docket No.: 048440-849001 WO may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and / or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and / or one or more double bonds in additional to the one or more triple bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0087] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R", -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. AAttorney Docket No.: 048440-849001 WO heteroalkenyl ene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds.

[0088] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2, 5, 6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0089] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In embodiments, cycloalkyl groups are fully saturated. A bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.

[0090] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. A bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is aAttorney Docket No.: 048440-849001 WO cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.

[0091] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, heterocycloalkyl groups are fully saturated. A bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.

[0092] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0093] The term “acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0094] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, whereinAttorney Docket No.: 048440-849001 WO one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5 -quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0095] A fused ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0096] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.Attorney Docket No.: 048440-849001 WO

[0097] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0098] Each of the above terms (e.g., "alkyl," "heteroalkyl,", "cycloalkyl", "heterocycloalkyl", "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0099] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-0R', -NR'R", -SR', -halogen,-SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0)2R', -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2N(R)('R"-NRSO2R'), -CN, and -NO2 in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5- , 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0100] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(0)NR"R"', NR"C(O)2R', NRC(NR'R")=NR'", S(O)R', -S(O)2R',Attorney Docket No.: 048440-849001 WO-S(O)2N(R')(R", -NRSO2R'), -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R1, R", R1", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R1, R", R1", and R"" groups when more than one of these groups is present.

[0101] Where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. For example, where a moiety herein is R1A-substituted or unsubstituted alkyl, a plurality of R1Asubstituents may be attached to the alkyl moiety wherein each R1Asubstituent is optionally different. Where an R-substituted moiety is substituted with a plurality of R substituents, each of the R- substituents may be differentiated herein using a prime symbol (') such as R', R", etc. For example, where a moiety is R3A-substituted or unsubstituted alkyl, and the moiety is substituted with a plurality of R3Asubstituents, the plurality of R3Asubstituents may be differentiated as R3Al, R3A", R3Al", etc. In some embodiments, the plurality of R substituents is 3.

[0102] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ringforming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ringforming substituents are attached to non-adjacent members of the base structure.

[0103] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR')q-U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.Attorney Docket No.: 048440-849001 WOAlternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -S(O)2-, -S(0)2NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"R"')d-, where variables s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(0)2NR'-. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0104] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0105] A "substituent group," as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -C0NH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:(i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (O)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:Attorney Docket No.: 048440-849001 WO(a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(O) NH2, - NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO2CI, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0106] A "size-limited substituent" or "size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0107] A "lower substituent" or "lower substituent group," as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.Attorney Docket No.: 048440-849001 WO

[0108] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0109] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0110] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and / or each substituted orAttorney Docket No.: 048440-849001 WO unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-Cio arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0111] As used herein, the term "conjugate" refers to the association between atoms or molecules. The association can be direct or indirect. For example, a conjugate between a nucleic acid and a protein can be direct, e.g., by covalent bond, or indirect, e.g., by non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g. dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, conjugates are formed using conjugate chemistry including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982.

[0112] Useful reactive moieties or functional groups used for conjugate chemistries (including "click chemistries" as known in the art) herein include, for example:(a) carboxyl groups and various derivatives thereof including, but not limited to, N- hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;(b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.Attorney Docket No.: 048440-849001 WO(c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;(d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido groups;(e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;(f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides;(g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold;(h) amine or sulfhydryl groups, which can be, for example, acylated, alkylated or oxidized;(i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.;(j) epoxides, which can react with, for example, amines and hydroxyl compounds;(k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis;(l) metal silicon oxide bonding;(m) metal bonding to reactive phosphorus groups (e.g. phosphines) to form, for example, phosphate diester bonds; and(n) sulfones, for example, vinyl sulfone.

[0113] Chemical synthesis of compositions by joining small modular units using conjugate (“click”) chemistry is well known in the art and described, for example, in H. C. Kolb, M. G. Finn and K. B. Sharpless ((2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions". Angewandte Chemie International Edition 40 (11): 2004-2021); R. A. Evans ((2007). "The Rise of Azide-Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification". Australian Journal of Chemistry 60 (6): 384-395; W.C. Guida et al. Med. Res. Rev. p 3 1996; Spiteri, Christian and Moses, John E. ((2010)."Copper-Catalyzed Azide-Alkyne Cycloaddition: Regioselective Synthesis of 1,4,5-Attorney Docket No.: 048440-849001 WOTrisubstituted 1,2, 3 -Triazoles". Angewandte Chemie International Edition 49 (1): 31-33); Hoyle, Charles E. and Bowman, Christopher N. ((2010). "Thiol-Ene Click Chemistry". Angewandte Chemie International Edition 49 (9): 1540-1573); Blackman, Melissa L. and Royzen, Maksim and Fox, Joseph M. ((2008). "Tetrazine Ligation: Fast Bioconjugation Based on Inverse- Electron-Demand Diels- Alder Reactivity". Journal of the American Chemical Society 130 (41): 13518-13519); Devaraj, Neal K. and Weissleder, Ralph and Hilderbrand, Scott A. ((2008). "Tetrazine Based Cycloadditions: Application to Pretargeted Live Cell Labeling". Bioconjugate Chemistry 19 (12): 2297-2299); Stockmann, Henning; Neves, Andre; Stairs, Shaun; Brindle, Kevin; Leeper, Finian ((2011). "Exploring isonitrile-based click chemistry for ligation with biomolecules". Organic & Biomolecular Chemistry), all of which are hereby incorporated by reference in their entirety and for all purposes.

[0114] The reactive functional groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the proteins or nucleic acids described herein. By way of example, the nucleic acids can include a vinyl sulfone or other reactive moiety (e.g., maleimide). Optionally, the nucleic acids can include a reactive moiety having the formula -S-S-R. R can be, for example, a protecting group. Optionally, R is hexanol. As used herein, the term hexanol includes compounds with the formula CeHoOH and includes, 1 -hexanol, 2-hexanol, 3 -hexanol, 2-methyl-l -pentanol, 3 -methyl- 1 -pentanol, 4-methyl-l -pentanol, 2-methyl-2-pentanol, 3-methyl- 2-pentanol, 4-methyl-2-pentanol, 2-methyl-3 -pentanol, 3 -methyl-3 -pentanol, 2,2-dimethyl-l- butanol, 2,3-dimethyl-l-butanol, 3,3-dimethyl-l-butanol, 2,3-dimethyl-2-butanol, 3,3-dimethyl- 2-butanol, and 2-ethyl-l -butanol. Optionally, R is 1-hexanol.

[0115] The term “reactive moiety” as provided herein refers to a chemically functional group of a molecule (e.g., compound or antigen binding domain provided herein), which is capable of forming a covalent or non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g. dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like) (e.g., covalent or non-covalent bonds) with another reactive moiety of the same or a different molecule. In embodiments, the reactive moiety is a click chemistry reactive group or click chemistry reactive moiety (i.e., a reactive moiety or functional group useable for conjugate chemistries (including "click chemistries" as known in the art)). As described above a clickAttorney Docket No.: 048440-849001 WO chemistry reactive group is a chemically functional group useful for conjugate chemistry. Thus, in embodiments, the reactive moiety is an azide moiety. In embodiments, the reactive moiety has the structure of-N=N+=N'. In embodiments, the reactive moiety is alkyne.

[0116] In embodiments, the reactive moiety is DBCO. The term "DBCO" as provided herein refers in a customary sense to dibenzocyclooctyl identified by PubChem No. 77078258 or any reactive group including DBCO. In embodiments, the reactive moiety has or includes the structure:wherein / wwc indicates the point of attachment to the reminder of the molecule. In embodiments, the reactive moiety is 30 kDa pegylated-DBCO.

[0117] In embodiments, the reactive moiety is a trans-cyclooctene (TCO) moiety. The term "TCO" as provided herein refers in a customary sense to trans-cyclooctene identified by PubChem No. 89994470 or any reactive group including TCO. In embodiments, the reactive moiety has or includes the structure:wherein indicates the point of attachment to the reminder of the molecule.

[0118] In embodiments, the reactive moiety is a tetrazine moiety. The term "tetrazine" as provided herein refers in a customary sense to tetrazine identified by PubChem No. 9263 or any reactive group including tetrazine. In embodiments, the reactive moiety has or includes the structure:wherein indicates the point of attachment to the reminder of the molecule.Attorney Docket No.: 048440-849001 WO

[0119] A “chemical linker,” as provided herein, is a covalent linker, a non-covalent linker, a peptide or peptidyl linker (a linker including a peptide moiety), a cleavable peptide linker, a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene or any combination thereof.

[0120] The chemical linker as provided herein may be a bond, -O-, -S-, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2NH-, -NH-, -NHC(O)NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted arylene or substituted (e.g., substituted with a substituent group, a size-limited substituent or a lower substituent group) or unsubstituted heteroarylene.

[0121] The chemical linker as provided herein may be a bond, -O-, -S-, -C(O)-, -C(O)O- , -C(O)NH-, -S(O)2NH-, -NH-, -NHC(O)NH-, substituted or unsubstituted (e.g., C1-C20, C1-C10, C1-C5) alkylene, substituted or unsubstituted (e.g., 2 to 20 membered, 2 to 10 membered, 2 to 5 membered) heteroalkylene, substituted or unsubstituted (e.g., C3-C8, C3-C6, C3-C5) cycloalkylene, substituted or unsubstituted (e.g., 3 to 8 membered, 3 to 6 membered, 3 to 5 membered) heterocycloalkylene, substituted or unsubstituted (e.g., Ce-Cio, Ce-Cs, Ce-Cs) arylene or substituted or unsubstituted (e.g., 5 to 10 membered, 5 to 8 membered, 5 to 6 membered,) heteroarylene.

[0122] In embodiments, the chemical linker is a covalent linker. In embodiments, the chemical linker is a hydrocarbon linker. In embodiments, the chemical linker is a cleavable peptide linker.Attorney Docket No.: 048440-849001 WO

[0123] Thus, a chemical linker as provided herein may include a plurality of chemical moieties, wherein each of the plurality of chemical moieties is chemically different. Alternatively, the chemical linker may be a non-covalent linker. Examples of non-covalent linkers include without limitation, ionic bonds, hydrogen bonds, halogen bonds, van der Waals interactions (e.g. dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), and hydrophobic interactions. In embodiments, a chemical linker is formed using conjugate chemistry including, but not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).

[0124] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0125] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA andAttorney Docket No.: 048440-849001 WORNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0126] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[0127] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSEAttorney Docket No.: 048440-849001 WORESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0128] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism. In embodiments, the nonspecific nucleic acid sequence does not encode a biological function. In embodiments, the nonspecific nucleic acid sequence is a scrambled nucleic acid sequence. A “scrambled nucleic acid sequence” as provided herein is a recombinant nucleic acid sequence that includes nucleotides randomly linked to each other in vitro. Scrambled nucleic acid sequences are commonly used in the art as control or reference sequences relative to the activity (biological function) of test nucleic acid sequences.

[0129] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0130] A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include32P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonlyAttorney Docket No.: 048440-849001 WO used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any appropriate method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0131] A "labeled protein or polypeptide" is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the labeled protein or polypeptide may be detected by detecting the presence of the label bound to the labeled protein or polypeptide. Alternatively, methods using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., biotin, streptavidin.

[0132] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0133] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.Attorney Docket No.: 048440-849001 WO

[0134] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0135] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that may be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0136] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected antibody (or Fab domain) corresponds to light chain threonine at Kabat position 40, when the selected residue occupies the same essential spatial or other structural relationship as a light chain threonine at Kabat position 40. In some embodiments, where a selected protein is aligned for maximum homology with the light chain of an antibody (or Fab domain), the position in the alignedAttorney Docket No.: 048440-849001 WO selected protein aligning with threonine 40 is said to correspond to threonine 40. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the light chain threonine at Kabat position 40, and the overall structures compared. In this case, an amino acid that occupies the same essential position as threonine 40 in the structural model is said to correspond to the threonine 40 residue.

[0137] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0138] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.

[0139] The following eight groups each contain amino acids that are conservative substitutions for one another:Attorney Docket No.: 048440-849001 WO1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E);3) Asparagine (N), Glutamine (Q);4) Arginine (R), Lysine (K);5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);7) Serine (S), Threonine (T); and8) Cysteine (C), Methionine (M)(see, e.g., Creighton, Proteins (1984)).

[0140] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity over a specified region, e.g., of the entire polypeptide sequences of the invention or individual domains of the polypeptides of the invention), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be "substantially identical." This definition also refers to the complement of a test sequence. Optionally, the identity exists over a region that is at least about 50 nucleotides in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides in length.

[0141] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the totalAttorney Docket No.: 048440-849001 WO number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0142] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

[0143] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. AppL Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0144] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valuedAttorney Docket No.: 048440-849001 WO threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et cd., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Set. USA 89: 10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0145] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Set. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0146] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, forAttorney Docket No.: 048440-849001 WO example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0147] “ CD38" as referred to herein includes any of the recombinant or naturally-occurring forms of the Cluster of Differentiation 38 (CD38) protein, also known as ADP-ribosyl cyclase / cyclic ADP -ribose hydrolase 1, 2'-phospho- ADP-ribosyl cyclase, 2'-phospho-cyclic- ADP-ribose transferase, ADP-ribosyl cyclase 1, or variants or homologs thereof that maintain CD38 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to CD38). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring CD38 protein. In embodiments, the CD38 protein is substantially identical to the protein identified by the UniProt reference number P28907 or a variant or homolog having substantial identity thereto.

[0148] The term "isolated", when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0149] Antibodies are large, complex molecules (molecular weight of -150,000 or about 1320 amino acids) with intricate internal structure. A natural antibody molecule contains two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light chain and heavy chain in turn consists of two regions: a variable (“V”) region, involved in binding the target antigen, and a constant (“C”) region that interacts with other components of the immune system. The light and heavy chain variable regions (also referred to herein as light chain variable (VL) domain and heavy chain variable (VH) domain, respectively) come togetherAttorney Docket No.: 048440-849001 WO in 3 -dimensional space to form a variable region that binds the antigen (for example, a receptor on the surface of a cell). Within each light or heavy chain variable region, there are three short segments (averaging 10 amino acids in length) called the complementarity determining regions (“CDRs”). The six CDRs in an antibody variable domain (three from the light chain and three from the heavy chain) fold up together in 3 -dimensional space to form the actual antibody binding site which docks onto the target antigen. The position and length of the CDRs have been precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1983, 1987. The part of a variable region not contained in the CDRs is called the framework ("FR"), which forms the environment for the CDRs.

[0150] The term "antibody" is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well -characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CHI by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).

[0151] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain or light chain variable region and variable heavy chain (VH), variable heavy chain (VH) domain or heavyAttorney Docket No.: 048440-849001 WO chain variable region refer to these light and heavy chain regions, respectively. The terms variable light chain (VL), variable light chain (VL) domain and light chain variable region as referred to herein may be used interchangeably. The terms variable heavy chain (VH), variable heavy chain (VH) domain and heavy chain variable region as referred to herein may be used interchangeably. The Fc (i.e. fragment crystallizable region; also referred to herein as “Fc domain”) is the "base" or "tail" of an immunoglobulin and is typically composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. In embodiments, the Fc region includes a constant heavy chain domain 3 (CH3 domain) and a constant heavy chain domain 2 (CH2 domain).

[0152] The epitope of an antibody is the region of its antigen to which the antibody binds. Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a lx, 5x, lOx, 20x or lOOx excess of one antibody inhibits binding of the other by at least 30% but preferably 50%, 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50: 1495, 1990). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0153] The term "biparatopic antibody" provided herein is used according to its common meaning in the biological arts, and refers to a bispecific antibody including two antigen binding domains, each of which recognizes unique, non-overlapping epitopes on the same target antigen. Compared to monoclonal antibodies, biparatopic antibodies may exhibit a superior ability to promote receptor clustering, which may in turn result in improved receptor internalization, lysosomal trafficking, and receptor down regulation and therefore improved drug potency. In embodiments, a biparatopic antibody includes a first antigen binding domain including a heavy chain and a light chain; and a second antigen binding domain including a heavy chain and a light chain. In embodiments, the heavy chain of the first antigen binding domain and the heavy chainAttorney Docket No.: 048440-849001 WO of the second antigen binding domain are different. In embodiments, the light chain of the first antigen binding domain and the light chain of the second antigen binding domain are different. In embodiments, a biparatopic antibody includes a first heavy chain, a first light chain, a second heavy chain and a second light chain, wherein the first heavy chain and the second heavy chain are different and wherein the first light chain and the second light chain are different.

[0154] In embodiments, the heavy chain of the first antigen binding domain and the heavy chain of the second antigen binding domain are the same and the light chain of the first antigen binding domain and the light chain of the second antigen binding domain are the same. A first antibody and a second antibody may be provided herein, wherein the first antibody binds a different epitope than the second antibody.

[0155] The term "antigen" as provided herein refers to molecules capable of binding to the antigen binding domain provided herein. An "antigen binding domain" as provided herein is a region of an antibody that binds to an antigen (epitope). As described above, the antigen binding domain is generally composed of one constant and one variable domain of each of the heavy and the light chain (VL, VH, CL and CHI, respectively). The paratope or antigen-binding site is formed on the N-terminus of the antigen binding domain. The two variable domains of an antigen binding domain typically bind the epitope on an antigen. The antibodies provided herein may be biparatopic antibodies. In embodiments, the biparatopic antibody includes a first paratope binding a first epitope and a second paratope binding a second epitope. In embodiments, the first paratope and the second paratope are different. In further embodiments, the first epitope and the second epitope are different.

[0156] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). "Monoclonal" antibodies (mAb) refer to antibodies derived from a single clone. Techniques for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments thatAttorney Docket No.: 048440-849001 WO specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).

[0157] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Patent 4,946,778, U.S. Patent No. 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93 / 08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121 :210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980 , WO 91 / 00360; WO 92 / 200373; and EP 03089).Attorney Docket No.: 048440-849001 WO

[0158] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U.S. Patent Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762;5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87 / 02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321 :522; and Verhoyen et al. (1988) Science 239: 1534). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81 :6851-6855 (1984), Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239: 1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3): 169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.

[0159] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and / or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or alteredAttorney Docket No.: 048440-849001 WO antigen specificity. The preferred antibodies of, and for use according to the invention include humanized and / or chimeric monoclonal antibodies.

[0160] An “antibody variant” as provided herein refers to a polypeptide capable of binding to an antigen and including one or more structural domains of an antibody or fragment thereof. Non-limiting examples of antibody variants include single-domain antibodies or nanobodies, affibodies (polypeptides smaller than monoclonal antibodies (e.g., about 6kDA) and capable of binding antigens with high affinity and imitating monoclonal antibodies, monospecific Fab?, bispecific Fab?, trispecific Fab?, monovalent IgGs, scFv, bispecific diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNAR, V-NAR, hcIgG, VhH, or peptibodies. A “nanobody” or “single domain antibody” as described herein is commonly well known in the art and refers to an antibody fragment consisting of a single monomeric variable antibody domain (e.g., a VH or a VL domain). Like a whole antibody, it is able to bind selectively to a specific antigen. A “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non- covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camelids. A general description of antibodies from camelids and the variable regions thereof and methods for their production, isolation, and use may be found in references WO97 / 49805 and WO 97 / 49805 which are incorporated by reference herein in their entirety and for all purposes. Likewise, antibodies from cartilaginous fish and the variable regions thereof and methods for their production, isolation, and use may be found in W02005 / 118629, which is incorporated by reference herein in its entirety and for all purposes.

[0161] The terms "daratumumab" or "dara" as provided herein refer to the therapeutic monoclonal anti-CD38 antibody also known by its commercial name "Darzalex" and, in a customary sense, refer to the compound identified by the ChemIDplus reference number 945721- 28-8.

[0162] An “affibody” as described herein is commonly well known in the art and refers to small, robust proteins engineered to bind to a large number of target proteins or peptides with high affinity, by imitating monoclonal antibodies. Affibodies are therefore a member of the family of antibody mimetics. In embodiments, an affibody is a molecule including of three alpha helices with about 58 amino acids and a molar mass of about 6 kDa.Attorney Docket No.: 048440-849001 WO

[0163] A “single domain antibody” as provided herein refers to an antibody fragment including a single monomeric variable antibody domain (e.g., a VH or a VL domain). Like a whole antibody, a single domain antibody is able to bind selectively to a specific antigen. The molecular weight of a single domain antibody is 12-15 kDa, single domain antibody. In embodiments, a single domain antibody is a variable heavy chain domain. In embodiments, a single domain antibody includes a variable heavy chain domain. In embodiments, a single domain antibody is a variable light chain domain. In embodiments, a single domain antibody includes a variable light chain domain. Non-limiting examples of single domain antibodies include camelid-derived VHH fragments and VNAR (variable immunoglobulin new antigen receptor) fragments. In embodiments, the single-domain antibody is a peptide domain of about 110 amino acids.

[0164] A single-chain variable fragment (scFv) is typically a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of 10 to about 25 amino acids. The linker may usually be rich in glycine for flexibility, as well as serine or threonine for solubility. The linker can either connect the N- terminus of the VH with the C-terminus of the VL, or vice versa.

[0165] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, UsingAttorney Docket No.: 048440-849001 WOAntibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0166] A "ligand" refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a ligand binding domain (e.g., receptor or antibody, antibody variant, antibody region or fragment thereof).

[0167] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells, an antibody provided herein and its epitope) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0168] The term "contacting" may include allowing two species to react, interact, or physically touch (e.g., bind), wherein the two species may be, for example, an antibody construct as described herein and a cancer protein. In embodiments, contacting includes, for example, allowing an antibody construct to bind to a cancer protein expressed on a cancer cell.

[0169] A "cell" as used herein, refers to a cell carrying out metabolic or other functions sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0170] The term "plasmid," "expression vector," or “viral vector” refers to a nucleic acid molecule that encodes for genes and / or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, gene and regulatory elements are encoded by the same plasmid. Expression in trans refers toAttorney Docket No.: 048440-849001 WO the instance where the gene and the regulatory elements are encoded by separate plasmids. Suitable viral vectors contemplated herein include, for example, lentiviral vectors and onco- retroviral vectors.

[0171] "Biological sample" or "sample" refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluid, joint tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. A biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. In some embodiments, the sample is obtained from a human.

[0172] A "control" sample or value refers to a sample that serves as a reference, usually a known reference, for comparison to a test sample. For example, a test sample can be taken from a test condition, e.g., in the presence of a test compound, and compared to samples from known conditions, e.g., in the absence of the test compound (negative control), or in the presence of a known compound (positive control). A control can also represent an average value gathered from a number of tests or results. One of skill in the art will recognize that controls can be designed for assessment of any number of parameters. For example, a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). One of skill in the art will understand which controls are valuable in a given situation and be able to analyze data based on comparisons to control values. Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant.

[0173] "Patient" or "subject in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein. Non-limiting examples include humans, otherAttorney Docket No.: 048440-849001 WO mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

[0174] The terms "disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In embodiments, the disease is cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma (Mantel cell lymphoma), head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0175] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma (e.g., Mantel cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zona lymphoma, Burkitt’s lymphoma), sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g. triple negative, ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma) , lung cancer (e.g. non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastomaAttorney Docket No.: 048440-849001 WO multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget’s Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

[0176] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). The P388 leukemia model is widely accepted as being predictive of in vivo antileukemic activity. It is believed that a compound that tests positive in the P388 assay will generally exhibit some level of anti -leukemic activity in vivo regardless of the type of leukemia being treated. Accordingly, the present application includes a method of treating leukemia, and, preferably, a method of treating acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,Attorney Docket No.: 048440-849001 WO promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0177] As used herein, the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and / or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells. The secondary tumor in the breast is referred to a metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases non-metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.

[0178] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., cancer) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.

[0179] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement isAttorney Docket No.: 048440-849001 WO observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment includes preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; preventing re-occurring of the disease and / or relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance. For example, certain methods herein treat cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma). For example, certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer; or treat cancer by decreasing a symptom of cancer. Symptoms of cancer (e.g. lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) would be known or may be determined by a person of ordinary skill in the art.

[0180] A "therapeutic agent" or "therapeutic moiety" as referred to herein, is a composition useful in treating or preventing a disease such as cancer (e.g., myeloma). In embodiments, the therpaeutic agent is an anti-cancer agent. “Anti-cancer agent” is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In embodiments, an anti-cancer agent is a chemotherapeutic. In embodiments, an anticancer agent is a tubulin polymerization inhibitor. In embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In embodiments, an anti-Attorney Docket No.: 048440-849001 WO cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.

[0181] As used herein the terms “treatment,” “treat,” or “treating” refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.

[0182] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein,Attorney Docket No.: 048440-849001 WO refers to an amount of antagonist required to decrease the activity of an enzyme or protein relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. For example, for the given parameter, an effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0183] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention canAttorney Docket No.: 048440-849001 WO be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0184] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the antibodies provided herein suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, com starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0185] Pharmaceutical compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized sepharose(TM), agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes). Additionally, these carriers can function as immunostimulating agents (z.e., adjuvants).

[0186] Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged nucleic acid with a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the compound of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons.

[0187] Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterileAttorney Docket No.: 048440-849001 WO injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally. Parenteral administration, oral administration, and intravenous administration are the preferred methods of administration. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.

[0188] Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Cells transduced by nucleic acids for ex vivo therapy can also be administered intravenously or parenterally as described above.

[0189] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents.

[0190] The combined administration contemplates co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

[0191] Effective doses of the compositions provided herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. However, a person of ordinary skill in the art would immediately recognize appropriate and / or equivalent doses looking at dosages of approved compositions for treating and preventing cancer for guidance.Attorney Docket No.: 048440-849001 WO

[0192] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances, and the like, that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0193] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0194] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0195] The pharmaceutical preparation is optionally in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The unit dosage form can be of a frozen dispersion.Attorney Docket No.: 048440-849001 WO

[0196] The compositions of the present invention may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In embodiments, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al-Muhammed, J. MicroencapsuL 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576- 1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.BIPARATOPIC ANTI-CD38 ANTIBODIES

[0197] Provided herein are, inter alia, antibodies (e.g., humanized antibodies, chimeric antibodies, monoclonal antibodies, biparatopic antibodies, antibody fragments (e.g., Fab’)), which bind CD38 with high efficiency and specificity. Further provided herein are, inter alia, biparatopic antibodies specific for CD38. The biparatopic antibodies provided herein may have an increased binding avidity relative to the monoclonal antibodies they are derived from. For example, a biparatopic antibody of the invention provided herein may include a first antigen binding domain derived from a first monoclonal antibody and a second antigen binding domain derived from a second monoclonal antibody, wherein the first and second antigen binding domain are different and wherein the biparatopic antibody has an increased binding avidity relative to first and / or the second monoclonal antibody. In embodiments, the avidity of theAttorney Docket No.: 048440-849001 WO biparatopic antibody is increased by about 10-106-fold relative to the avidity of the first or the second monoclonal antibody. In embodiments, the avidity of the biparatopic antibody is increased by about 10-106-fold relative to the avidity of the first and the second monoclonal antibody. In embodiments, the avidity of the biparatopic antibody is increased by about 10-106- fold relative to combined avidity of the first and the second monoclonal antibody. The biparatopic antibodies provided herein may be used, for example, to deliver therapeutic or diagnostic moieties. The antibodies provided herein including embodiments thereof may include a modified Fc portion that does not elicit an antibody dependent cellular cytotoxicity (ADCC).

[0198] In an aspect is provided a biparatopic anti-CD38 antibody including a first antigen binding domain and a second antigen binding domain independently including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and wherein the light chain variable domain includes a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2.

[0199] In another aspect is provided an anti-CD38 antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and wherein the light chain variable domain includes a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2.

[0200] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO:92, and a CDR L3 as set forth in SEQ ID NO:93. In embodiments, the antibody is referred to herein as CD38-1.

[0201] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NON, a CDR H2 as set forth in SEQ ID NO:5 and a CDR H3 as set forth in SEQ ID NO: 6; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 94, aAttorney Docket No.: 048440-849001 WOCDR L2 as set forth in SEQ ID NO:95, and a CDR L3 as set forth in SEQ ID NO:96. In embodiments, the antibody is referred to herein as CD38-2.

[0202] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 7, a CDR H2 as set forth in SEQ ID NO: 8 and a CDR H3 as set forth in SEQ ID NO:9; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO:97, a CDR L2 as set forth in SEQ ID NO:98, and a CDR L3 as set forth in SEQ ID NO:99. In embodiments, the antibody is referred to herein as CD38-6.

[0203] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 10, a CDR H2 as set forth in SEQ ID NO: 11 and a CDR H3 as set forth in SEQ ID NO: 12; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 100, a CDR L2 as set forth in SEQ ID NO: 101, and a CDR L3 as set forth in SEQ ID NO: 102. In embodiments, the antibody is referred to herein as CD38-9.

[0204] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 13, a CDR H2 as set forth in SEQ ID NO: 14 and a CDR H3 as set forth in SEQ ID NO: 15; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 103, a CDR L2 as set forth in SEQ ID NO: 104, and a CDR L3 as set forth in SEQ ID NO: 105. In embodiments, the antibody is referred to herein as CD38-10.

[0205] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 16, a CDR H2 as set forth in SEQ ID NO: 17 and a CDR H3 as set forth in SEQ ID NO: 18; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 106, a CDR L2 as set forth in SEQ ID NO: 107, and a CDR L3 as set forth in SEQ ID NO: 108. In embodiments, the antibody is referred to herein as CD38-11.

[0206] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 19, a CDR H2 as set forth in SEQ ID NO:20 and a CDR H3 as set forth in SEQ ID NO:21; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 109, a CDR L2 as set forth in SEQ ID NO: 110, and a CDR L3 as set forth in SEQ ID NO: 111. In embodiments, the antibody is referred to herein as CD38-17.

[0207] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:22, a CDR H2 as set forth i s set forth in SEQ IDAttorney Docket No.: 048440-849001 WONO:24; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 112, a CDR L2 as set forth in SEQ ID NO: 113, and a CDR L3 as set forth in SEQ ID NO: 114. In embodiments, the antibody is referred to herein as CD38-19.

[0208] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:25, a CDR H2 as set forth in SEQ ID NO:26 and a CDR H3 as set forth in SEQ ID NO:27; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 115, a CDR L2 as set forth in SEQ ID NO: 116, and a CDR L3 as set forth in SEQ ID NO: 117. In embodiments, the antibody is referred to herein as CD38-20.

[0209] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:28, a CDR H2 as set forth in SEQ ID NO:29 and a CDR H3 as set forth in SEQ ID NO:30; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 118, a CDR L2 as set forth in SEQ ID NO: 119, and a CDR L3 as set forth in SEQ ID NO: 120. In embodiments, the antibody is referred to herein as CD38-21.

[0210] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:31, a CDR H2 as set forth in SEQ ID NO:32 and a CDR H3 as set forth in SEQ ID NO:33; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 121, a CDR L2 as set forth in SEQ ID NO: 122, and a CDR L3 as set forth in SEQ ID NO: 123. In embodiments, the antibody is referred to herein as CD38-23.

[0211] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:34, a CDR H2 as set forth in SEQ ID NO:35 and a CDR H3 as set forth in SEQ ID NO:36; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 124, a CDR L2 as set forth in SEQ ID NO: 125, and a CDR L3 as set forth in SEQ ID NO: 126. In embodiments, the antibody is referred to herein as CD38-24.

[0212] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 37, a CDR H2 as set forth in SEQ ID NO:38 and a CDR H3 as set forth in SEQ ID NO:39; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 127, a CDR L2 as set forth in SEQ ID NO: 128, and a CDR L3 as set forth in SEQ ID NO: 129. In embodiments, the antibody is referred to herein as CD38-25.Attorney Docket No.: 048440-849001 WO

[0213] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:40, a CDR H2 as set forth in SEQ ID NO:41 and a CDR H3 as set forth in SEQ ID NO:42; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 130, a CDR L2 as set forth in SEQ ID NO: 131, and a CDR L3 as set forth in SEQ ID NO: 132. In embodiments, the antibody is referred to herein as CD38-26.

[0214] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:43, a CDR H2 as set forth in SEQ ID NO:44 and a CDR H3 as set forth in SEQ ID NO:45; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 133, a CDR L2 as set forth in SEQ ID NO: 134, and a CDR L3 as set forth in SEQ ID NO: 135. In embodiments, the antibody is referred to herein as CD38-27.

[0215] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:46, a CDR H2 as set forth in SEQ ID NO:47 and a CDR H3 as set forth in SEQ ID NO:48; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 136, a CDR L2 as set forth in SEQ ID NO: 137, and a CDR L3 as set forth in SEQ ID NO: 138. In embodiments, the antibody is referred to herein as CD38-30.

[0216] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO:50 and a CDR H3 as set forth in SEQ ID NO:51; and the light chain variable domain includes: a CDR Ll as set forth in SEQ ID NO: 139, a CDR L2 as set forth in SEQ ID NO: 140, and a CDR L3 as set forth in SEQ ID NO: 141. In embodiments, the antibody is referred to herein as CD38-31.

[0217] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:52, a CDR H2 as set forth in SEQ ID NO:53 and a CDR H3 as set forth in SEQ ID NO:54; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 142, a CDR L2 as set forth in SEQ ID NO: 143, and a CDR L3 as set forth in SEQ ID NO: 144. In embodiments, the antibody is referred to herein as CD38-32.

[0218] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:55, a CDR H2 as set forth in SEQ ID NO:56 and a CDR H3 as set forth in SEQ ID NO:57; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 145,Attorney Docket No.: 048440-849001 WO a CDR L2 as set forth in SEQ ID NO: 146, and a CDR L3 as set forth in SEQ ID NO: 147. In embodiments, the antibody is referred to herein as CD38-34.

[0219] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:58, a CDR H2 as set forth in SEQ ID NO:59 and a CDR H3 as set forth in SEQ ID NO:60; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 148, a CDR L2 as set forth in SEQ ID NO: 149, and a CDR L3 as set forth in SEQ ID NO: 150. In embodiments, the antibody is referred to herein as CD38-35.

[0220] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 61, a CDR H2 as set forth in SEQ ID NO: 62 and a CDR H3 as set forth in SEQ ID NO:63; and the light chain variable domain includes: a CDR Ll as set forth in SEQ ID NO: 151, a CDR L2 as set forth in SEQ ID NO: 152, and a CDR L3 as set forth in SEQ ID NO: 153. In embodiments, the antibody is referred to herein as CD38-36.

[0221] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 64, a CDR H2 as set forth in SEQ ID NO: 65 and a CDR H3 as set forth in SEQ ID NO:66; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 154, a CDR L2 as set forth in SEQ ID NO: 155, and a CDR L3 as set forth in SEQ ID NO: 156. In embodiments, the antibody is referred to herein as CD38-37.

[0222] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 67, a CDR H2 as set forth in SEQ ID NO: 68 and a CDR H3 as set forth in SEQ ID NO:69; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 157, a CDR L2 as set forth in SEQ ID NO: 158, and a CDR L3 as set forth in SEQ ID NO: 159. In embodiments, the antibody is referred to herein as CD38-38.

[0223] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 70, a CDR H2 as set forth in SEQ ID NO:71 and a CDR H3 as set forth in SEQ ID NO:72; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 160, a CDR L2 as set forth in SEQ ID NO: 161, and a CDR L3 as set forth in SEQ ID NO: 162. In embodiments, the antibody is referred to herein as CD38-39.

[0224] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 73, a CDR H2 as set forth i s set forth in SEQ IDAttorney Docket No.: 048440-849001 WONO:75; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 163, a CDR L2 as set forth in SEQ ID NO: 164, and a CDR L3 as set forth in SEQ ID NO: 165. In embodiments, the antibody is referred to herein as CD38-40.

[0225] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 76, a CDR H2 as set forth in SEQ ID NO: 77 and a CDR H3 as set forth in SEQ ID NO:78; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 166, a CDR L2 as set forth in SEQ ID NO: 167, and a CDR L3 as set forth in SEQ ID NO: 168. In embodiments, the antibody is referred to herein as CD38-42.

[0226] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 79, a CDR H2 as set forth in SEQ ID NO: 80 and a CDR H3 as set forth in SEQ ID NO:81; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 169, a CDR L2 as set forth in SEQ ID NO: 170, and a CDR L3 as set forth in SEQ ID NO: 171. In embodiments, the antibody is referred to herein as CD38-43.

[0227] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO: 82, a CDR H2 as set forth in SEQ ID NO: 83 and a CDR H3 as set forth in SEQ ID NO:84; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 172, a CDR L2 as set forth in SEQ ID NO: 173, and a CDR L3 as set forth in SEQ ID NO: 174. In embodiments, the antibody is referred to herein as CD38-46.

[0228] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:85, a CDR H2 as set forth in SEQ ID NO:86 and a CDR H3 as set forth in SEQ ID NO:87; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177. In embodiments, the antibody is referred to herein as CD38-48.

[0229] In embodiments, the heavy chain variable domain includes: a CDR Hl as set forth in SEQ ID NO:88, a CDR H2 as set forth in SEQ ID NO:89 and a CDR H3 as set forth in SEQ ID NO:90; and the light chain variable domain includes: a CDR LI as set forth in SEQ ID NO: 178, a CDR L2 as set forth in SEQ ID NO: 179, and a CDR L3 as set forth in SEQ ID NO: 180. In embodiments, the antibody is referred to herein as CD38-49.Attorney Docket No.: 048440-849001 WO

[0230] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence as set forth by Table 3. In embodiments, the antibody includes a heavy chain sequence as set forth by Table 3. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a light chain sequence as set forth by Table 3. In embodiments, the antibody includes a light chain sequence as set forth by Table 3. In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the heavy chain sequences of SEQ ID NO: 181-210. In embodiments, the antibody includes one of the heavy chain sequences of SEQ ID NO: 181-210. In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the light chain sequences of SEQ ID NO:211-240. In embodiments, the antibody includes one of the light chain sequences of SEQ ID NO:211-240.

[0231] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 181 and a light chain sequence of SEQ ID NO:211; a heavy chain sequence of SEQ ID NO: 182 and a light chain sequence of SEQ ID NO:212; a heavy chain sequence of SEQ ID NO: 183 and a light chain sequence of SEQ ID NO:213; a heavy chain sequence of SEQ ID NO:184 and a light chain sequence of SEQ ID NO:214; a heavy chain sequence of SEQ ID NO: 185 and a light chain sequence of SEQ ID NO:215; a heavy chain sequence of SEQ ID NO: 186 and a light chain sequence of SEQ ID NO:216; a heavy chain sequence of SEQ ID NO:187 and a light chain sequence of SEQ ID NO:217; a heavy chain sequence of SEQ ID NO: 188 and a light chain sequence of SEQ ID NO:218; a heavy chain sequence of SEQ ID NO: 189 and a light chain sequence of SEQ ID NO:219; a heavy chain sequence of SEQ ID NO: 190 and a light chain sequence of SEQ ID NO:220; a heavy chain sequence of SEQ ID NO: 191 and a light chain sequence of SEQ ID NO:221; a heavy chain sequence of SEQ ID NO: 192 and a light chain sequence of SEQ ID NO:222; a heavy chain sequence of SEQ ID NO: 193 and a light chain sequence of SEQ ID NO:223; a heavy chain sequence of SEQ ID NO: 194 and a light chain sequence of SEQ ID NO:224; a heavy chain sequence of SEQ ID NO: 195 and a light chain sequence of SEQ ID NO:225; a heavy chain sequence of SEQ ID NO: 196 and a light chain sequence of SEQ ID NO:226; a heavy chain sequence of SEQ ID NO: 197 and a light chain sequence of SEQ ID NO:227; a heavy chain sequence of SEQ ID NO: 198 and a light chain sequence of SEQ ID NO:228; a heavy chain sequence of SEQ ID NO: 199 and a light chainAttorney Docket No.: 048440-849001 WO sequence of SEQ ID NO:229; a heavy chain sequence of SEQ ID NO:200 and a light chain sequence of SEQ ID NO:230; a heavy chain sequence of SEQ ID NO:201 and a light chain sequence of SEQ ID NO:231; a heavy chain sequence of SEQ ID NO:202 and a light chain sequence of SEQ ID NO:232; a heavy chain sequence of SEQ ID NO:203 and a light chain sequence of SEQ ID NO:233; a heavy chain sequence of SEQ ID NO:204 and a light chain sequence of SEQ ID NO:234; a heavy chain sequence of SEQ ID NO:205 and a light chain sequence of SEQ ID NO:235; a heavy chain sequence of SEQ ID NO:206 and a light chain sequence of SEQ ID NO:236; a heavy chain sequence of SEQ ID NO:207 and a light chain sequence of SEQ ID NO:237; a heavy chain sequence of SEQ ID NO:208 and a light chain sequence of SEQ ID NO:238; a heavy chain sequence of SEQ ID NO:209 and a light chain sequence of SEQ ID NO:239; or a heavy chain sequence of SEQ ID NO:210 and a light chain sequence of SEQ ID NO:240.

[0232] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:241 and a light chain sequence of SEQ ID NO:242; a heavy chain sequence of SEQ ID NO:243 and a light chain sequence of SEQ ID NO:244 or a heavy chain sequence of SEQ ID NO:245 and a light chain sequence of SEQ ID NO:246. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO: 241 and the second antigen binding domain includes a light chain sequence of SEQ ID NO:242. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:243 and the second antigen binding domain includes a light chain sequence of SEQ ID NO:244. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:245 and the second antigen binding domain includes a light chain sequence of SEQ ID NO:246.

[0233] In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:241 and a light chain sequence of SEQ ID NO:242. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:243 and a light chain sequence of SEQ ID NO:244. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 245 and a light chain sequence of SEQ ID NO:246.

[0234] In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 181 and a light chain sequence of SEQ ID NO:211; a heavy chain sequence of SEQ ID NO: 182 and aAttorney Docket No.: 048440-849001 WO light chain sequence of SEQ ID NO:212; a heavy chain sequence of SEQ ID NO: 183 and a light chain sequence of SEQ ID NO:213; a heavy chain sequence of SEQ ID NO: 184 and a light chain sequence of SEQ ID NO:214; a heavy chain sequence of SEQ ID NO: 185 and a light chain sequence of SEQ ID NO:215; a heavy chain sequence of SEQ ID NO: 186 and a light chain sequence of SEQ ID NO:216; a heavy chain sequence of SEQ ID NO: 187 and a light chain sequence of SEQ ID NO:217; a heavy chain sequence of SEQ ID NO: 188 and a light chain sequence of SEQ ID NO:218; a heavy chain sequence of SEQ ID NO: 189 and a light chain sequence of SEQ ID NO:219; a heavy chain sequence of SEQ ID NO: 190 and a light chain sequence of SEQ ID NO:220; a heavy chain sequence of SEQ ID NO: 191 and a light chain sequence of SEQ ID NO:221; a heavy chain sequence of SEQ ID NO: 192 and a light chain sequence of SEQ ID NO:222; a heavy chain sequence of SEQ ID NO: 193 and a light chain sequence of SEQ ID NO:223; a heavy chain sequence of SEQ ID NO: 194 and a light chain sequence of SEQ ID NO:224; a heavy chain sequence of SEQ ID NO: 195 and a light chain sequence of SEQ ID NO:225; a heavy chain sequence of SEQ ID NO: 196 and a light chain sequence of SEQ ID NO:226; a heavy chain sequence of SEQ ID NO: 197 and a light chain sequence of SEQ ID NO:227; a heavy chain sequence of SEQ ID NO: 198 and a light chain sequence of SEQ ID NO:228; a heavy chain sequence of SEQ ID NO: 199 and a light chain sequence of SEQ ID NO:229; a heavy chain sequence of SEQ ID NO:200 and a light chain sequence of SEQ ID NO:230; a heavy chain sequence of SEQ ID NO:201 and a light chain sequence of SEQ ID NO:231; a heavy chain sequence of SEQ ID NO:202 and a light chain sequence of SEQ ID NO:232; a heavy chain sequence of SEQ ID NO:203 and a light chain sequence of SEQ ID NO:233; a heavy chain sequence of SEQ ID NO:204 and a light chain sequence of SEQ ID NO:234; a heavy chain sequence of SEQ ID NO:205 and a light chain sequence of SEQ ID NO:235; a heavy chain sequence of SEQ ID NO:206 and a light chain sequence of SEQ ID NO:236; a heavy chain sequence of SEQ ID NO:207 and a light chain sequence of SEQ ID NO:237; a heavy chain sequence of SEQ ID NO:208 and a light chain sequence of SEQ ID NO:238; a heavy chain sequence of SEQ ID NO:209 and a light chain sequence of SEQ ID NO:239; or a heavy chain sequence of SEQ ID NO:210 and a light chain sequence of SEQ ID NO:240.

[0235] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 181 and a light chainAttorney Docket No.: 048440-849001 WO sequence of SEQ ID NO:211. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 182 and a light chain sequence of SEQ ID NO:212. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 183 and a light chain sequence of SEQ ID NO:213. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 184 and a light chain sequence of SEQ ID NO:214. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 185 and a light chain sequence of SEQ ID NO:215. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 186 and a light chain sequence of SEQ ID NO:216. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 187 and a light chain sequence of SEQ ID NO:217. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 188 and a light chain sequence of SEQ ID NO:218. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 189 and a light chain sequence of SEQ ID NO:219; a heavy chain sequence of SEQ ID NO: 190 and a light chain sequence of SEQ ID NO:220. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 191 and a light chain sequence of SEQ ID NO:221. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 192 and a light chain sequence of SEQ ID NO:222. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 193 and a light chain sequence of SEQ ID NO:223.

[0236] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 194 and a light chain sequence of SEQ ID NO:224. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 195 and a light chain sequence of SEQ ID NO:225. In embodiments, the first antigen binding domain andAttorney Docket No.: 048440-849001 WO the second antigen binding domain independently include heavy chain sequence of SEQ ID NO: 196 and a light chain sequence of SEQ ID NO:226. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 197 and a light chain sequence of SEQ ID NO:227. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 198 and a light chain sequence of SEQ ID NO:228. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO: 199 and a light chain sequence of SEQ ID NO:229. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:200 and a light chain sequence of SEQ ID NO:230. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:201 and a light chain sequence of SEQ ID NO:231. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:202 and a light chain sequence of SEQ ID NO:232. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:203 and a light chain sequence of SEQ ID NO:233. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:204 and a light chain sequence of SEQ ID NO:234. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:205 and a light chain sequence of SEQ ID NO:235. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:206 and a light chain sequence of SEQ ID NO:236. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:207 and a light chain sequence of SEQ ID NO:237. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:208 and a light chain sequence of SEQ ID NO:238. In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:209 and a light chain sequence of SEQ ID NO:239. In embodiments, the first antigen binding domain and the second antigenAttorney Docket No.: 048440-849001 WO binding domain independently include a heavy chain sequence of SEQ ID NO:210 and a light chain sequence of SEQ ID NO:240.

[0237] In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 181 and a light chain sequence of SEQ ID NO:211. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 182 and a light chain sequence of SEQ ID NO:212. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 183 and a light chain sequence of SEQ ID NO:213. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 184 and a light chain sequence of SEQ ID NO:214. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 185 and a light chain sequence of SEQ ID NO:215. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 186 and a light chain sequence of SEQ ID NO:216. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 187 and a light chain sequence of SEQ ID NO:217. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 188 and a light chain sequence of SEQ ID NO:218. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 189 and a light chain sequence of SEQ ID NO:219; a heavy chain sequence of SEQ ID NO: 190 and a light chain sequence of SEQ ID NO:220. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 191 and a light chain sequence of SEQ ID NO:221. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 192 and a light chain sequence of SEQ ID NO:222. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 193 and a light chain sequence of SEQ ID NO:223.

[0238] In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 194 and a light chain sequence of SEQ ID NO:224. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 195 and a light chain sequence of SEQ ID NO:225. In embodiments, the antibody includes heavy chain sequence of SEQ ID NO: 196 and a light chain sequence of SEQ ID NO:226. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 197 and a light chain sequence of SEQ ID NO:227. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 198 and a light chain sequence of SEQ ID NO:228. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO: 199 and a light chain sequence of SEQ ID NO:229. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:200 and a light chain sequence of SEQ ID NO:230. In embodiments, the antibodyAttorney Docket No.: 048440-849001 WO includes a heavy chain sequence of SEQ ID NO:201 and a light chain sequence of SEQ ID NO:231. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:202 and a light chain sequence of SEQ ID NO:232. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:203 and a light chain sequence of SEQ ID NO:233. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:204 and a light chain sequence of SEQ ID NO:234. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:205 and a light chain sequence of SEQ ID NO:235. In embodiments, t the antibody includes a heavy chain sequence of SEQ ID NO:206 and a light chain sequence of SEQ ID NO:236. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:207 and a light chain sequence of SEQ ID NO:237. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:208 and a light chain sequence of SEQ ID NO:238. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:209 and a light chain sequence of SEQ ID NO:239. In embodiments, the antibody includes a heavy chain sequence of SEQ ID NO:210 and a light chain sequence of SEQ ID NO:240.

[0239] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the heavy chain sequences of SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, SEQ ID NO:262 or SEQ ID NO:264.

[0240] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the light chain sequences of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261 or SEQ ID NO:263.

[0241] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:248 and a light chain sequence of SEQ ID NO:247; a heavy chain sequence of SEQ ID NO:250 and a light chain sequence of SEQ ID NO:249; a heavy chain sequence of SEQ ID NO:252 and a light chain sequence of SEQ ID NO:251; a heavy chain sequence of SEQ ID NO:254 and a light chain sequence of SEQ ID NO:253; a heavy chain sequence of SEQ ID NO:256 and a light chain sequence of SEQ ID NO:255; a heavy chain sequence of SEQ ID NO:258 and a light chain sequence of SEQ ID NO:257; a heavy chain sequence of SEQ ID NO:260 and a light chainAttorney Docket No.: 048440-849001 WO sequence of SEQ ID NO:259; a heavy chain sequence of SEQ ID NO:262 and a light chain sequence of SEQ ID NO:261; or a heavy chain sequence of SEQ ID NO:264 and a light chain sequence of SEQ ID NO:263.

[0242] In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:248 and a light chain sequence of SEQ ID NO:247. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:250 and a light chain sequence of SEQ ID NO:249. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:252 and a light chain sequence of SEQ ID NO:251. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:254 and a light chain sequence of SEQ ID NO:253. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:256 and a light chain sequence of SEQ ID NO:255. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:258 and a light chain sequence of SEQ ID NO:257. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:260 and a light chain sequence of SEQ ID NO:259. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:262 and a light chain sequence of SEQ ID NO:261. In embodiments, the first antigen binding domain includes or a heavy chain sequence of SEQ ID NO:264 and a light chain sequence of SEQ ID NO:263.

[0243] In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:248 and a light chain sequence of SEQ ID NO:247. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:250 and a light chain sequence of SEQ ID NO:249. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:252 and a light chain sequence of SEQ ID NO:251. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:254 and a light chain sequence of SEQ ID NO:253. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:256 and a light chain sequence of SEQ ID NO:255. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:258 and a light chain sequence of SEQ ID NO:257. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:260 and a light chain sequence of SEQ ID NO:259. In embodiments, the second antigen binding domainAttorney Docket No.: 048440-849001 WO includes a heavy chain sequence of SEQ ID NO:262 and a light chain sequence of SEQ ID NO:261. In embodiments, the second antigen binding domain includes or a heavy chain sequence of SEQ ID NO:264 and a light chain sequence of SEQ ID NO:263.

[0244] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the heavy chain sequences of SEQ ID NO:265, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, SEQ ID NO:277, or SEQ ID NO:279. In embodiments, the first antigen binding domain and the second antigen binding domain are independently an scFv.

[0245] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the light chain sequences of SEQ ID NO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, SEQ ID NO:278, or SEQ ID NO:280. In embodiments, the first antigen binding domain and the second antigen binding domain are independently an scFv.

[0246] In embodiments, the first antigen binding domain and said second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:265 and a light chain sequence of SEQ ID NO:266; a heavy chain sequence of SEQ ID NO:267 and a light chain sequence of SEQ ID NO:268; a heavy chain sequence of SEQ ID NO:269 and a light chain sequence of SEQ ID NO:270; a heavy chain sequence of SEQ ID NO:271 and a light chain sequence of SEQ ID NO:272; a heavy chain sequence of SEQ ID NO:273 and a light chain sequence of SEQ ID NO:274; a heavy chain sequence of SEQ ID NO:275 and a light chain sequence of SEQ ID NO:276; a heavy chain sequence of SEQ ID NO:277 and a light chain sequence of SEQ ID NO:278; or a heavy chain sequence of SEQ ID NO:279 and a light chain sequence of SEQ ID NO:280. In embodiments, the first antigen binding domain and the second antigen binding domain are independently an scFv.

[0247] In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:265 and a light chain sequence of SEQ ID NO:266. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:267 and a light chain sequence of SEQ ID NO:268. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:269 and a light chain sequence of SEQ ID NO:270. InAttorney Docket No.: 048440-849001 WO embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:271 and a light chain sequence of SEQ ID NO:272. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:273 and a light chain sequence of SEQ ID NO:274. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:275 and a light chain sequence of SEQ ID NO:276. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:277 and a light chain sequence of SEQ ID NO:278. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:279 and a light chain sequence of SEQ ID NO:280. In embodiments, the first antigen binding domain is an scFv.

[0248] In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:265 and a light chain sequence of SEQ ID NO:266. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:267 and a light chain sequence of SEQ ID NO:268. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:269 and a light chain sequence of SEQ ID NO:270. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:271 and a light chain sequence of SEQ ID NO:272. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:273 and a light chain sequence of SEQ ID NO:274. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:275 and a light chain sequence of SEQ ID NO:276. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:277 and a light chain sequence of SEQ ID NO:278. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:279 and a light chain sequence of SEQ ID NO:280. In embodiments, the second antigen binding domain is an scFv.

[0249] In embodiments, the antibody is an scFv.

[0250] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the heavy chain sequences of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:293, SEQ ID NO:295, SEQ ID NO:297, SEQ ID NO:299, SEQ ID NO:301, SEQ ID NO: 303, or SEQ ID NO: 305. In embodiments, the first antigen binding domain and the second antigen binding domain are independently a humanized antibody. In embodiments, the firstAttorney Docket No.: 048440-849001 WO antigen binding domain and the second antigen binding domain are independently a humanized scFv.

[0251] In embodiments, the first antigen binding domain and the second antigen binding domain independently include one of the light chain sequences of SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, SEQ ID NO:288, SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:294, SEQ ID NO:296, SEQ ID NO:298, SEQ ID N0:300, SEQ ID NO:302, SEQ ID NO:304 or SEQ ID NO:306. In embodiments, the first antigen binding domain and the second antigen binding domain are independently a humanized antibody. In embodiments, the first antigen binding domain and the second antigen binding domain are independently a humanized scFv.

[0252] In embodiments, the first antigen binding domain and the second antigen binding domain independently include a heavy chain sequence of SEQ ID NO:281 and a light chain sequence of SEQ ID NO:282; a heavy chain sequence of SEQ ID NO:283 and a light chain sequence of SEQ ID NO:284; a heavy chain sequence of SEQ ID NO:285 and a light chain sequence of SEQ ID NO:286; a heavy chain sequence of SEQ ID NO:287 and a light chain sequence of SEQ ID NO:288; a heavy chain sequence of SEQ ID NO:289 and a light chain sequence of SEQ ID NO:290; a heavy chain sequence of SEQ ID NO:291 and a light chain sequence of SEQ ID NO:292; a heavy chain sequence of SEQ ID NO:293 and a light chain sequence of SEQ ID NO:294; a heavy chain sequence of SEQ ID NO:295 and a light chain sequence of SEQ ID NO:296; a heavy chain sequence of SEQ ID NO:297 and a light chain sequence of SEQ ID NO:298; a heavy chain sequence of SEQ ID NO:299 and a light chain sequence of SEQ ID NO: 300; a heavy chain sequence of SEQ ID NO:301 and a light chain sequence of SEQ ID NO: 302; a heavy chain sequence of SEQ ID NO: 303 and a light chain sequence of SEQ ID NO:304; or a heavy chain sequence of SEQ ID NO:305 and a light chain sequence of SEQ ID NO:306. In embodiments, the first antigen binding domain and the second antigen binding domain are independently a humanized antibody. In embodiments, the first antigen binding domain and the second antigen binding domain are independently a humanized scFv.

[0253] In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:281 and a light chain sequence of SEQ ID NO:282. In embodiments, the firstAttorney Docket No.: 048440-849001 WO antigen binding domain includes a heavy chain sequence of SEQ ID NO:283 and a light chain sequence of SEQ ID NO:284. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:285 and a light chain sequence of SEQ ID NO:286. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:287 and a light chain sequence of SEQ ID NO:288. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:289 and a light chain sequence of SEQ ID NO:290. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:291 and a light chain sequence of SEQ ID NO:292. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:293 and a light chain sequence of SEQ ID NO:294. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:295 and a light chain sequence of SEQ ID NO:296. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:297 and a light chain sequence of SEQ ID NO:298. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:299 and a light chain sequence of SEQ ID NO:300. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:301 and a light chain sequence of SEQ ID NO:302. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO: 303 and a light chain sequence of SEQ ID NO:304. In embodiments, the first antigen binding domain includes a heavy chain sequence of SEQ ID NO:305 and a light chain sequence of SEQ ID NO:306. In embodiments, the first antigen binding domain is a humanized antibody. In embodiments, the first antigen binding domain is a humanized scFv.

[0254] In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:281 and a light chain sequence of SEQ ID NO:282. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:283 and a light chain sequence of SEQ ID NO:284. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:285 and a light chain sequence of SEQ ID NO:286. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:287 and a light chain sequence of SEQ ID NO:288. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:289 and a light chain sequence of SEQ ID NO:290. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:291 and a light chain sequence of SEQ ID NO:292. In embodiments,Attorney Docket No.: 048440-849001 WO the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:293 and a light chain sequence of SEQ ID NO:294. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:295 and a light chain sequence of SEQ ID NO:296. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:297 and a light chain sequence of SEQ ID NO:298. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:299 and a light chain sequence of SEQ ID NO:300. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:301 and a light chain sequence of SEQ ID NO: 302. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO:303 and a light chain sequence of SEQ ID NO:304. In embodiments, the second antigen binding domain includes a heavy chain sequence of SEQ ID NO: 305 and a light chain sequence of SEQ ID NO:306. In embodiments, the second antigen binding domain is a humanized antibody. In embodiments, the second antigen binding domain is a humanized scFv.

[0255] In embodiments, the antibody is a humanized antibody. In embodiments, the antibody is a humanized scFv.

[0256] The antibodies provided herein including embodiments thereof may bind CD38 as a monoclonal antibody or as a biparatopic antibody. The antibodies may therefore bind CD38 such that both paratopes (e.g., first paratope and second paratope) or antigen binding domains (e.g., first antigen binding domain and second antigen binding domain) of the antibody bind the same epitope of CD38. Alternatively, the antibody may include a first paratope binding a first epitope of CD38 and a second paratope binding a second epitope of CD38, wherein the first epitope and the second epitope are different (not the same). Where the first epitope and the second epitope are different, the first and the second epitope include amino acid sequences that are not the same. The first epitope and the second epitope may overlap. Where the first epitope and the second epitope overlap, a portion of the amino acid sequence of the first epitope may be same as a portion of the amino acid sequence of the second epitope with the remainder of amino acid sequence of the first epitope and the remainder of the amino acid sequence of the second epitope being different (e.g., a difference in the sequence identity of at least 5% or more). In embodiments, the antibody is capable of binding to CD38. In embodiments, the first antigen binding domain binds a first epitope of CD38 and the second antigen binding domain binds aAttorney Docket No.: 048440-849001 WO second epitope of CD38. In embodiments, the first epitope of CD38 and the second epitope of CD38 are different. In embodiments, the first antigen binding domain and the second antigen binding domain are the same. Therefore, in embodiments, the first antigen binding domain and the second antigen binding domain bind the same epitope of CD38. Where the first antigen binding domain and the second antigen binding domain bind the same epitope of CD38, the amino acid sequence of the first epitope and the amino acid sequence of the second epitope are the same (e.g., 100% identical over the entire contiguous amino acid sequence).

[0257] In embodiments, the first antigen binding domain includes: (i) a first heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO:7, a CDR H2 as set forth in SEQ ID NO: 8 and a CDR H3 as set forth in SEQ ID NO: 9; and (ii) a first light chain variable domain including a CDR LI as set forth in SEQ ID NO:97, a CDR L2 as set forth in SEQ ID NO: 98, and a CDR L3 as set forth in SEQ ID NO: 99; and the second antigen binding domain includes: (iii) a second heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO:85, a CDR H2 as set forth in SEQ ID NO:86 and a CDR H3 as set forth in SEQ ID NO:87; and (iv) a second light chain variable domain including a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177.

[0258] In embodiments, the first antigen binding domain includes a first heavy chain including the sequence of SEQ ID NO: 183 and a first light chain including the sequence of SEQ ID NO:213; and the second antigen binding domain includes a second heavy chain including the sequence of SEQ ID NO:209 and a second light chain including the sequence of SEQ ID NO:239.

[0259] In embodiments, the first antigen binding domain includes: (i) a first heavy chain variable domain including a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and (ii) a first light chain variable domain including a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2; and the second antigen binding domain includes: (iii) a second heavy chain variable domain, wherein the second heavy chain variable domain includes a daratumumab heavy chain variable domain; and (iv) a second light chain variable domain,Attorney Docket No.: 048440-849001 WO wherein the second light chain variable domain includes a daratumumab light chain variable domain.

[0260] In embodiments, the first antigen binding domain includes: (i) a first heavy chain variable domain including a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and (ii) a first light chain variable domain including a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2; and the second antigen binding domain includes: (iii) a second heavy chain variable domain, wherein the second heavy chain variable domain is a daratumumab heavy chain variable domain; and (iv) a second light chain variable domain, wherein the second light chain variable domain is a daratumumab light chain variable domain.

[0261] In embodiments, the second antigen binding domain includes: (iii) a second heavy chain variable domain including a daratumumab CDR Hl sequence, a daratumumab CDR H2 sequences and a daratumumab CDR H3 sequences; and (iv) a second light chain variable domain including a daratumumab CDR LI sequences, a daratumumab CDR L2 sequence and a daratumumab CDR L3 sequence.

[0262] In embodiments, the first antigen binding domain includes: (i) a first heavy chain including one of the heavy chain sequences of SEQ ID NO: 181-210; and (ii) a first light chain including one of the light chain sequences of SEQ ID NO:211-240; and the second antigen binding domain includes: (iii) a second heavy chain, wherein the second heavy chain includes a daratumumab heavy chain; and (iv) a second light chain, wherein the second light chain includes a daratumumab light chain. In embodiments, the first antigen binding domain includes: (i) a first heavy chain including one of the heavy chain sequences of SEQ ID NO: 181-210; and (ii) a first light chain including one of the light chain sequences of SEQ ID NO:211-240; and the second antigen binding domain includes: (iii) a second heavy chain, wherein the second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein the second light chain is a daratumumab light chain.

[0263] In embodiments, the first antigen binding domain includes (i) a first heavy chain including one of the heavy chain sequences of SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, SEQ IDAttorney Docket No.: 048440-849001 WONO:262 or SEQ ID NO:264; and (ii) a first light chain including one of the light chain sequences of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261 or SEQ ID NO:263; and the second antigen binding domain includes: (iii) a second heavy chain, wherein the second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein the second light chain is a daratumumab light chain.

[0264] In embodiments, the first antigen binding domain includes (i) a first heavy chain including one of the heavy chain sequences of SEQ ID NO:265, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, SEQ ID NO:277, or SEQ ID NO:279; and (ii) a first light chain including one of the light chain sequences of SEQ ID NO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, SEQ ID NO:278, or SEQ ID NO:280; and the second antigen binding domain includes:(iii) a second heavy chain, wherein the second heavy chain is a daratumumab heavy chain; and(iv) a second light chain, wherein the second light chain is a daratumumab light chain.

[0265] In embodiments, the first antigen binding domain includes: (i) a first heavy chain including one of the heavy chain sequences of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:293, SEQ ID NO:295, SEQ ID NO:297, SEQ ID NO:299, SEQ ID NO:301, SEQ ID NO:303, or SEQ ID NO: 305; and (ii) a first light chain including one of the light chain sequences of SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, SEQ ID NO:288, SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:294, SEQ ID NO:296, SEQ ID NO:298, SEQ ID NO:300, SEQ ID NO: 302, SEQ ID NO: 304 or SEQ ID NO: 306; and the second antigen binding domain includes:(iii) a second heavy chain, wherein the second heavy chain is a daratumumab heavy chain; and(iv) a second light chain, wherein the second light chain is a daratumumab light chain.

[0266] In embodiments, the antibody is a humanized antibody, a Fab’ fragment, or a chimeric antibody. In embodiments, the antibody is a humanized antibody. In embodiments, the anti- CD38 is a Fab’ fragment. In embodiments, the antibody is a chimeric antibody. In embodiments, the antibody includes a fragment crystallizable (Fc) domain.Attorney Docket No.: 048440-849001 WO

[0267] In embodiments, the Fc domain includes an effector cell inhibiting substitution. In the presence of an effector cell inhibiting substitution the binding of the Fc domain to the effector cell ligand decreases activation of an effector cell relative to the absence of said substitution. In embodiments, the binding of the Fc domain to the effector cell ligand results in substantially no activation of an effector cell relative to the absence of said substitution. In embodiments, the Fc domain includes: (i) a N297G substitution, a R292C substitution, a V302C substitution or a combination thereof. In embodiments, the Fc domain includes a N297G substitution, a R292C substitution, a V302C substitution or a combination thereof. In embodiments, the Fc domain includes a N297G substitution. In embodiments, the Fc domain includes a R292C substitution. In embodiments, the Fc domain includes a V302C substitution. In embodiments, the antibody including inhibiting substitutions is referred to as an FcSTR including antibody. STR refers to a combination of three substitutions in the CH2 domain of the Fc to obtain minimal binding to Fc receptors and Clq.

[0268] In embodiments, the antibody is a monoclonal antibody. A monoclonal antibody as provided herein includes a first antigen binding domain and a second antigen binding domain, wherein the first and second antigen binding domain include the same heavy chain variable domain and the same light chain variable domain. In embodiments, the monoclonal antibody binds CD38 with the equilibrium dissociation constants (KD) described in this paragraph. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 900 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 800 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 700 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 600 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 500 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 400 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 300 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 200 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 100 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 90 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 80 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 70 nM to about 0.1 nM. InAttorney Docket No.: 048440-849001 WO embodiments, the antibody binds CD38 with a KD of about 60 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 50 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 40 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 30 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 20 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 10 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 9 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 8 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 7 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 6 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 5 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 4 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 3 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 2 nM to about 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 0.1 nM.

[0269] In embodiments, the monoclonal antibody binds CD38 with the equilibrium dissociation constants (KD) described in this paragraph. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 2 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 3 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 4 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 5 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 6 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 7 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 8 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 9 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 10 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 20 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 30 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 40 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 50 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 60 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 70 nM. InAttorney Docket No.: 048440-849001 WO embodiments, the antibody binds CD38 with a KD of about 1 pM to about 80 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 90 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 100 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 200 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 300 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 400 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 500 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 600 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 700 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 800 nM. In embodiments, the antibody binds CD38 with a KD of about 1 pM to about 900 nM.

[0270] In embodiments, the monoclonal antibody binds CD38 with the equilibrium dissociation constants (KD) described in this paragraph. In embodiments, the antibody binds CD38 with a KD of 1 pM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 900 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 800 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 700 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 600 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 500 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 400 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 300 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 200 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 100 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 90 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 80 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 70 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 60 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 50 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 40 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 30 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 20 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 10 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 9 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 8 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 7 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 6 nM to 0.1 nM. InAttorney Docket No.: 048440-849001 WO embodiments, the antibody binds CD38 with a KD of 5 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 4 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 3 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of about 2 nM to 0.1 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 0.1 nM.

[0271] In embodiments, the monoclonal antibody binds CD38 with the equilibrium dissociation constants (KD) described in this paragraph. In embodiments, the antibody binds CD38 with a KD of 1 pM to 2 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 3 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 4 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 5 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 6 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 7 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 8 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 9 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 10 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 20 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 30 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 40 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 50 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 60 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 70 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 80 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 90 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 100 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 200 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 300 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 400 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 500 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 600 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 700 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 800 nM. In embodiments, the antibody binds CD38 with a KD of 1 pM to 900 nM.

[0272] In embodiments the antibody is attached to a therapeutic moiety or a diagnostic moiety. In embodiments, the antibody is attached to a therapeutic moiety. In embodiments the antibody is attached to a diagnostic moiety. In embodiments, the therapeutic moiety is a cytotoxic moietyAttorney Docket No.: 048440-849001 WO(i.e., a moiety including a cytotoxin). Non-limiting examples of cytotoxins include, for example, microtubule inhibitors (e.g. monomethyl auristatin E or MMAE), DNA damaging agents, or RNA polymerase II inhibitors (e.g., aminitin).

[0273] A "variable light chain (VL) domain" as provided herein refers to the variable region of the light chain of an antibody, an antibody variant or fragment thereof. Likewise, the "variable heavy chain (VH) domain" as provided herein refers to the variable region of the heavy chain of an antibody, an antibody variant or fragment thereof. As described above, the variable light chain domain and the variable heavy chain domain together form the paratope, which binds an antigen (epitope). The paratope or antigen-binding site is formed at the N-terminus of an antibody, an antibody variant or fragment thereof. In embodiments, the variable light chain (VL) domain includes CDR LI, CDR L2, CDR L3 and FR LI, FR L2, FR L3 and FR L4 (framework regions) of an antibody light chain. In embodiments, the variable heavy chain (VH) domain includes CDR Hl, CDR H2, CDR H3 and FR Hl, FR H2, FR H3 and FR H4 (framework regions) of an antibody heavy chain.

[0274] The terms "CDR L1", "CDR L2" and "CDR L3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody or fragment thereof. In embodiments, the variable light chain includes in N-terminal to C-terminal direction a CDR LI, a CDR L2 and a CDR L3. Likewise, the terms "CDR Hl", "CDR H2" and "CDR H3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody or fragment thereof. In embodiments, the variable heavy chain includes in N-terminal to C-terminal direction a CDR Hl, a CDR H2 and a CDR H3.

[0275] "Framework regions" (FRs) are variable region residues other than the CDR residues. The FRs of VH are also referred to herein as FR Hl, FR H2, FR H3 and FR H4, respectively, wherein FR Hl corresponds to FR 1 of VH, FR H2 corresponds to FR 2 of VH, FR H3 corresponds to FR 3 of VH and FR H4 corresponds to FR 4 of VH. Likewise, the FRs of VL are referred to herein as FR LI, FR L2, FR L3 and FR L4, respectively, wherein FR LI corresponds to FR 1 of VL, FR L2 corresponds to FR 2 of VL, FR L3 corresponds to FR 3 of VL and FR L4 corresponds to FR 4 of VL.Attorney Docket No.: 048440-849001 WO

[0276] In embodiments, the variable light chain (VL) domain and a constant light chain (CL) domain form part of an antibody light chain. In embodiments, the variable heavy chain (VH) domain and a constant heavy chain (CHI) domain form part of an antibody heavy chain. In embodiments, the variable heavy chain (VH) domain and one or more constant heavy chain (CHI, CH2, or CH3) domains form part of an antibody heavy chain. In embodiments, the variable light chain (VL) domain forms part of an antibody fragment. In embodiments, the variable heavy chain (VH) domain forms part of an antibody fragment. In embodiments, the variable light chain (VL) domain forms part of an antibody variant. In embodiments, the variable heavy chain (VH) domain forms part of an antibody variant. In embodiments, the variable light chain (VL) domain forms part of a Fab. In embodiments, the variable heavy chain (VH) domain forms part of a Fab. In embodiments, the variable light chain (VL) domain forms part of a biparatopic Fab. In embodiments, the variable heavy chain (VH) domain forms part of a biparatopic Fab. In embodiments, the variable light chain (VL) domain forms part of a scFv. In embodiments, the variable heavy chain (VH) domain forms part of a scFv.ANTIBODY DRUG CONJUGATES

[0277] The antibody compositions provided herein may be used, inter alia, for therapeutic or diagnostic purposes by conjugation to a therapeutic moiety or a diagnostic (detectable) moiety, respectively. Thus, any of the antibody compisitions provided herein may be attached to a therapeutic moiety thereby forming an antibody-drug conjugate (ADC).

[0278] In an aspect is provided an anti-CD38 antibody including (i) a heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3, and (ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO:92, and a CDR L3 as set forth in SEQ ID NO:93. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 181 and the light chain variable domain includes the sequence of SEQ ID NO:211. In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO:247 and wherein the heavy chain includes the sequence of SEQ ID NO:248. In embodiments, the anti-CD38 antibody is referred to as Abl, CD38-1, antiCD38 Ab 1 or scFv 1.Attorney Docket No.: 048440-849001 WO

[0279] In another aspect is provided an anti-CD38 antibody including (i) a heavy chain variable domain including a CDR Hl as set forth in SEQ ID NO: 85, a CDR H2 as set forth in SEQ ID NO: 86 and a CDR H3 as set forth in SEQ ID NO: 87, and (ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:209 and the light chain variable domain includes the sequence of SEQ ID NO:239. In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO:263 and wherein the heavy chain includes the sequence of SEQ ID NO:264. In embodiments, the anti- CD38 antibody is referred to as Ab48, CD48-1, antiCD38 Ab 48 or scFv 48.

[0280] The anti-CD38 antibodies provided herein may include one or more amino substitutions that improve the affinity of the antibody to CD38 relative to the absence of the one or more substitutions. In embodiments, the antibody includes an aspartic acid or a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248, or a combination thereof. In embodiments, the antibody includes an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248. In embodiments, the antibody includes a serine at a position corresponding to position 27 of SEQ ID NO:248. In embodiments, the antibody includes a serine at a position corresponding to position 29 of SEQ ID NO:248. In embodiments, the antibody includes an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248. In embodiments, the antibody includes a serine at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248.

[0281] In embodiments, the antibody includes a lysine at a position corresponding to position 50 of SEQ ID NO:247. In embodiments, the antibody includes a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247. In embodiments, the antibody is referred to as Abl AM. In embodiments, the antibody has an improved melting temperature compared to an antibody including a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO:247 and wherein the heavy chain includes the sequence of SEQ ID NO:248. InAttorney Docket No.: 048440-849001 WO embodiments, the improved melting temperature is increased relative to the melting temperature of the antibody including a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO:247 and wherein the heavy chain includes the sequence of SEQ ID NO:248. In embodiments, the increased temperature is by at least 2 “Celsius.

[0282] In embodiments, the antibody includes a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247. In embodiments, the antibody includes an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

[0283] In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO: 263 and wherein the heavy chain includes the sequence of SEQ ID NO:264.

[0284] The antibody provided herein may be a Fab or an IgG or an affinity matured Fab or affinity matured IgG. In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO: 308 and wherein the heavy chain includes the sequence of SEQ ID NO:307.

[0285] In embodiments, the antibody includes an arginine at a position corresponding to position 44 of SEQ ID NO:264, a phenylalanine at a position corresponding to position 45 of SEQ ID NO:264, a glutamine at a position corresponding to position 76 of SEQ ID NO:264, a threonine at a position corresponding to position 23 of SEQ ID NO:264, an asparagine at a position corresponding to position 30 of SEQ ID NO:264, a leucine at a position corresponding to position 112 of SEQ ID NO:264, or a combination thereof. In embodiments, the antibody includes an isoleucine at a position corresponding to position 32 of SEQ ID NO:263, an isoleucine at a position corresponding to position 50 of SEQ ID NO:263, a leucine at a position corresponding to position 29 of SEQ ID NO:263, or a combination thereof. In embodiments, the antibody is referred to as Ab48 AM.

[0286] In embodiments, the antibody is a humanized antibody. In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQAttorney Docket No.: 048440-849001 WOID N0:310 and wherein the heavy chain includes the sequence of SEQ ID NO:309. In embodiments, the antibody is referred to herein as hu Fab l AM _6nov.

[0287] In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO: 312 and wherein the heavy chain includes the sequence of SEQ ID NO:311. In embodiments, the antibody is referred to herein as hu Fab_l_AM _2qqn.

[0288] In embodiments, the antibody includes a meditope binding site. The anti-CD38 antibodies provided herein may be modified to include amino acid substitutions in the FR region (excluding CDRs) to be able to bind a peptide compound referred to herein as “meditope. This process of modification is also referred to herein as “meditope-enabled” or “meditope- enablement.” A meditope enabled antibody is capable of binding (non-covalently or covalently) to a peptide compound provided herein also referred to as “meditope.” The peptide compound provided herein may include or be a peptidyl moiety also referred to herein as “meditope.” Any of the meditopes and meditope-binding sites described in WO 2013 / 055404, or WO / 2018 / 106842, which are incorporated herein in their entirety and for all purposes, may be used for the compositions or methods provided herein. The modified antibodies as described herein, including embodiments thereof, may be referred to herein, for as “meditope-enabled (me) antibodies.” In embodiments, the meditope-enabled antibody is a monoclonal antibody (memAb). In embodiments, the meditope-enabled antibody is a humanized antibody. In embodiments, the Fab region of an antibody may be meditope enabled. In embodiments, the meditope-enabled antibody is a Fab. The term “meditope” as used herein refers to a peptidyl moiety included in the peptide compound as described herein. Thus, in embodiments, a meditope is a peptidyl moiety.

[0289] Meditope-enabled antibodies allow for the binding (e.g., covalent, non-covalent) of peptidyl moieties to a region in the Fab portion of the antibody without negatively influencing antibody binding site behavior. For example, a meditope bound to a meditope-enabled antibody does not interfere with the binding of the antibody to its antigen. The meditope binding site of an antibody does not include residues of the CDRs of the antibody. The peptidyl moieties (also referred to herein as meditopes) may be functionalized. For example, the peptidyl moieties may be conjugated to therapeutic or diagnostic agents through a covalent linker (e.g., using, forAttorney Docket No.: 048440-849001 WO example, suitable reactive groups and click chemistry). A functionalized peptidyl moiety may be referred to herein as a peptide compound. The ability of the antibody to bind (covalently, non- covalently) a peptide compound endows the meditope-enabled antibody with the functionality to simultaneously target its specific antigen via its antibody binding site and deliver a therapeutic or diagnostic agent.

[0290] The antibodies contemplated herein are anti-CD38 antibodies that include a Fab domain capable of binding (e.g., covalently, non-covalently) a peptidyl moiety (meditope), where the peptidyl moiety (meditope) may be further conjugated to one or multiple ligands (e.g., a diagnostic or a therapeutic agent / moiety).

[0291] In embodiments, the antibody is attached to a therapeutic or a diagnostic moiety. In embodiments, the antibody is attached to a therapeutic. In embodiments, the antibody is attached to a diagnostic moiety. In embodiments, the antibody is non-covalently or covalently bound to a peptide-compound. In embodiments, the antibody is non-covalently bound to a peptide- compound. In embodiments, the antibody is covalently bound to a peptide-compound. In embodiments, the antibody is non-covalently or covalently bound to a meditope. In embodiments, the antibody is non-covalently bound to a meditope. In embodiments, the antibody is covalently bound to a meditope.

[0292] The term "peptidyl" and "peptidyl moiety" refers to a peptide attached to the remainder of a molecule. A peptidyl moiety may be substituted with a chemical linker that serves to attach the peptidyl moiety to a molecule. The peptidyl moiety may also be substituted with additional chemical moieties (e.g., additional R substituents). The term “meditope” as used herein refers to a peptidyl moiety included in the peptide compound as described herein. Thus, in embodiments, a meditope is a peptidyl moiety.

[0293] The peptidyl moiety (e.g., meditope) may be a linear or a cyclic peptide moiety. Various methods for cyclization of a peptide moiety may be used, e.g., to address in vivo stability and to enable chemo-selective control for subsequent conjugation chemistry. In some embodiments, the cyclization strategy is a lactam cyclization strategy, including head-to-tail (head-tail) lactam cyclization (between the terminal residues of the acyclic peptide) and / or lactam linkage between other residues. Lactam formation may also be affected by incorporatingAttorney Docket No.: 048440-849001 WO residues such as glycine, P-Ala, and / or 7-aminoheptanoic acid, and the like, into the acyclic peptide cyclization precursors to produce different lactam ring sizes and modes of connectivity. Additional cyclization strategies such as “click” chemistry and olefin metathesis also can be used. Such methods of peptide and peptidomimetic cyclization are well known in the art. In embodiments, the peptidyl moiety (e.g., meditope) is a linear peptidyl moiety (e.g., linear meditope). In embodiments, the peptidyl moiety (e.g., meditope) is a cyclic peptidyl moiety (e.g., cyclic meditope).

[0294] The term "peptide compound" refers to a compound including a peptidyl portion. In embodiments, the peptide compound includes a peptide or peptidyl moiety directly (covalently) or indirectly (non-covalently) attached to one or more chemical substituents. In embodiments, the peptide compound includes a peptidyl moiety. In embodiments, the peptide compound is a compound as described in WO 2013 / 055404 or WO 2019 / 028190. Thus, the compounds provided herein may include a non-covalent linker including a peptidyl moiety, wherein the peptidyl moiety is a meditope. In embodiments, the chemical linker is a non-covalent peptidyl linker including a meditope. In embodiments, the chemical linker is a covalent peptidyl linker including a meditope.

[0295] In embodiments, the antigen binding domain of the anti-CD38 antibody includes a central cavity formed by a heavy chain variable (VH) domain, a light chain variable (VL) domain, a heavy chain constant domain (CH) and a light chain constant domain (CL), and wherein the central cavity forms a peptide binding site including framework domain amino acid residues. Thus, the antibody provided herein may include a meditope binding site.

[0296] In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO: 316 and wherein the heavy chain comprises the sequence of SEQ ID NO:315. In embodiments the antibody is referred to herein as meditope enabl ed_v 1 _huF ab_ 1 _AM_6nov .

[0297] In embodiments, the antibody includes a light chain and a heavy chain, wherein the light chain includes the sequence of SEQ ID NO: 318 and wherein the heavy chain includes the sequence of SEQ ID NO:317. In embodiments the antibody is referred to herein as meditope_enabled_v2_huFab_l_AM_6nov.Attorney Docket No.: 048440-849001 WO

[0298] In embodiments, the antibody is bound to a meditope.

[0299] In embodiments, the antibody is a chimeric antibody. In embodiments, the antibody is a Fab' fragment. In embodiments, the antibody is a single chain antibody (scFv). In embodiments, the antibody is an IgG. In embodiments, the antibody comprises a fragment crystallizable (Fc) domain. In embodiments, the Fc domain includes aN297G substitution, a R292C substitution, a V302C substitution or a combination thereof. In embodiments, the Fc domain includes a F405L substitution or K409R substitution, or a combination thereof.

[0300] In embodiments, the antibody is attached to a therapeutic moiety or a diagnostic moiety. In embodiments, the antibody is attached to the therapeutic moiety or the diagnostic moiety through a chemical linker. In embodiments, the linker is attached to the antibody by click chemistry. In embodiments, the linker is a covalent linker. In embodiments, the linker is a cleavable linker. The linker may be attached to a lysine or a cysteine of the antibody. The linker may include a spacer. In embodiments, the linker is an enzyme-liable linker. In embodiments, the linker is a cathepsin cleavable linker. In embodiments, the linker is a pH sensitive (acid- liable) linker. In embodiments, the linker is a redox-liable linker. In embodiments, the linker includes a hydrophilicity domain. In embodiments, the hydrophilicity domain is a PEG domain. Any of the linkers and payloads described in ChemMedChem 2025, 20, e202500262, which is hereby incorporate in its entirety and for all purposes, may be used for the antibody compositions provided herein including embodiments thereof.

[0301] In embodiments, the linker includes DBCO-PEG4-Val-Cit-PAB. In embodiments, the linker includes a therapeutic moiety. The therapeutic moiety may be a microtubule inhibitor. In embodiments, the linker is DBCO-PEG4-Val-Cit-PAB-MMAE. In embodiments, the linker is DBCO-PEG4-Val-Cit-PAB-MMAF. Val-Cit-PAB-MMAE as provided herein refers in a customary sense to a linker peptide identified by Cas Reg. No. 644981-35-1. In embodiments, the linker includes a therapeutic moiety and is DBCO-PEG4-Val-Cit-PAB-MMAF. In embodiments, the therapeutic moiety is MMAE. MMAE as provided herein refers in a customary sense to monomethyl auristatin E identified by CAS Reg. No.: 474645-27-7. In embodiments, the therapeutic moiety is MMAF. MMAF as provided herein refers in a customary sense to monomethyl auristatin F identified by CAS Reg. No.: 745017-94-1.Attorney Docket No.: 048440-849001 WO

[0302] In embodiments, the therapeutic moiety includes an anti-cancer agent. In embodiments, the therapeutic moiety is a cytotoxic moiety. In embodiments, the cytotoxic moiety is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

[0303] In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of less than 520 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 15 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 20 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 25 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 30 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 35 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 40 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 45 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 15 nM, 20 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, or 50 nM.

[0304] In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 15 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 20 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 25 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 30 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 35 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 40 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 50 nM to 45 nM. In embodiments, the antibody is capable ofAttorney Docket No.: 048440-849001 WO binding a CD38 protein with an equilibrium dissociation constant (KD) of 15 nM, 20 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, or 50 nM.

[0305] In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 25 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 21 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 22 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 31 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 32 nM.

[0306] In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 25 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 21 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 22 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 31 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 32 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 25.3 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 31.7 nM. In embodiments, the antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of 21.7 nM.

[0307] In an aspect is provided a nucleic acid composition including a sequence encoding the antibody provided herein including embodiments thereof.

[0308] In another aspect an expression vector including the nucleic acid provided herein including embodiments is provided. In embodiments, the expression vector is a viral vector.

[0309] In an aspect is provided a pharmaceutical composition including a therapeutically effective amount of an antibody provided herein including embodiments thereof and a pharmaceutically acceptable excipient.Attorney Docket No.: 048440-849001 WO

[0310] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to a subject a therapeutically effective amount of an antibody provided herein including embodiments thereof. In embodiments, the cancer is multiple myeloma.

[0311] In embodiments, the antibody is part of an antibody drug conjugate (ADC). In embodiments, the antibody is capable of binding to CD38 protein. In embodiments, the CD38 protein is expressed on the cell surface. In embodiments, the cell is a cancer cell.PHARMACEUTICAL COMPOSITIONS

[0312] In an aspect is provided a pharmaceutical composition including a therapeutically effective amount of an antibody as disclosed herein including embodiments thereof and a pharmaceutically acceptable excipient.METHODS OF TREATMENT

[0313] The compositions provided herein, including embodiments thereof, are contemplated as providing effective treatments for diseases such as cancer. Thus, in an aspect is provided a method of treating cancer in a subject in need thereof. The method includes administering to a subject a therapeutically effective amount of an antibody provided herein, including embodiments thereof. In embodiments, the cancer is a CD38-expressing cancer. A “CD38- expressing cancer” as provided herein includes any cancer wherein the subject suffering from the cancer has one or more cancer cells that express CD38. In embodiments, the cancer is multiple myeloma.

[0314] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.Attorney Docket No.: 048440-849001 WOEXAMPLES

[0315] We have identified a set of novel anti-CD38 monoclonal antibodies which allow for the manufacture of biparatopic monoclonal antibodies. These monoclonal antibodies enhance binding and internalization, allowing them to deliver, for example, cytotoxins such as radionuclides. Moreover, we have created Fc-silenced monoclonal antibodies to avoid liver accumulation. The combination of Fc-silencing, biparatopic antibodies with potent toxins addresses the significant unmet medical need.Example 1: Anti-CD38 antibody and Fab’ fragment binding to CD38 in vitro

[0316] Anti-CD38 antibody binding to CD38 was assessed using surface plasmon resonance (SPR). Human CD38 protein was immobilized on a CM5 chip at a density of 1000 RU though EDC / NHS coupling. The anti-CD38 antibodies CD38-1, CD38-6, CD38-17, CD38-23, CD38- 25, CD38-27, CD38-40, CD38-48, and daratumumab were prepared in HBS-EP+running buffer and were injected at concentrations of 0 nM, 3 nM, 10 nM, 30 nM and 100 nM at 25 °C (FIGS 3A-3C).

[0317] In a separate set of experiments, cynomolgus monkey CD38 protein was immobilized on a CM5 chip at a density of 1000 RU through EDC / NHS coupling. The anti-CD38 antibodies CD38-1, CD38-6, CD38-17, CD38-23, CD38-25, CD38-27, CD38-40, CD38-48, and daratumumab were prepared in HBS-EP+running buffer and were injected at concentrations of 0 nM, 3 nM, 10 nM, 30 nM and 100 nM at 25 °C (FIGS 4A-4C).

[0318] Human CD38 protein was immobilized on a CM5 chip at a density of 1000 RU through EDC / NHS coupling. The anti-CD38 Fab’ fragments CD38-1, CD38-6, CD38-17, CD38-23, CD38-25, CD38-27, CD38-40, CD38-48, and daratumumab were prepared in HBS-EP+running buffer and were injected at concentrations of 0 nM, 3 nM, 10 nM, 30 nM and 100 nM at 25 °C (FIGS 5A-5C).

[0319] The CD38-6 Fab’ was immobilized on a CM5 chip at a density of 200 RU through EDC / NHS coupling. Human CD38 protein was prepared in HBS-EP+running buffer and was injected at a concentration of 100 nM at 25 °C (FIGS. 7A-7B). The anti-CD38 Fab’ fragments CD38-1, CD38-6, CD38-23, CD38-25, CD38-34, and CD38-48 were prepared in HBS-EP+running buffer. Following the injection of the CD38 protein, these Fab’ fragments were injected at a concentration of 100 nM at 25 °C (FIGS. 7A-7B). The experiments demonstrate dual binding of two anti-CD38 Fab’ fragments to a single CD38 protein (FIGS. 7A-7B).Attorney Docket No.: 048440-849001 WOExample 2: Anti-CD38 antibody-induced cytotoxicity of multiple myeloma cells

[0320] Peripheral blood mononuclear cells (PMBCs) from a human donor (effector) were cocultured with MM1. S GFP cells (target) at an effector-to-target ratio of 8 : 1. The culture was treated for 16 hours with IgG, daratumumab (DARA), CD38-1, CD38-6, CD38-17, CD38-23, CD38-25, CD38-27, CD38-34, CD38-40, or CD38-48 (10 pg / ML concentration for each). After the 16-hour incubation, cytotoxicity was assessed as a percentage of 7-AAD fluorescence. The experiment was repeated in triplicates. FIGS. 8A-8B shows experimental results from these experiments.

[0321] In a separate set of experiments, Natural Killer (NK) cells from a human donor (effector) were co-cultured with MM1. S GFP cells (target) at an effector-to-target ratio of 8 : 1. The culture was treated for 4 hours with IgG, daratumumab (DARA), CD38-1, CD38-6, CD38- 17, CD38-23, CD38-25, CD38-27, CD38-34, CD38-40, or CD38-48 (10 pg / ML concentration for each). After the 4-hour incubation, cytotoxicity was assessed as a percentage of 7-AAD fluorescence. The experiment was repeated in triplicates. FIGS. 9A-9B show experimental results from these experiments.Example 3: Antibody labeling to AF647 results (glyco-conjugation method)

[0322] Antibodies can be conjugated to payloads through modification of native glycans on the Fc region. Antibodies were conjugated to AF647 using the SiteClick™ Antibody Azido Modification Kit. Nanodrop was used to measure concentration and degree of labeling (DOL).Dye AF-647 F-6 AF-6A280 0.68 0.78 0.64A650 1.2 1.3 1.1 mg / 0.46 0.53 0.43DOL1.41.41.5Attorney Docket No.: 048440-849001 WOINFORMAL SEQUENCE LISTING

[0323] TABLE 1. CDR sequences of exemplary antibody heavy chains.Attorney Docket No.: 048440-849001 WOAttorney Docket No.: 048440-849001 WO

[0324] TABLE 2. CDR sequences of exemplary antibody light chains.Attorney Docket No.: 048440-849001 WOAttorney Docket No.: 048440-849001 WOAttorney Docket No.: 048440-849001 WO

[0325] TABLE 3. Exemplary sequences of variable heavy and variable light chain domains of antibodies provided hereinAttorney Docket No.: 048440-849001 WO

[0326] TABLE 4. Heavy and light chains for anti-CD38 antibodies.Attorney Docket No.: 048440-849001 WO

[0327] Heavy and light chain sequences of exemplary anti-CD38 antibodies

[0328] antiCD38 Ab 1 Light Chain - SEQ ID NO:247:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0329] antiCD38 Ab 1 Heavy Chain - SEQ ID NO:248:QVQLQQPGTELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI<Attorney Docket No.: 048440-849001 WOTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0330] antiCD38 Ab 6 Light Chain- SEQ ID NO:249:DVVMTQTPLTLSVTIGQPASISCKSSQSLLYSNGKTYLNWLLQRPGQSPKRLISLVSKLDSGIPDRFTGSGSGTVFTLKISRVEAEDLGVYYCVQGTHFPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0331] antiCD38 Ab 6 Heavy Chain- SEQ ID NO:250:QIQLVQSGPELKKPGETVKISCKASGYTFTDFGMNWVKQAPGKGLQWMGWINTYTGEPTYVDDFKGRFAFSLETSASTAYLQINNLKNEDRATYFCTREVDLDSWGQGTTLTVSTASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0332] antiCD38 Ab 17 Light Chain- SEQ ID NO:251 :DVVMTQTPLTLSVTIGQPAAISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPQTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0333] antiCD38 Ab 17 Heavy Chain- SEQ ID NO:252:EVQLQQSGAELVRSGASVKLSCTASGFNIKDLYMQWMKQRPEQGLEWIGWIDPENGDTEYAPKFQGKATLTADTSSNTASLQLSSLTSEDTAVYYCKGGTGFEYAMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAAttorney Docket No.: 048440-849001 WOKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0334] antiCD38 Ab 23 Light Chain- SEQ ID NO:253 :DVVMTQTPLTLSVTIGQPASISCTSSQSLLYSNGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPYTFGGGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0335] antiCD38 Ab 23 Heavy Chain- SEQ ID NO:254:QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSASTAYLQINNLKNEDTATYFCARGGNYEDAIDYWGQGTSLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0336] antiCD38 Ab 25 Light Chain- SEQ ID NO:255:DIQMTQSPASLSASVGETVTITCRVSGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWTTPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0337] antiCD38 Ab 25 Heavy Chain- SEQ ID NO:256:QVQLKESGPGLVAPSQSLSITCTVSGFSLTGYGVNWVRQPPGKGLEWLGMIWGDGSTDFNSPLKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCARARDGDLGFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAAttorney Docket No.: 048440-849001 WOKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0338] antiCD38 Ab 27 Light Chain- SEQ ID NO:257:DVVMTQSPATLSVTPGDSVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPLTFGAGTKLELKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0339] antiCD38 Ab 27 Heavy Chain- SEQ ID NO:258:EVQLQQSGAELVRPGALVKLSCKPSGFNIDDYYMHWVKQRPEQGLEWIGWIDPENGNTRYDPKFQGKASITSDTSSNTAYLQLSSLTSEDTAVYYCARGWLPLYYAMDYWGQ GTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0340] antiCD38 Ab 34 Light Chain- SEQ ID NO:259:DVVMTQTPLTLSVTIGQPASISCKSRQSLLYSNGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPYTFGGGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0341] antiCD38 Ab 34 Heavy Chain- SEQ ID NO:260:EVKLVESGGGLVQPGGSLRLSCATSGFTFSDFYMEWVRQPPGKRLEWIAASRNKANGYTTEYSASVRGRFIVSRDTSQSILYLQMNALRAEDTAIYYCTRETNWAFDYWGQG TTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAAttorney Docket No.: 048440-849001 WOKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0342] antiCD38 Ab 40 Light Chain- SEQ ID NO:261 :SIVMTQTPKFLLVSAGDRVTITCKASQSVKNDVAWYQQKPGQSPKLLIYFASNRYTGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYISPCTFGGGTKLEIERTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0343] antiCD38 Ab 40 Heavy Chain- SEQ ID NO:262:EVQLQQSGPELVKPGASVKMSCKASGYTFTDYYMKWVKQSHGKSLEWIGDINPNNGDTFYNQRFKGKATLTADKSSSTAYMQLNSLTSEDSAVYYCARGARAMGFYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI<TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0344] antiCD38 Ab 48 Light Chain- SEQ ID NO:263 :ENVLTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSSTSPKLWIYDTSKLASGVPGRFSGSGSGNSYSLTISSMEAEDVATYYCFQGSGYPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0345] antiCD38 Ab 48 Heavy Chain- SEQ ID NO:264:EVQLVESGGDLVKPGGSLKLSCAASGFTFSTYGMSWVRQTPDKRLEWVATISSGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARLYDYRYDEEVFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<Attorney Docket No.: 048440-849001 WOTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0346] scFv sequences of exemplary anti-CD38 antibodies

[0347] scFvl WT HC- SEQ ID NO:265:QVQLQQPGTELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0348] scFvl WT LC- SEQ ID NO:266:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0349] scFvl clonel HC- SEQ ID NO:267:QVQLQQPGTELVKPGASVKLSCKASGDTFTSYWMHWVKQRPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0350] scFvl clonel LC- SEQ ID NO:268:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0351] scFvl_clone2_HC- SEQ ID NO:269:QVQLQQPGTELVKPGASVKLSCKASGYTSTSYWMHWVKQRPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0352] scFvl_clone2_LC- SEQ ID NO:270:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0353] scFvl_clone3_HC- SEQ ID NO:271 :Attorney Docket No.: 048440-849001 WOQVQLQQPGTELVKPGASVKLSCKASGYTSTSYWMHWVKQRPGQGLEWIGEITPSNG RTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVFS

[0354] scFvl_clone3_LC- SEQ ID NO:272:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPKLLIYKVS NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0355] scFvl_clone4_HC- SEQ ID NO:273 :HVQLQQPGTELVKPGASVKLSCKASGYTSTSYWMHWVKQRPGQGLEWIGEITPSNG RTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0356] scFvl_clone4_LC- SEQ ID NO:274:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVS NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0357] scFvl_clone5_HC- SEQ ID NO:275:QVQLQQPGTELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEITPSNG RTNYNEKFKSKATLTFDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0358] scFvl_clone5_LC- SEQ ID NO:276:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVS NRISGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0359] scFvl_clone7_HC- SEQ ID NO:277:QVQLQQPGTELVKPGASVKLSCKAPGYTFTSYWMHWVKQRPGQGLEWIGEITPSNG RTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0360] scFvl_clone7_LC- SEQ ID NO:278:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVS NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKAttorney Docket No.: 048440-849001 WO

[0361] scFvl_clonel2_HC- SEQ ID NO:279:QVQLQQPGTELVKPGASVKLSCKASGSTFTSYWMHWVKQRPGQGLEWIGEITPSNG RTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSS

[0362] scFvl_clonel2_LC- SEQ ID NO:280:DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPNLLIYKVS NRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIK

[0363] humanized scFv sequences of exemplary anti-CD38 antibodies

[0364] scFv_hu48_WT_HC- SEQ ID NO:281 :EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0365] scFv_hu48_WT_LC- SEQ ID NO:282:DNQLTQ SP S SLS AS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDT SKL ASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0366] scFv_hu48_clonel_HC- SEQ ID NO:283 :EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGFEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0367] scFv_hu48_clonel_LC- SEQ ID NO:284:DNQLTQSPSSLSASVGDRVTITCSASSSLSYMHWYQQKPGKSPKVWIYDTSKLASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0368] scFv_hu48_clone3_HC- SEQ ID NO:285:EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSC

[0369] scFv_hu48_clone3_LC- SEQ ID NO:286:Attorney Docket No.: 048440-849001 WODNQLTQSPSSLSASVGDRVTITCSASSSVSYMHWYQQKPGKSLKLWIYDTSKLASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGSKVEIK

[0370] scFv_hu48_clone4_HC- SEQ ID NO:287:EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKRFEWVATISSGGS YTYYPDSVKGRFTISRDNSQNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0371] scFv_hu48_clone4_LC- SEQ ID NO:288:DNQLTQ SP S SLS AS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDT SKL ASGV PGRFSGSGSGNDYTLTISSLQPEDYATYYCFQGSGYPLTFGQGTKVEIK

[0372] scFv_hu48_clone5_HC- SEQ ID NO:289:EVQLVESGGGLVQPGGSLRLSCTASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0373] scFv_hu48_clone5_LC- SEQ ID NO:290:DNQLTQSPSSLSASVGDRVTITCSASSSLSYIHWYQQKPGKSLKLWIYDTSKLASGVP GRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0374] scFv_hu48_clone6_HC- SEQ ID NO:291 :EVQLVESGGGLVQPGGSLGLSCAASGFTFGTYGMSWVRQAPGKGMEWVATISSGG SYTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYSARLYDYRYDEEVFDY WGQGTLVTVSS

[0375] scFv_hu48_clone6_LC- SEQ ID NO:292:DNQLTQ SP S SLS AS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDT SKL ASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0376] scFv_hu48_clone7_HC- SEQ ID NO:293 :EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGSYTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSSAttorney Docket No.: 048440-849001 WO

[0377] scFv_hu48_clone7_LC- SEQ ID NO:294:DNQLTQSPSSLSASVGDRVTITCSASSSVSYMHWYQQKPGKSLKLWIYDTSKLASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0378] scFv_hu48_clonel5_HC- SEQ ID NO:295:EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWLRQAPGKGFEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDY WGQSTLVTVSS

[0379] scFv_hu48_clonel5_LC- SEQ ID NO:296:DNQLTQ SP S SLS AS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDT SKL ASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEVK

[0380] scFv_hu48_clonel6_HC- SEQ ID NO:297:EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKKLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDNRYDEEVFDY WGQGTLVTVSS

[0381] scFv_hu48_clonel6_LC- SEQ ID NO:298:DNQLTQ SP S SLS VS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDT SKL ASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0382] scFv_hu48_clonel7_HC- SEQ ID NO:299:EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNRLRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0383] scFv_hu48_clonel7_LC- SEQ ID N0:300:DNQLTQSPSSLSASVGDRVTITCSASSSVSYMHWYQQKPGKSLKLWIYDTSKLASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0384] scFv_hu48_clonel8_HC- SEQ ID NO:301 :Attorney Docket No.: 048440-849001 WOEVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNRMRAEDTAVYYCARLYDYRYDEEVFDY WGQGTLVTVSS

[0385] scFv_hu48_clonel8_LC- SEQ ID NO:302:DNQLTQ SP S SLS AS VGDRVTITC SASS SIS YMHW YQQKPGKSLKLWIYDT SKL ASGVP GRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0386] scFv_hu48_clonel9_HC- SEQ ID NO: 303 :EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEEVFDYL GQGTLVTVSS

[0387] scFv_hu48_clonel9_LC- SEQ ID NO:304:DNQLTQ SP S SLS AS VGDRVTITC SASS S VS YMHW YQQKPGKSPKLWIYDISKL ASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0388] scFv_hu48_clone20_HC- SEQ ID NO: 305:EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQAPGKGLEWVATISSGGS YTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLYDYRYDEELFDYW GQGTLVTVSS

[0389] scFv_hu48_clone20_LC- SEQ ID NO:306:DNRLTQSPSSLSASVGDRVTITCSASSSVSYMHWYQQKPGKSPKLWIYDTSKLASGV PGRFSGSGSGNDYTLTISSLQPEDFATYYCFQGSGYPLTFGQGTKVEIK

[0390] Fab l AM HC - SEQ ID NO:307:QVQLQQPGTELVKPGASVKLSCKASGSTSTSYWMHWVKQRPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKYSSTAYMQLSSLTSEDSAVYYCAREDYGSIPYYYAMDY WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

[0391] Fab l AM LC- SEQ ID NO:308:Attorney Docket No.: 048440-849001 WODVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPYTFGGGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0392] Fab l AM _6nov HC - SEQ ID NO:309:QVQLVQSGAEVKKPGSSVKVSCKASGSTSTSYWMHWVRQAPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKSTSTAYMELSSLRSEDTAVYYCAREDYGSIPYYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

[0393] huFab_l_AM_6nov_LC- SEQ ID NO:310:DVVMTQTPLSLSVTPGQPASISCRSSQSLLHSNGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPYTFGQGTKLEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0394] Fab l AM _2qqn HC - SEQ ID NO:311 :EVQLVESGGGLVQPGGSLRLSCAASGSTSTSYWMHWVRQAPGKGLEWIGEITPSNGRTNYNEKFKSRATLSVDKSKNTAYLQMNSLRAEDTAVYYCAREDYGSIPYYYAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

[0395] huFab_l_AM_2qqn_LC - SEQ ID NO:312:DVQMTQSPSSLSASVGDRVTITCRSSQSLLHSNGNTYLHWYQQKPGKAPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISSLQPEDFATYFCSQSTHVPYTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0396] mehuFab_48_AM_HC - SEQ ID NO:313EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYGMSWVRQSPGKRFEWVATISSGGSYTYYPDSVKGRFTISRDNSQNTLYLQMNSLRAEDTAIYYCARLYDYRYDEEVFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC:Attorney Docket No.: 048440-849001 WO

[0397] mehuFab_48_AM_LC- SEQ ID NO: 314:DNQLTQSPILLSASVGDRVTITCSASSSVSYMHWYQQRTNGSPRLLIYDISKLASGVP GRFSGSGSGNDYTLTISSLQPEDEADYYCFQGSGYPLTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0398] meditope_enabled_vl_huFab_l_AM_6nov_HC - SEQ ID NO:315QVQLVQSGAEVKKPGSSVKVSCKASGSTSTSYWMHWVRQAPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKSTSTAYMELSSLRSEDTAIYYCAREDYGSIPYYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

[0399] meditope_enabled_vl_huFab_l_AM_6nov_LC- SEQ ID NO:316DVVMTQTPILLSVTPGQPASISCRSSQSLLHSNGNTYLHWYLQRTNGSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDIADYYCSQSTHVPYTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0400] meditope_enabled_v2_huFab_l_AM_6nov_HC- SEQ ID NO:317QVQLVQSGAEVKKPGSSVKVSCKASGSTSTSYWMHWVRQAPGQGLEWIGEITPSNGRTNYNEKFKSKATLTVDKSTSTAYMELSSLRSEDTAIYYCAREDYGSIPYYYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC

[0401] meditope_enabled_v2_huFab_l_AM_6nov_LC - - SEQ ID NO:318DVVMTQTPILLSVTPGQPASISCRSSQSLLHSNGNTYLHWYLQRTNGSPRLLIYKVS NRFSGVPDRFSGSGSGTDFTLKISRVEAEDEADYYCSQSTHVPYTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(meditope mutations indicated in bold font)Attorney Docket No.: 048440-849001 WOP EMBODIMENTS

[0402] P Embodiment 1. A biparatopic anti-CD38 antibody comprising a first antigen binding domain and a second antigen binding domain independently comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and wherein said light chain variable domain comprises a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2.

[0403] P Embodiment 2. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO: 92, and a CDR L3 as set forth in SEQ ID NO: 93.

[0404] P Embodiment 3. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:4, a CDR H2 as set forth in SEQ ID NO: 5 and a CDR H3 as set forth in SEQ ID NO: 6; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO:94, a CDR L2 as set forth in SEQ ID NO:95, and a CDR L3 as set forth in SEQ ID NO:96.

[0405] P Embodiment 4. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:7, a CDR H2 as set forth in SEQ ID NO: 8 and a CDR H3 as set forth in SEQ ID NO: 9; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO:97, a CDR L2 as set forth in SEQ ID NO:98, and a CDR L3 as set forth in SEQ ID NO:99.

[0406] P Embodiment 5. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO: 10, a CDR H2 as set forth in SEQ ID NO: 11 and a CDR H3 as set forth in SEQ ID NO: 12; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 100, a CDR L2 as set forth in SEQ ID NO: 101, and a CDR L3 as set forth in SEQ ID NO: 102.

[0407] P Embodiment 6. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO: 13, a CDR H2 as set forth in SEQAttorney Docket No.: 048440-849001 WOID NO: 14 and a CDR H3 as set forth in SEQ ID NO: 15; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 103, a CDR L2 as set forth in SEQ ID NO: 104, and a CDR L3 as set forth in SEQ ID NO: 105.

[0408] P Embodiment 7. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO: 16, a CDR H2 as set forth in SEQ ID NO: 17 and a CDR H3 as set forth in SEQ ID NO: 18; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 106, a CDR L2 as set forth in SEQ ID NO: 107, and a CDR L3 as set forth in SEQ ID NO: 108.

[0409] P Embodiment 8. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO: 19, a CDR H2 as set forth in SEQ ID NO:20 and a CDR H3 as set forth in SEQ ID NO:21; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 109, a CDR L2 as set forth in SEQ ID NO: 110, and a CDR L3 as set forth in SEQ ID NO: 111.

[0410] P Embodiment 9. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:22, a CDR H2 as set forth in SEQ ID NO:23 and a CDR H3 as set forth in SEQ ID NO:24; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 112, a CDR L2 as set forth in SEQ ID NO: 113, and a CDR L3 as set forth in SEQ ID NO: 114.

[0411] P Embodiment 10. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:25, a CDR H2 as set forth in SEQ ID NO:26 and a CDR H3 as set forth in SEQ ID NO:27; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO:115, a CDR L2 as set forth in SEQ ID NO: 116, and a CDR L3 as set forth in SEQ ID NO: 117.

[0412] P Embodiment 11. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:28, a CDR H2 as set forth in SEQ ID NO:29 and a CDR H3 as set forth in SEQ ID NO: 30; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO:118, a CDR L2 as set forth in SEQ ID NO: 119, and a CDR L3 as set forth in SEQ ID NO: 120.

[0413] P Embodiment 12. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:31, a CDR H2 as set forthAttorney Docket No.: 048440-849001 WO in SEQ ID NO:32 and a CDR H3 as set forth in SEQ ID NO:33; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 121, a CDR L2 as set forth in SEQ ID NO : 122, and a CDR L3 as set forth in SEQ ID NO : 123.

[0414] P Embodiment 13. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:34, a CDR H2 as set forth in SEQ ID NO:35 and a CDR H3 as set forth in SEQ ID NO:36; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 124, a CDR L2 as set forth in SEQ ID NO: 125, and a CDR L3 as set forth in SEQ ID NO: 126.

[0415] P Embodiment 14. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:37, a CDR H2 as set forth in SEQ ID NO:38 and a CDR H3 as set forth in SEQ ID NO:39; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 127, a CDR L2 as set forth in SEQ ID NO: 128, and a CDR L3 as set forth in SEQ ID NO: 129.

[0416] P Embodiment 15. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:40, a CDR H2 as set forth in SEQ ID NO:41 and a CDR H3 as set forth in SEQ ID NO:42; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 130, a CDR L2 as set forth in SEQ ID NO: 131, and a CDR L3 as set forth in SEQ ID NO: 132.

[0417] P Embodiment 16. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:43, a CDR H2 as set forth in SEQ ID NO:44 and a CDR H3 as set forth in SEQ ID NO:45; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 133, a CDR L2 as set forth in SEQ ID NO: 134, and a CDR L3 as set forth in SEQ ID NO: 135.

[0418] P Embodiment 17. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:46, a CDR H2 as set forth in SEQ ID NO:47 and a CDR H3 as set forth in SEQ ID NO:48; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 136, a CDR L2 as set forth in SEQ ID NO: 137, and a CDR L3 as set forth in SEQ ID NO: 138.

[0419] P Embodiment 18. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forthAttorney Docket No.: 048440-849001 WO in SEQ ID NO:50 and a CDR H3 as set forth in SEQ ID N0:51; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 139, a CDR L2 as set forth in SEQ ID NO: 140, and a CDR L3 as set forth in SEQ ID NO: 141.

[0420] P Embodiment 19. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:52, a CDR H2 as set forth in SEQ ID NO:53 and a CDR H3 as set forth in SEQ ID NO:54; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 142, a CDR L2 as set forth in SEQ ID NO: 143, and a CDR L3 as set forth in SEQ ID NO: 144.

[0421] P Embodiment 20. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:55, a CDR H2 as set forth in SEQ ID NO:56 and a CDR H3 as set forth in SEQ ID NO:57; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 145, a CDR L2 as set forth in SEQ ID NO: 146, and a CDR L3 as set forth in SEQ ID NO: 147.

[0422] P Embodiment 21. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:58, a CDR H2 as set forth in SEQ ID NO:59 and a CDR H3 as set forth in SEQ ID NO:60; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 148, a CDR L2 as set forth in SEQ ID NO: 149, and a CDR L3 as set forth in SEQ ID NO: 150.

[0423] P Embodiment 22. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:61, a CDR H2 as set forth in SEQ ID NO:62 and a CDR H3 as set forth in SEQ ID NO:63; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 151, a CDR L2 as set forth in SEQ ID NO: 152, and a CDR L3 as set forth in SEQ ID NO: 153.

[0424] P Embodiment 23. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:64, a CDR H2 as set forth in SEQ ID NO:65 and a CDR H3 as set forth in SEQ ID NO:66; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 154, a CDR L2 as set forth in SEQ ID NO: 155, and a CDR L3 as set forth in SEQ ID NO: 156.

[0425] P Embodiment 24. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:67, a CDR H2 as set forthAttorney Docket No.: 048440-849001 WO in SEQ ID NO:68 and a CDR H3 as set forth in SEQ ID NO:69; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 157, a CDR L2 as set forth in SEQ ID NO: 158, and a CDR L3 as set forth in SEQ ID NO: 159.

[0426] P Embodiment 25. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:70, a CDR H2 as set forth in SEQ ID NO:71 and a CDR H3 as set forth in SEQ ID NO:72; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 160, a CDR L2 as set forth in SEQ ID NO: 161, and a CDR L3 as set forth in SEQ ID NO: 162.

[0427] P Embodiment 26. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:73, a CDR H2 as set forth in SEQ ID NO:74 and a CDR H3 as set forth in SEQ ID NO:75; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 163, a CDR L2 as set forth in SEQ ID NO: 164, and a CDR L3 as set forth in SEQ ID NO: 165.

[0428] P Embodiment 27. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:76, a CDR H2 as set forth in SEQ ID NO:77 and a CDR H3 as set forth in SEQ ID NO:78; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 166, a CDR L2 as set forth in SEQ ID NO: 167, and a CDR L3 as set forth in SEQ ID NO: 168.

[0429] P Embodiment 28. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:79, a CDR H2 as set forth in SEQ ID NO: 80 and a CDR H3 as set forth in SEQ ID NO:81; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 169, a CDR L2 as set forth in SEQ ID NO: 170, and a CDR L3 as set forth in SEQ ID NO: 171.

[0430] P Embodiment 29. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:82, a CDR H2 as set forth in SEQ ID NO: 83 and a CDR H3 as set forth in SEQ ID NO: 84; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 172, a CDR L2 as set forth in SEQ ID NO: 173, and a CDR L3 as set forth in SEQ ID NO: 174.

[0431] P Embodiment 30. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:85, a CDR H2 as set forthAttorney Docket No.: 048440-849001 WO in SEQ ID NO: 86 and a CDR H3 as set forth in SEQ ID NO: 87; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177.

[0432] P Embodiment 31. The antibody of embodiment 1, wherein said heavy chain variable domain comprises: a CDR Hl as set forth in SEQ ID NO:88, a CDR H2 as set forth in SEQ ID NO: 89 and a CDR H3 as set forth in SEQ ID NO: 90; and wherein said light chain variable domain comprises: a CDR LI as set forth in SEQ ID NO: 178, a CDR L2 as set forth in SEQ ID NO: 179, and a CDR L3 as set forth in SEQ ID NO: 180.

[0433] P Embodiment 32. The antibody of any one of embodiments 1-31, wherein said first antigen binding domain and said second antigen binding domain independently comprise a heavy chain sequence as set forth by Table 3.

[0434] P Embodiment 33. The antibody of any one of embodiments 1-32, wherein said first antigen binding domain and said second antigen binding domain independently comprise a light chain sequence as set forth by Table 3.

[0435] P Embodiment 34. The antibody of any one of embodiments 1-33, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the heavy chain sequences of SEQ ID NO: 181-210.

[0436] P Embodiment 35. The antibody of any one of embodiments 1-34, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the light chain sequences of SEQ ID NO:211-240.

[0437] P Embodiment 36. The antibody of any one of embodiments 1-35, wherein said first antigen binding domain and said second antigen binding domain independently comprise a heavy chain sequence of SEQ ID NO: 181 and a light chain sequence of SEQ ID NO:211; a heavy chain sequence of SEQ ID NO: 182 and a light chain sequence of SEQ ID NO:212; a heavy chain sequence of SEQ ID NO: 183 and a light chain sequence of SEQ ID NO:213; a heavy chain sequence of SEQ ID NO: 184 and a light chain sequence of SEQ ID NO:214; a heavy chain sequence of SEQ ID NO: 185 and a light chain sequence of SEQ ID NO:215; a heavy chain sequence of SEQ ID NO: 186 and a light chain sequence of SEQ ID NO:216; a heavy chain sequence of SEQ ID NO: 187 and a light chain sequence of SEQ ID NO:217; a heavy chain sequence of SEQ ID NO: 188 and a light chain sequence of SEQ ID NO:218; aAttorney Docket No.: 048440-849001 WO heavy chain sequence of SEQ ID NO: 189 and a light chain sequence of SEQ ID NO:219; a heavy chain sequence of SEQ ID NO: 190 and a light chain sequence of SEQ ID NO:220; a heavy chain sequence of SEQ ID NO: 191 and a light chain sequence of SEQ ID NO:221; a heavy chain sequence of SEQ ID NO: 192 and a light chain sequence of SEQ ID NO:222; a heavy chain sequence of SEQ ID NO: 193 and a light chain sequence of SEQ ID NO:223; a heavy chain sequence of SEQ ID NO: 194 and a light chain sequence of SEQ ID NO:224; a heavy chain sequence of SEQ ID NO: 195 and a light chain sequence of SEQ ID NO:225; a heavy chain sequence of SEQ ID NO: 196 and a light chain sequence of SEQ ID NO:226; a heavy chain sequence of SEQ ID NO: 197 and a light chain sequence of SEQ ID NO:227; a heavy chain sequence of SEQ ID NO: 198 and a light chain sequence of SEQ ID NO:228; a heavy chain sequence of SEQ ID NO: 199 and a light chain sequence of SEQ ID NO:229; a heavy chain sequence of SEQ ID NO:200 and a light chain sequence of SEQ ID NO:230; a heavy chain sequence of SEQ ID NO:201 and a light chain sequence of SEQ ID NO:231; a heavy chain sequence of SEQ ID NO:202 and a light chain sequence of SEQ ID NO:232; a heavy chain sequence of SEQ ID NO:203 and a light chain sequence of SEQ ID NO:233; a heavy chain sequence of SEQ ID NO:204 and a light chain sequence of SEQ ID NO:234; a heavy chain sequence of SEQ ID NO:205 and a light chain sequence of SEQ ID NO:235; a heavy chain sequence of SEQ ID NO:206 and a light chain sequence of SEQ ID NO:236; a heavy chain sequence of SEQ ID NO:207 and a light chain sequence of SEQ ID NO:237; a heavy chain sequence of SEQ ID NO:208 and a light chain sequence of SEQ ID NO:238; a heavy chain sequence of SEQ ID NO:209 and a light chain sequence of SEQ ID NO:239; or a heavy chain sequence of SEQ ID NO:210 and a light chain sequence of SEQ ID NO:240.

[0438] P Embodiment 37. The antibody of any one of embodiments 1-33, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the heavy chain sequences of SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, SEQ ID NO:262 or SEQ ID NO:264.

[0439] P Embodiment 38. The antibody of any one of embodiments 1-33 or 37, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the light chain sequences of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261 or SEQ ID NO:263.Attorney Docket No.: 048440-849001 WO

[0440] P Embodiment 39. The antibody of any one of embodiments 1-33 or 37-38, wherein said first antigen binding domain and said second antigen binding domain independently comprise a heavy chain sequence of SEQ ID NO:248 and a light chain sequence of SEQ ID NO:247; a heavy chain sequence of SEQ ID NO:250 and a light chain sequence of SEQ ID NO:249; a heavy chain sequence of SEQ ID NO:252 and a light chain sequence of SEQ ID NO:251; a heavy chain sequence of SEQ ID NO:254 and a light chain sequence of SEQ ID NO:253; a heavy chain sequence of SEQ ID NO:256 and a light chain sequence of SEQ ID NO:255; a heavy chain sequence of SEQ ID NO:258 and a light chain sequence of SEQ ID NO:257; a heavy chain sequence of SEQ ID NO:260 and a light chain sequence of SEQ ID NO:259; a heavy chain sequence of SEQ ID NO:262 and a light chain sequence of SEQ ID NO:261; or a heavy chain sequence of SEQ ID NO:264 and a light chain sequence of SEQ ID NO:263.

[0441] P Embodiment 40. The antibody of any one of embodiments 1-33, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the heavy chain sequences of SEQ ID NO:265, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, SEQ ID NO:277, or SEQ ID NO:279.

[0442] P Embodiment 41. The antibody of any one of embodiments 1-33 or 40, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the light chain sequences of SEQ ID NO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, SEQ ID NO:278, or SEQ ID NO:280.

[0443] P Embodiment 42. The antibody of any one of embodiments 1-33 or 40-41, wherein said first antigen binding domain and said second antigen binding domain independently comprise a heavy chain sequence of SEQ ID NO:265 and a light chain sequence of SEQ ID NO:266; a heavy chain sequence of SEQ ID NO:267 and a light chain sequence of SEQ ID NO:268; a heavy chain sequence of SEQ ID NO:269 and a light chain sequence of SEQ ID NO:270; a heavy chain sequence of SEQ ID NO:271 and a light chain sequence of SEQ ID NO:272; a heavy chain sequence of SEQ ID NO:273 and a light chain sequence of SEQ ID NO:274; a heavy chain sequence of SEQ ID NO:275 and a light chain sequence of SEQ ID NO:276; a heavy chain sequence of SEQ ID NO:277 and a light chainAttorney Docket No.: 048440-849001 WO sequence of SEQ ID NO:278; or a heavy chain sequence of SEQ ID NO:279 and a light chain sequence of SEQ ID NO:280.

[0444] P Embodiment 43. The antibody of any one of embodiments 1-42, wherein said first antigen binding domain and said second antigen binding domain are independently an scFv.

[0445] P Embodiment 44. The antibody of any one of embodiments 1-33, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the heavy chain sequences of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:293, SEQ ID NO:295, SEQ ID NO:297, SEQ ID NO:299, SEQ ID NO:301, SEQ ID NO:303, or SEQ ID NO:305.

[0446] P Embodiment 45. The antibody of any one of embodiments 1-33 or 44, wherein said first antigen binding domain and said second antigen binding domain independently comprise one of the light chain sequences of SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, SEQ ID NO:288, SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:294, SEQ ID NO:296, SEQ ID NO:298, SEQ ID NO:300, SEQ ID NO:302, SEQ ID NO:304 or SEQ ID NO:306.

[0447] P Embodiment 46. The antibody of any one of embodiments 1-33 or 44-45, wherein said first antigen binding domain and said second antigen binding domain independently comprise a heavy chain sequence of SEQ ID NO:281 and a light chain sequence of SEQ ID NO:282; a heavy chain sequence of SEQ ID NO:283 and a light chain sequence of SEQ ID NO:284; a heavy chain sequence of SEQ ID NO:285 and a light chain sequence of SEQ ID NO:286; a heavy chain sequence of SEQ ID NO:287 and a light chain sequence of SEQ ID NO:288; a heavy chain sequence of SEQ ID NO:289 and a light chain sequence of SEQ ID NO:290; a heavy chain sequence of SEQ ID NO:291 and a light chain sequence of SEQ ID NO:292; a heavy chain sequence of SEQ ID NO:293 and a light chain sequence of SEQ ID NO:294; a heavy chain sequence of SEQ ID NO:295 and a light chain sequence of SEQ ID NO:296; a heavy chain sequence of SEQ ID NO:297 and a light chain sequence of SEQ ID NO:298; a heavy chain sequence of SEQ ID NO:299 and a light chain sequence of SEQ ID NO:300; a heavy chain sequence of SEQ ID NO:301 and a light chain sequence of SEQ ID NO: 302; a heavy chain sequence of SEQ ID NO: 303 and a light chainAttorney Docket No.: 048440-849001 WO sequence of SEQ ID NO:304; or a heavy chain sequence of SEQ ID NO:305 and a light chain sequence of SEQ ID NO:306.

[0448] P Embodiment 47. The antibody of any one of embodiments 1-46, wherein said first antigen binding domain and said second antigen binding domain are independently a humanized antibody.

[0449] P Embodiment 48. The antibody of any one of embodiments 1-47, wherein said first antigen binding domain and said second antigen binding domain are independently a humanized scFv.

[0450] P Embodiment 49. The antibody of any one of embodiments 1-48, wherein said antibody is capable of binding to CD38.

[0451] P Embodiment 50. The antibody of any one of embodiments 1-49, wherein said first antigen binding domain binds a first epitope of CD38 and said second antigen binding domain binds a second epitope of CD38.

[0452] P Embodiment 51. The antibody of embodiment 50, wherein said first epitope of CD38 and said second epitope of CD38 are different.

[0453] P Embodiment 52. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain variable domain comprising a CDR Hl as set forth in SEQ ID NO: 7, a CDR H2 as set forth in SEQ ID NO: 8 and a CDR H3 as set forth in SEQ ID NO:9; and (ii) a first light chain variable domain comprising a CDR LI as set forth in SEQ ID NO: 97, a CDR L2 as set forth in SEQ ID NO: 98, and a CDR L3 as set forth in SEQ ID NO:99; and wherein said second antigen binding domain comprises: (iii) a second heavy chain variable domain comprising a CDR Hl as set forth in SEQ ID NO:85, a CDR H2 as set forth in SEQ ID NO: 86 and a CDR H3 as set forth in SEQ ID NO: 87; and (iv) a second light chain variable domain comprising a CDR LI as set forth in SEQ ID NO: 175, a CDR L2 as set forth in SEQ ID NO: 176, and a CDR L3 as set forth in SEQ ID NO: 177.

[0454] P Embodiment 53. The antibody of any one of embodiments 1-52, wherein said first antigen binding domain comprises a first heavy chain comprising the sequence of SEQ ID NO: 183 and a first light chain comprising the sequence of SEQ ID NO:213; and wherein said second antigen binding domain comprises a second heavy chain comprising the sequence of SEQ ID NO:209 and a second light chain comprising the sequence of SEQ ID NO:239.Attorney Docket No.: 048440-849001 WO

[0455] P Embodiment 54. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain variable domain comprising a CDR Hl sequence, a CDR H2 sequence and a CDR H3 sequence of any one of the antibody clones set forth by Table 1; and (ii) a first light chain variable domain comprising a CDR LI sequence, a CDR L2 sequence and a CDR L3 sequence of any one of the antibody clones set forth by Table 2; and wherein said second antigen binding domain comprises: (iii) a second heavy chain variable domain, wherein said second heavy chain variable domain is a daratumumab heavy chain variable domain; and (iv) a second light chain variable domain, wherein said second light chain variable domain is a daratumumab light chain variable domain.

[0456] P Embodiment 55. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain comprising one of the heavy chain sequences of SEQ ID NO: 181-210; and (ii) a first light chain comprising one of the light chain sequences of SEQ ID NO:211-240; and wherein said second antigen binding domain comprises: (iii) a second heavy chain, wherein said second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein said second light chain is a daratumumab light chain.

[0457] P Embodiment 56. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain comprising one of the heavy chain sequences of SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, SEQ ID NO:262 or SEQ ID NO:264; and (ii) a first light chain comprising one of the light chain sequences of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261 or SEQ ID NO:263; and wherein said second antigen binding domain comprises: (iii) a second heavy chain, wherein said second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein said second light chain is a daratumumab light chain.

[0458] P Embodiment 57. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain comprising one of the heavy chain sequences of SEQ ID NO:265, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, SEQ ID NO:277, or SEQ ID NO:279; and (ii) a first lightAttorney Docket No.: 048440-849001 WO chain comprising one of the light chain sequences of SEQ ID NO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, SEQ ID NO:278, or SEQ ID NO:280; and wherein said second antigen binding domain comprises: (iii) a second heavy chain, wherein said second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein said second light chain is a daratumumab light chain.

[0459] P Embodiment 58. The antibody of any one of embodiments 1-51, wherein said first antigen binding domain comprises: (i) a first heavy chain comprising one of the heavy chain sequences of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:293, SEQ ID NO:295, SEQ ID NO:297, SEQ ID NO:299, SEQ ID NO:301, SEQ ID NO:303, or SEQ ID NO:305; and (ii) a first light chain comprising one of the light chain sequences of SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, SEQ ID NO:288, SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:294, SEQ ID NO:296, SEQ ID NO:298, SEQ ID NO:300, SEQ ID NO:302, SEQ ID NO:304 or SEQ ID NO:306; and wherein said second antigen binding domain comprises: (iii) a second heavy chain, wherein said second heavy chain is a daratumumab heavy chain; and (iv) a second light chain, wherein said second light chain is a daratumumab light chain.

[0460] P Embodiment 59. The antibody of any one of embodiments 1-58, wherein said antibody is a humanized antibody, a Fab' fragment, or a chimeric antibody.

[0461] P Embodiment 60. The antibody of any one of embodiments 1-58, wherein said antibody comprises a fragment crystallizable (Fc) domain.

[0462] P Embodiment 61. The antibody of embodiment 60, wherein said Fc domain comprises a N297G substitution, a R292C substitution, a V302C substitution or a combination thereof.

[0463] P Embodiment 62. The antibody of any one of embodiments 1-61, wherein said antibody is attached to a therapeutic moiety or a diagnostic moiety.

[0464] P Embodiment 63. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of any one of embodiments 1-62 and a pharmaceutically acceptable excipient.Attorney Docket No.: 048440-849001 WO

[0465] P Embodiment 64. A method of treating cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of an antibody of any one of embodiments 1-62.

[0466] P Embodiment 65. The method of embodiment 64, wherein said cancer is multiple myeloma.EMBODIMENTS

[0467] Embodiment 1. An anti-CD38 antibody comprising:(i) a heavy chain variable domain comprising a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3, and(ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO:92, and a CDR L3 as set forth in SEQ ID NO:93.

[0468] Embodiment 2. The antibody of embodiment 1, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 181 and said light chain variable domain comprises the sequence of SEQ ID NO:211.

[0469] Embodiment 3. The antibody of any one of embodiments 1-2, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:247 and wherein said heavy chain comprises the sequence of SEQ ID NO:248.

[0470] Embodiment 4. The antibody of any one of embodiments 1-3, comprising an aspartic acid or a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248, or a combination thereof.

[0471] Embodiment 5. The antibody of any one of embodiments 1-4, comprising a lysine at a position corresponding to position 50 of SEQ ID NO:247.

[0472] Embodiment 6. The antibody of any one of embodiments 1-5, comprising a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.Attorney Docket No.: 048440-849001 WO

[0473] Embodiment 7. The antibody of any one of embodiments 1-5, comprising a serine at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248.

[0474] Embodiment 8. The antibody of any one of embodiments 1-5, comprising an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248.

[0475] Embodiment 9. The antibody of any one of embodiments 1-5, comprising a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

[0476] Embodiment 10. The antibody of any one of embodiments 1-5, comprising an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

[0477] Embodiment 11. The antibody of any one of embodiments 1-5, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:308 and wherein said heavy chain comprises the sequence of SEQ ID NO:307.

[0478] Embodiment 12. The antibody of any one of embodiments 1 or 4-10, wherein said antibody is a humanized antibody.

[0479] Embodiment 13. The antibody of embodiment 12, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:310 and wherein said heavy chain comprises the sequence of SEQ ID NO:309.

[0480] Embodiment 14. The antibody of embodiment 12, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:312 and wherein said heavy chain comprises the sequence of SEQ ID NO:311.

[0481] Embodiment 15. The antibody of any one of embodiments 1-32, comprising a meditope binding site.Attorney Docket No.: 048440-849001 WO

[0482] Embodiment 16. The antibody of embodiment 15, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:316 and wherein said heavy chain comprises the sequence of SEQ ID NO:315.

[0483] Embodiment 17. The antibody of embodiment 15, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:318 and wherein said heavy chain comprises the sequence of SEQ ID NO:317.

[0484] Embodiment 18. The antibody of any one of embodiments 15-17, wherein said antibody is bound to a meditope.

[0485] Embodiment 19. The antibody of any one of embodiments 1-18, wherein said antibody is a chimeric antibody.

[0486] Embodiment 20. The antibody of any one of embodiments 1-19, wherein said antibody is a Fab' fragment.

[0487] Embodiment 21. The antibody of any one of embodiments 1-18, wherein said antibody is a single chain antibody (scFv).

[0488] Embodiment 22. The antibody of any one of embodiments 1-19, wherein said antibody is an IgG.

[0489] Embodiment 23. The antibody of any one of embodiments 1-22, wherein said antibody comprises a fragment crystallizable (Fc) domain.

[0490] Embodiment 24. The antibody of embodiment 23, wherein said Fc domain comprises a N297G substitution, a R292C substitution, a V302C substitution or a combination thereof.

[0491] Embodiment 25. The antibody of embodiment 23, wherein said Fc domain comprises a F405L substitution or K409R substitution, or a combination thereof.

[0492] Embodiment 26. The antibody of any one of embodiments 1-25, wherein said antibody is attached to a therapeutic moiety or a diagnostic moiety.

[0493] Embodiment 27. The antibody of embodiment 26, wherein said antibody is attached to said therapeutic moiety or said diagnostic moiety through a chemical linker.Attorney Docket No.: 048440-849001 WO

[0494] Embodiment 28. The antibody of embodiment 27, wherein said linker is a covalent linker.

[0495] Embodiment 29. The antibody of embodiment 26 or 28, wherein said linker is a cleavable linker.

[0496] Embodiment 30. The antibody of any one of embodiments 26-28, wherein said therapeutic moiety comprises an anti -cancer agent.

[0497] Embodiment 31. The antibody of any one of embodiments 26-30, wherein said therapeutic moiety is a cytotoxic moiety.

[0498] Embodiment 32. The antibody of embodiment 31, wherein said cytotoxic moiety is monomethyl auri statin E (MMAE) or monomethyl auri statin F (MMAF).

[0499] Embodiment 33. The antibody of any one of embodiments 1-32, wherein said antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of less than 520 nM.

[0500] Embodiment 34. The antibody of any one of embodiments 1-33, wherein said antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 15 nM.

[0501] Embodiment 35. The antibody of any one of embodiments 1-34, wherein said antibody is part of an antibody drug conjugate (ADC).

[0502] Embodiment 36. The antibody of any one of embodiments 1-35, wherein said antibody is capable of binding to CD38 protein.

[0503] Embodiment 37. The antibody of embodiment 36, wherein said CD38 protein is expressed on the cell surface.

[0504] Embodiment 38. The antibody of embodiment 37, wherein said cell is a cancer cell.

[0505] Embodiment 39. A nucleic acid composition comprising a sequence encoding the antibody of any one of embodiments 1-38.

[0506] Embodiment 40. An expression vector comprising the nucleic acid of embodiment 39.Attorney Docket No.: 048440-849001 WO

[0507] Embodiment 41. The expression vector of embodiment 40, wherein said expression vector is a viral vector.

[0508] Embodiment 42. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of any one of embodiments 1-38 and a pharmaceutically acceptable excipient.

[0509] Embodiment 43. A method of treating cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of an antibody of any one of embodiments 1-38.

[0510] Embodiment 44. The method of embodiment 43, wherein said cancer is multiple myeloma.

Claims

Attorney Docket No.: 048440-849001 WOWHAT IS CLAIMED IS:

1. An anti-CD38 antibody comprising:(i) a heavy chain variable domain comprising a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2 and a CDR H3 as set forth in SEQ ID NO:3, and(ii) a light chain variable domain comprising a CDR LI as set forth in SEQ ID NO:91, a CDR L2 as set forth in SEQ ID NO:92, and a CDR L3 as set forth in SEQ ID NO:93.

2. The antibody of claim 1, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 181 and said light chain variable domain comprises the sequence of SEQ ID NO:211.

3. The antibody of claim 1, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:247 and wherein said heavy chain comprises the sequence of SEQ ID NO:248.

4. The antibody of claim 1, comprising an aspartic acid or a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248, or a combination thereof.

5. The antibody of claim 1, comprising a lysine at a position corresponding to position 50 of SEQ ID NO:247.

6. The antibody of claim 1, comprising a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

7. The antibody of claim 1, comprising a serine at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248.

8. The antibody of claim 1, comprising an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248 and a serine at a position corresponding to position 29 of SEQ ID NO:248.Attorney Docket No.: 048440-849001 WO9. The antibody of claim 1, comprising a serine at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

10. The antibody of claim 1, comprising an aspartic acid at a position corresponding to position 27 of SEQ ID NO:248, a serine at a position corresponding to position 29 of SEQ ID NO:248 and a lysine at a position corresponding to position 50 of SEQ ID NO:247.

11. The antibody of claim 1, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:308 and wherein said heavy chain comprises the sequence of SEQ ID NO:307.

12. The antibody of claim 1, wherein said antibody is a humanized antibody.

13. The antibody of claim 12, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:310 and wherein said heavy chain comprises the sequence of SEQ ID NO:309.

14. The antibody of claim 12, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:312 and wherein said heavy chain comprises the sequence of SEQ ID NO:311.

15. The antibody of claim 1, comprising a meditope binding site.

16. The antibody of claim 15, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:316 and wherein said heavy chain comprises the sequence of SEQ ID NO:315.

17. The antibody of claim 15, wherein said antibody comprises a light chain and a heavy chain, wherein said light chain comprises the sequence of SEQ ID NO:318 and wherein said heavy chain comprises the sequence of SEQ ID NO:317.Attorney Docket No.: 048440-849001 WO18. The antibody of any one of claims 15-17, wherein said antibody is bound to a meditope.

19. The antibody of claim 1, wherein said antibody is a chimeric antibody.

20. The antibody of claim 1, wherein said antibody is a Fab' fragment.

21. The antibody of claim 1, wherein said antibody is a single chain antibody (scFv).

22. The antibody of claim 1, wherein said antibody is an IgG.

23. The antibody of claim 1, wherein said antibody comprises a fragment crystallizable (Fc) domain.

24. The antibody of claim 23, wherein said Fc domain comprises a N297G substitution, a R292C substitution, a V302C substitution or a combination thereof.

25. The antibody of claim 23, wherein said Fc domain comprises a F405L substitution or K409R substitution, or a combination thereof.

26. The antibody of claim 1, wherein said antibody is attached to a therapeutic moiety or a diagnostic moiety.

27. The antibody of claim 26, wherein said antibody is attached to said therapeutic moiety or said diagnostic moiety through a chemical linker.

28. The antibody of claim 27, wherein said linker is a covalent linker.

29. The antibody of claim 26 or 28, wherein said linker is a cleavable linker.

30. The antibody of any one of claims 26-28, wherein said therapeutic moiety comprises an anti -cancer agent.

31. The antibody of any one of claims 26-30, wherein said therapeutic moiety is a cytotoxic moiety.Attorney Docket No.: 048440-849001 WO32. The antibody of claim 31, wherein said cytotoxic moiety is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

33. The antibody of claim 1, wherein said antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of less than 520 nM.

34. The antibody of claim 1, wherein said antibody is capable of binding a CD38 protein with an equilibrium dissociation constant (KD) of about 50 nM to about 15 nM.

35. The antibody of claim 1, wherein said antibody is part of an antibody drug conjugate (ADC).

36. The antibody of claim 1, wherein said antibody is capable of binding to CD38 protein.

37. The antibody of claim 36, wherein said CD38 protein is expressed on the cell surface.

38. The antibody of claim 37, wherein said cell is a cancer cell.

39. A nucleic acid composition comprising a sequence encoding the antibody of claim 1.

40. An expression vector comprising the nucleic acid of claim 39.

41. The expression vector of claim 40, wherein said expression vector is a viral vector.

42. A pharmaceutical composition comprising a therapeutically effective amount of an antibody of claim 1 and a pharmaceutically acceptable excipient.

43. A method of treating cancer in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of an antibody of claim 1.

44. The method of claim 43, wherein said cancer is multiple myeloma.

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