Antibodies targeting DLL3 and methods of use thereof

Abstract

Provided herein are antibodies and antigen binding portions thereof that specifically bind to Delta-like ligand 3 ("DLL3"), and various compositions of such antibodies or antigen binding portions thereof. Also provided are methods and compositions for using the antibodies or antigen binding portions thereof in cancer therapeutics and diagnostics.

Description

Attorney Docket No.: 090723-1514853-MDA23-109PCTANTIBODIES TARGETING DLL3 AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional Patent Application Serial No. 63 / 680,828, filed August 8, 2024, the content of which is incorporated herein by this reference as if fully set forth herein.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted herewith and is hereby incorporated by reference in its entirety. The .xml copy, created on August 07, 2025, is named 090723-1514853-MDA23-109PCT and is 265,999 bytes in size.BACKGROUND

[0003] Lung cancer may be the most common cause of cancer death in many countries, and small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers in the United States each year (approximately 30,000 patients). Despite some high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis (about 7%. 5-year survival rate). Treatment options for recurrent or refractory disease are limited, and the treatments that do exist may be associated with significant treatment-related toxicities. Deltalike ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is thus being explored as a therapeutic target in SCLC. Development of efficacious fully human antibodies against the target DLL3 for diagnostic and therapeutic use in the identification and treatment of tumors such as Small Cell Lung Cancer (SCLC) and other DLL3+ related malignancies may therefore advance the standard of medical care.SUMMARY

[0004] The terms “invention,” “the invention,” “this invention,” and “the present invention,” as used in this document, are intended to refer broadly to all of the subject matter of this patent application and the claims below. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the patent claims below. Covered embodiments are defined by the claims, not this summary. This summary is a high-level overview of various aspects and introduces some of the concepts that are describedAttorney Docket No.: 090723-1514853-MDA23-109PCT and illustrated in the present document and the accompanying figures. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures and each claim. Some of the exemplary embodiments are discussed below.

[0005] The present disclosure provides antibodies or antigen-binding fragments thereof that target DLL3. Also provided are methods and compositions for using the antibodies or antigenbinding portions thereof in cancer therapeutics and diagnostics.

[0006] In one aspect, the disclosure provides an isolated antibody or antigen-binding fragment that comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, 106, 112, 115, 118, or 121; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, 107, 113, 116, 119, or 122; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 105, 108, 111, 114, 117, 120, or 123; and (b) a light chain variable region comprising: (i) a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, 259, 265, 268, 271, or 274; (ii) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, 260, 266, 269, 272, or 275; and (iii) a VLCDR3 amino acid sequence comprising SEQ ID NO: 258, 261, 267, 270, 273, or 276.

[0007] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 103; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 104; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and (b) a light chain variable region comprising: (i) a VLCDR1 amino acid sequence comprising SEQ ID NO: 256; (ii) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257; and (iii) a VLCDR3 amino acid sequence comprising SEQ ID NO: 258.

[0008] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 106; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 107; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 108; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 259; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 260; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

[0009] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 106; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 107; and (iii) aAttorney Docket No.: 090723-1514853-MDA23-109PCTVHCDR3 amino acid sequence comprising SEQ ID NO: 111; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 259; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 260; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

[0010] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 112; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 113; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 114; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 265; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 266; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 267.

[0011] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 115;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 116; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 117; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 268; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 269; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 270.

[0012] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 118; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 119; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 120; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 271; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 272; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 273.

[0013] In another aspect, an isolated antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising: (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 121; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 122; and (iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 123; and (b) a light chain variable region comprising: (iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 274; (v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257; and (vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0014] In some embodiments, (a) the heavy chain variable region of the isolated antibody or antigen-binding fragment comprises an amino acid sequence having at least 90% identity toAttorney Docket No.: 090723-1514853-MDA23-109PCT any one of SEQ ID NOs: 1-34, 38-51, 418, and 419, and (b) the light chain variable region of the isolated antibody or antigen-binding fragment comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, and 421. In some embodiments, (a) the heavy chain variable region of the isolated antibody or antigen-binding fragment comprises an amino acid sequence comprising any one of SEQ ID NOs: 1-34, 38-51, 418, and 419, and (b) the light chain variable region of the isolated antibody or antigen-binding fragment comprises an amino acid sequence comprising any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, and 421.

[0015] In some embodiments, the isolated antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 52. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 2 and a light chain variable region comprising SEQ ID NO: 53. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 3 and a light chain variable region comprising SEQ ID NO: 53. In some embodiments, the antibody or antigenbinding fragment comprises a heavy chain variable region comprising SEQ ID NO: 4 and a light chain variable region comprising SEQ ID NO: 55. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 5 and a light chain variable region comprising SEQ ID NO: 56. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 6 and a light chain variable region comprising SEQ ID NO: 57. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising SEQ ID NO: 7 and a light chain variable region comprising SEQ ID NO: 58.

[0016] In some embodiments, the isolated antigen-binding fragment is a monovalent scFv (single chain fragment variable) antibody, divalent scFv, Fab fragment, F(ab’)2 fragment, F(ab’)3 fragment, Fv fragment, or single chain antibody. In some embodiments, the antibody or antigen-binding fragment is a chimeric antibody, bispecific antibody, trispecific antibody, or other multi-specific antibody. In some embodiments, the antibody is an IgG antibody or a recombinant IgG antibody or antibody fragment.

[0017] In some embodiments, the antibody or antigen-binding fragment is conjugated or fused to an imaging agent, a cytotoxic agent, a metal, a photosensitizer, or a radioactive moiety. In some embodiments, the antibody or antigen-binding fragment is conjugated or fused to an imaging agent, and wherein the imaging agent is a fluorophore. In some embodiments, theAttorney Docket No.: 090723-1514853-MDA23-109PCT antibody or antigen-binding fragment is conjugated or fused to a radioactive moiety, and the radioactive moiety is Zr-89, Cu-64, F-18, Y-90, Lu-177, At-211, Ac-225, or Pb-212. In some embodiments, the antibody is an immune conjugate. In some embodiments, the antibody is an antibody-drug conjugate.

[0018] In another aspect, the disclosure provides a pharmaceutical composition comprising an isolated antibody or antigen-binding fragment of the present disclosure and a pharmaceutically acceptable carrier.

[0019] In another aspect, an isolated nucleic acid is provided that encodes an antibody heavy and / or a light chain variable region of an antibody or antigen-binding fragment of the present disclosure.

[0020] In another aspect, an expression vector is provided that comprises a nucleic acid encoding an antibody or antigen-binding fragment of the present disclosure.

[0021] In another aspect, a hybridoma or engineered cell is provided that comprises a nucleic acid encoding an antibody or antigen-binding fragment of the present disclosure.

[0022] In another aspect, the disclosure provides a method of making an isolated antibody or antigen-binding fragment of the present disclosure. In some embodiments, the method comprises culturing a hybridoma or engineered cell of the present disclosure under conditions that allow expression of the antibody or antigen-binding fragment and, optionally, isolating the antibody or antigen-binding fragment from the culture.

[0023] In another aspect, the disclosure provides a chimeric antigen receptor (CAR) that comprises: (a) an extracellular target-binding domain comprising an antibody or an antigenbinding fragment of the present disclosure; (b) a transmembrane domain; and (c) a signaling domain.

[0024] In another aspect, a chimeric antigen receptor (CAR) comprises:(a) a CDRH1 comprising SEQ ID NO: 103, a CDRH2 comprising SEQ ID NO: 104, and a CDRH3 comprising SEQ ID NO: 105; and comprising a CDRL1 comprising SEQ ID NO: 256, a CDRL2 comprising SEQ ID NO: 257, and a CDRL3 comprising SEQ ID NO: 258; or(b) a CDRH1 comprising SEQ ID NO: 106, a CDRH2 comprising SEQ ID NO: 107, and a CDRH3 comprising SEQ ID NO: 108; and comprising a CDRL1 comprising SEQ ID NO: 259, a CDRL2 amino SEQ ID NO: 260, and a CDRL3 comprising SEQ ID NO: 261; or(c) a CDRH1 comprising SEQ ID NO: 106, a CDRH2 comprising SEQ ID NO: 107, and a CDRH3 comprising SEQ ID NO: 111; and comprising a CDRL1 comprising SEQ IDAttorney Docket No.: 090723-1514853-MDA23-109PCTNO: 259, a CDRL2 comprising SEQ ID NO: 260, and a CDRL3 comprising SEQ ID NO: 261; or(d) a CDRH1 comprising SEQ ID NO: 112, a CDRH2 comprising SEQ ID NO: 113, and a CDRH3 comprising SEQ ID NO: 114; and comprising a CDRL1 comprising SEQ ID NO: 265, a CDRL2 comprising SEQ ID NO: 266, and a CDRL3 comprising SEQ ID NO: 267; or(e) a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 116, and a CDRH3 comprising SEQ ID NO: 117; and comprising a CDRL1 comprising SEQ ID NO: 268, a CDRL2 comprising SEQ ID NO: 269, and a CDRL3 comprising SEQ ID NO: 270; or(f) a CDRH1 comprising SEQ ID NO: 118, a CDRH2 comprising SEQ ID NO: 119, and a CDRH3 comprising SEQ ID NO: 120; and comprising a CDRL1 comprising SEQ ID NO: 271, a CDRL2 comprising SEQ ID NO: 272, and a CDRL3 comprising SEQ ID NO: 273; or(g) a CDRH1 comprising SEQ ID NO: 121, a CDRH2 comprising SEQ ID NO: 122, and a CDRH3 comprising SEQ ID NO: 123; and comprising a CDRL1 comprising SEQ ID NO: 274, a CDRL2 comprising SEQ ID NO: 257, and a CDRL3 comprising SEQ ID NO: 276.

[0025] In some embodiments, the antigen-binding domain of the CAR protein comprises:(a) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 1; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 52;(b) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 2; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53;(c) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 3; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53;(d) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 4; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 55;Attorney Docket No.: 090723-1514853-MDA23-109PCT(e) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 5; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 56;(f) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 6; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 57; or(g) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 7; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 58.

[0026] In some embodiments, the antigen-binding domain of the CAR protein comprises:(a) a heavy chain variable sequence set forth in SEQ ID NO: 1 and a light chain variable sequence set forth in SEQ ID NO: 52;(b) a heavy chain variable sequence set forth in SEQ ID NO: 2 and a light chain variable sequence set forth in SEQ ID NO: 53;(c) a heavy chain variable sequence set forth in SEQ ID NO: 3 and a light chain variable sequence set forth in SEQ ID NO: 53;(d) a heavy chain variable sequence set forth in SEQ ID NO: 4 and a light chain variable sequence set forth in SEQ ID NO: 55;(e) a heavy chain variable sequence set forth in SEQ ID NO: 5 and a light chain variable sequence set forth in SEQ ID NO: 56;(f) a heavy chain variable sequence set forth in SEQ ID NO: 6 and a light chain variable sequence set forth in SEQ ID NO: 57; or(g) a heavy chain variable sequence set forth in SEQ ID NO: 7 and a light chain variable sequence set forth in SEQ ID NO: 58.

[0027] In some embodiments, the antigen-binding domain of the CAR protein specifically binds delta-like ligand 3 (DLL3). In some embodiments, the CAR further comprises a hinge domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the hinge domain is a CD8a hinge domain or an IgG4 hinge domain. In some embodiments, the transmembrane domain is a CD8a transmembrane domain or a CD28 transmembrane domain. In some embodiments, the intracellular signaling domain comprises a CD3z intracellular signaling domain.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0028] In another aspect, a nucleic acid is provided that encodes a CAR of the present disclosure. In some embodiments, the nucleic acid sequence encoding the CAR is operatively linked to an expression control sequence.

[0029] In another aspect, provided is an expression vector that comprises a nucleic acid encoding a CAR of the present disclosure.

[0030] In another aspect, an engineered cell is provided that comprises a nucleic acid encoding a CAR of the present disclosure. In some embodiments, the cell is a T cell or an NK cell. In some embodiments, the nucleic acid is integrated into a genome of the cell. In some embodiments, the cell is a human cell.

[0031] In another aspect, the disclosure provides a pharmaceutical composition comprising a population of engineered cells of the present disclosure and a pharmaceutically acceptable carrier.

[0032] In another aspect, a method of treating cancer in a subject is provided. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the composition comprises a population of engineered cells of the present disclosure, and the cells are allogeneic cells or autologous cells. In some embodiments, the cells are HLA matched to the subject.

[0033] In some embodiments, the pharmaceutical composition comprises an isolated antibody or antigen-binding fragment of the present disclosure conjugated to a therapeutic agent. In some embodiments, the therapeutic agent is at least one of a cytotoxic agent, a photosensitizer, a chemotherapeutic agent, or an immunosuppressive agent. In some embodiments, the therapeutic agent is a moiety that specifically binds to an immune cell. In some embodiments, the immune cell is a T cell or a natural killer cell. In some embodiments, the cancer has been determined to express an elevated level of DLL3 relative to a healthy tissue. In some embodiments, the cancer is a small cell lung cancer (SCLC), prostate cancer, or a neuroendocrine cancer. In some embodiments, the patient has previously failed to respond to at least one of: an immune checkpoint inhibitor, chemotherapy, or radiation therapy. In some embodiments, the subject has relapsed cancer or recurrent cancer. In some embodiments, the therapeutic agent is a photosensitizer, and the method further comprises administration of near infrared photoimmunotherapy to the subject.

[0034] In some embodiments, the method further comprises administering at least a second anti-cancer therapy. In some embodiments, the second anti-cancer therapy is a chemotherapy, molecular targeted therapy, immunotherapy, radiotherapy, radioimmunotherapy,Attorney Docket No.: 090723-1514853-MDA23-109PCT phototherapy, gene therapy, surgery, hormonal therapy, epigenetic modulation, anti- angiogenic therapy or cytokine therapy.

[0035] In another aspect, a method of detecting the presence of DLL3 in a biological sample is provided. In some embodiments, the method comprises: (a) contacting a biological sample with an isolated antibody or antigen-binding fragment thereof of the present disclosure, and (b) detecting an amount of binding of the isolated antibody or antigen-binding fragment thereof as a determination of the presence of DLL3 in the biological sample. In some embodiments, the biological sample comprises cancer cells. In some embodiments, the biological sample comprises a sample from a tumor from a patient.

[0036] In another aspect, a method of imaging a tumor in a subject with an DLL3 expressing cancer is provided. In some embodiments, the method comprises: (a) administering to the subject an isolated antibody or antigen-binding fragment thereof of the present disclosure conjugated to an imaging label, and (b) detecting the imaging label in the subject to obtain an image of the tumor.

[0037] In another aspect, a method of monitoring response of a subject with a DLL3 expressing cancer to cancer therapy is provided. In some embodiments, the method comprises: (a) administering to the subject the isolated antibody or antigen-binding fragment thereof of the present disclosure conjugated to an imaging label at a first time point before the subject receives cancer therapy; (b) detecting the imaging label in the subject to obtain a first image of a tumor; (c) administering to the subject an isolated antibody or antigen-binding fragment thereof of the present disclosure conjugated to an imaging label at a second time point after the subject receives cancer therapy; (d) detecting the imaging label in the subject to obtain a second image of the tumor; and (e) comparing the first image to the second image to determine whether a change in tumor size has occurred. In some embodiments, steps (c) to (e) are repeated at a third time point after the subject receives cancer therapy. In some embodiments, the imaging label comprises a radioisotope, a bioluminescent label, a chemiluminescent label, or a paramagnetic compound.

[0038] In another aspect, a method of assessing the likelihood of responsiveness of a subject with cancer to treatment with a DLL3 targeted therapy is provided. In some embodiments, the method comprises: (a) measuring in a tumor sample from a subject an amount of expression of DLL3; and (b) determining if the subject has a cancer characterized as having a high level of DLL3 expression. In some embodiments, the amount of DLL3 expression in the tumor sample is measured using the isolated antibody or antigen-binding fragment thereof of the presentAttorney Docket No.: 090723-1514853-MDA23-109PCT disclosure. In some embodiments, the DLL3 targeted therapy comprises administration of the pharmaceutical composition of the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The present application includes the following figures. The figures are intended to illustrate certain embodiments and / or features of the compositions and methods, and to supplement any description(s) of the compositions and methods. The figures do not limit the scope of the compositions and methods, unless the written description expressly indicates that such is the case.

[0040] FIGS. 1A-1B illustrate DLL3 therapeutic antibody single B-cell cloning statistics according to certain aspects of this disclosure. FIG. 1 A shows the avidities to human DLL3 of the discovered 48 unique clones. FIG. IB shows cross-reactivities to human DLL3 and Cyno DLL3 from bio-layer interferometry (BLI) and indicates 42 of 48 clones cross-reacted to cyno DLL3 at a high level.

[0041] FIG. 2A and FIG. 2B illustrate the binding of DLL3 -specific antibodies to the cell surface of HEK293T immortalized human embryonic kidney cells that overexpressed Human DLL3 (FIG. 2A) or Cyno DLL3 (FIG. 2B) according to certain aspects of this disclosure.

[0042] FIG. 2C illustrates the relationship between bins for the DLL3 -specific antibodies, based on epitopes from binning data. Competition bindings between two groups or between two clones are denoted by straight lines that connect the circles.

[0043] FIG. 3 illustrates that DLL3 -specific antibodies do not bind to non-cancer cell plasma proteins. The graph shows the ratio of antibody binding to plasma membrane proteins from HEK293 cells that either express human DLL3 (positive control) or do not express DLL3.

[0044] FIG. 4 shows internalization of exemplary anti-DLL3 antibodies in the human SHP77 SCLC cell line in the presence or absence of the inhibitor chlorhexidine (CHX) according to certain aspects of this disclosure.

[0045] FIG. 5A shows a schematic of an anti -DLL3 -ADC structure according to certain aspects of this disclosure. The anti-DLL3 antibody is linked to a Vc-Pab-MMAE payload via a maleimide linkage at S239C in the Fc region. MMAE represents monomethyl auristatin E. FIGS. 5B-5C demonstrate that DLL3-specific antibody drug conjugates (ADCs) (DLL3-68, DLL3-73, DLL3-79 antibodies linked to MMAE) are localized to NCI-H82 small cell lung cancer cells. Camptothecin was used as a positive control, and unconjugated (no payload) versions of the antibodies were used as negative controls. DLL3-ABBV refers to rovalpituzumab tesirine (Abb Vie).Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0046] FIGS. 6A-6D show assessment of anti-DLL3xCD3e bispecific antibodies. FIG. 6A is a schematic diagram illustrating an anti-DLL3 Fab / anti-CD3 scFv bispecific antibody structure. FIG. 6B is a graph showing binding of DLL3xCD3e bispecific antibodies to Jurkat T-cells. FIG. 6C and FIG. 6D are graphs of the data from HEK293T (293T) cell surface binding assays showing the binding of DLL3xCD3e bispecific antibodies to human DLL3 and cyno DLL3, respectively.

[0047] FIGS. 7A-7B show in vitro killing assessment of selected DLL3xCD3e bispecific antibody leads according to certain aspects of this disclosure. FIG. 7A shows T-cell engaged killing of HEK293T cells overexpressing DLL3 by DLL3xCD3e bispecific antibodies. FIG. 7B shows T-cell engaged killing of SHP77 cells by DLL3xCD3e bispecific antibodies. Velo CTRL refers to a bispecific antibody with an active CD3e arm and a non-functional anti-DLL3 arm that was used as a negative control. Amgen refers to an anti-DLL3 positive control bispecific antibody.

[0048] FIG. 8A shows proliferation assay results of lentivirus transfected anti-DLL3 CAR- T cells. FIG. 8B shows the phenotype of lentivirus transfected anti-DLL3 CAR-T cells from four healthy donors.

[0049] FIGS. 9A-9C show DLL-3 CAR-T cells in vitro killing efficacy according to certain aspects of this disclosure. FIGS. 9A and 9B show in vitro killing of SHP77 cells by DLL3 CAR-T cells in the absence or presence of IL-2, respectively. FIG. 9C shows the amount of secretion of IFNy in the presence or absence of tumors (H82 cells) from two donors in the CAR-T killing assay, as measured by enzyme-linked immuno-assay ELISA.

[0050] FIGS. 10A-10C show re-challenge killing by DLL3 CAR-T as monitored by IncuCyte® system according to certain aspects of this disclosure. FIG. 10A shows growth of H82 tumor cells over time in the presence of different DLL3 CAR-T cells or no T cells (control). Tumor cells were re-added on day 3 and day 6 for re-challenging. FIG. 10B shows the phenotype of different DLL3 CAR-T cells after 9 days with two rounds of re-challenging. Tcm refers to CD45ROpos CD62Lpos; Tnaive refers to CD45ROneg CD62Lpos; Tern refers to CD45ROpos CD62Lneg; and Temra refers to CD45ROneg CD62Lneg. FIG. 10C shows the percentage of final CAR+ T-cells among the total population of T-cells after 9 days with two rounds of re-challenging.

[0051] FIGS. 11A-11D show the in vivo evaluation of exemplary DLL3 CAR-T cells in SHP77 cell line-derived xenograft (CDX) mice. FIG. 11A is a schematic diagram of the in vivo study. FIG. 11B shows tumor growth in mice treated with PBS, non-transduced T cellsAttorney Docket No.: 090723-1514853-MDA23-109PCT(NT-T; also referred to as parental T cells from the same donor), and DLL3 CAR-T cells (Clone 22 CAR-T). FIG. 11C shows total T cell infiltration at the tumor site (bottom panel) and percentage of transgene expression within tumor infiltrated T cells (top panel). The term “TILs” refers to tumor-infiltrating lymphocytes. FIG. 11D shows exhaustion marker (PD1 and LAG3) expression on tumor infiltrated T cells measured by flow cytometry.DETAILED DESCRIPTIONI. Introduction

[0052] Provided herein are novel antibodies, and methods for their production and use, targeting small cell lung cancer (“SCLC”) and other cancers characterized by over-expression of the Delta-like ligand 3 (“DLL3”) protein on cell surfaces. The discovery and development of novel antibodies against DLL3, including fully human antibodies, as described in this disclosure can be used in the treatment of SCLC and other DLL3 positive malignancies.

[0053] DLL3 is an inhibitory ligand of the Notch pathway that is highly conserved in developing lung neuroendocrine cells. DLL3-mediated downregulation of the pathway involves the growth of neuroendocrine tumor cells. DLL3 is overexpressed on the cell surface of neuroendocrine tumor cells in about 80% of SCLCs, while it is normally expressed in the cytoplasmic area in healthy cells. DLL3 expression is also regulated by the transcription factor achaete-scute homolog 1 (ASCL1), which has been identified as an oncogenic driver whose alteration is present in about 60% of all SCLCs. The differential expression profile of DLL3 in normal vs. oncogenic tissue makes this target particularly interesting from a therapeutic point of view.

[0054] Small cell lung cancer (SCLC) can be subdivided into four transcriptional subtypes. Three are defined by presence or absence of the transcription factors ASCL1 (SCLC-A), NEURODI (SCLC-N), or POU2F3 (SCLC-P), while a fourth features inflammatory features (SCLC-Inflamed, or SCLC-I). The most common subtypes, SCLC-A and SCLC-N, derive little benefit from the current standard of care immunotherapy that for instance may include chemotherapy plus atezolizumab. Notably, these immunotherapy-resistant subtypes display the highest level of expression of DLL3 (George et al., Nature, 524:47-53, 2015). DLL3 can be exploited as a target to engage SCLC tumors with a patient’s immune system, for instance via bi-specific antibody, antibody-drug conjugate (“ADC”), or chimeric antigen receptor T-cell therapy (“CAR T”) approaches. In addition, near infrared photoimmunotherapy (NIR-PIT) may be employed for SCLC treatment that employs a DLL3 antibody-photosensitizer conjugate followed by NIR light exposure to damage DLL3-positive tumor cells.Attorney Docket No.: 090723-1514853-MDA23-109PCTII. Definitions

[0055] A number of terms and concepts are discussed below. They are intended to facilitate the understanding of various embodiments of the present disclosure in conjunction with the rest of the present document and the accompanying figures. These terms and concepts may be further clarified and understood based on the accepted conventions in the fields of the present disclosure, as well as the description provided throughout the present document and / or the accompanying figures. Some other terms can be explicitly or implicitly defined in other sections of this document and in the accompanying figures and may be used and understood based on the accepted conventions in the fields of the present disclosure, the description provided throughout the present document and / or the accompanying figures. The terms not explicitly defined can also be defined and understood based on the accepted conventions in the fields of the present disclosure and interpreted in the context of the present document and / or the accompanying figures.

[0056] Unless otherwise defined, all terms of art, notations, and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of ordinary skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference over the definition of the term as generally understood in the art.

[0057] Articles “a” and “an” are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, “an element” means at least one element and can include more than one element.

[0058] The use herein of the terms “including,” “comprising,” or “having,” and variations thereof, is meant to encompass the elements listed thereafter and equivalents thereof as well as additional elements. Embodiments recited as “including,” “comprising,” or “having” certain elements are also contemplated as “consisting essentially of and “consisting of those certain elements. As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations where interpreted in the alternative (“or”).

[0059] As used herein, the transitional phrase “consisting essentially of’ (and grammatical variants) is to be interpreted as encompassing the recited materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. See, e.g., In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis in theAttorney Docket No.: 090723-1514853-MDA23-109PCT original); see also MPEP § 2111.03. Thus, the term “consisting essentially of’ as used herein should not be interpreted as equivalent to “comprising.”

[0060] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0061] The terms “about” and “approximately” as used herein shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20% (%); preferably, within 10%; and more preferably, within 5% of a given value or range of values. Any reference to “about X” or “approximately X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, expressions “about X” or “approximately X” are intended to teach and provide written support for a claim limitation of, for example, “0.98X.” Numerical quantities given herein are approximate unless stated otherwise, meaning that the term “about” or “approximately” can be inferred when not expressly stated. When “about” is applied to the beginning of a numerical range, it applies to both ends of the range.

[0062] As used throughout, the terms “nucleic acid,” “nucleic acid sequence,” “oligonucleotide,” “nucleotides,” or other grammatical equivalents as used herein mean at least two nucleotides, either deoxyribonucleotides or ribonucleotides, or analogs thereof, covalently linked together. Polynucleotides are polymers of any length, including, e.g., 20, 50, 100, 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. A polynucleotide described herein generally contains phosphodiester bonds, although in some cases, nucleic acid analogs are included that may have at least one different linkage, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphophoroamidite linkages, and peptide nucleic acid backbones and linkages. Mixtures of naturally occurring polynucleotides and analogs can be made; alternatively, mixtures of different polynucleotide analogs, and mixtures of naturally occurring polynucleotides and analogs may be made. The following are non-limiting examples of polynucleotides: a gene or gene fragment, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, cRNA, recombinant polynucleotides, branchedAttorney Docket No.: 090723-1514853-MDA23-109PCT polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. The term also includes both double- and single-stranded molecules. Unless otherwise specified or required, the term polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. Unless otherwise indicated, a particular polynucleotide sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues.

[0063] Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof, alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated.

[0064] The terms “polypeptide,” “protein,” and “peptide” are used interchangeably herein to refer to a polymer of amino acid residues in a single chain. 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. Amino acid polymers may comprise entirely L-amino acids, entirely D-amino acids, or a mixture of L and D amino acids. The term “protein” as used herein refers to either a polypeptide or a dimer (z.e., two) or multimer (z.e., three or more) of single chain polypeptides. The single chain polypeptides of a protein may be joined by a covalent bond, e.g., a disulfide bond, or non-covalent interactions. The terms “portion” and “fragment” are used interchangeably herein to refer to parts of a polypeptide, nucleic acid, or other molecular construct.

[0065] The amino acids in the polypeptides described herein can be any of the 20 naturally occurring amino acids, D-stereoisomers of the naturally occurring amino acids, unnaturalAttomey Docket No.: 090723-1514853-MDA23-109PCT amino acids and chemically modified amino acids. Unnatural amino acids (that is, those that are not naturally found in proteins) are also known in the art, as set forth in, for example, Zhang el al.. 2013, “Protein engineering with unnatural amino acids,” Curr. Opin. Struct. Biol. 23(4): 581-87; Xie et al.. 2005, “Adding amino acids to the genetic repertoire,” Curr. Opin. Chem. Biol. 9(6): 548-54; and all references cited therein. Beta and gamma amino acids are known in the art and are also contemplated herein as unnatural amino acids.

[0066] As used herein, a chemically modified amino acid refers to an amino acid whose side chain has been chemically modified. For example, a side chain can be modified to comprise a signaling moiety, such as a fluorophore or a radiolabel. A side chain can also be modified to comprise a new functional group, such as a thiol, carboxylic acid, or amino group. Post- translationally modified amino acids are also included in the definition of chemically modified amino acids.

[0067] The term “identity” or “substantial identity,” as used in the context of a polynucleotide or polypeptide sequence described herein, refers to a sequence that has at least 60% sequence identity to a reference sequence. Alternatively, percent identity can be any integer from 60% to 100%. Exemplary embodiments include at least: 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, as compared to a reference sequence using the programs described herein; preferably BLAST using standard parameters, as described below. One of ordinary skill in the art will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning and the like.

[0068] 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.

[0069] 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 from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 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-Attorney Docket No.: 090723-1514853-MDA23-109PCT known in the art. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith & Waterman, 1981, Add. APL. Math. 2:482, by the homology alignment algorithm of Needleman & Wunsch, 1970, J. Mol. Biol. 48:443, by the search for similarity method of Pearson & Lipman, 1988, Proc. Natl. Acad. Sci. (U.S.A.) 85:2444, by computerized implementations of these algorithms (e.g., BLAST), or by manual alignment and visual inspection.

[0070] Algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., 1990, J. Mol. Biol. 215: 403-10 and Altschul et al., 1977, Nucleic Acids Res. 25: 3389-402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI) web site. The 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-valued 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 al. (1977)). These initial neighborhood word hits acts as seeds for initiating searches to find longer HSPs containing them. The word hits are then 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 negativescoring 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 size (W) of 28, an expectation (E) of 10, M=l, N=-2, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word size (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, 1989, Proc. Natl. Acad. Sci. USA 89: 10915).

[0071] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, 1993, Proc. Nat’l. Acad. Sci. USA 90:5873-87). 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 isAttorney Docket No.: 090723-1514853-MDA23-109PCT 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 0.01, more preferably less than about 10'5, and most preferably less than about IO'20.

[0072] As used herein, DLL3 refers to the Delta-like ligand 3 (“DLL3”) marker. Certain cancers, including Small Cell Lung Cancer, may be characterized by production of the DLL3 marker on cell surfaces. Therefore, the targeting of this cell surface marker for instance during immunotherapy may yield positive therapeutic outcomes.

[0073] As such, provided herein are antibodies and antigen-binding portions thereof that specifically bind to DLL3. Also provided herein are various compositions of such antibodies or antigen-binding fragments thereof, recombinant nucleic acids encoding the antibodies and antigen-binding portions thereof, and associated methods of use. The disclosed anti-DLL3 antibodies are capable of high DLL3-binding affinity and of high anti-tumor efficacy. The antibodies and antigen-binding portions thereof, and associated methods provided herein, represent a novel approach for treating patients with SCLC and other cancers that express DLL3.III. Antibodies

[0074] In one aspect, the present disclosure provides antibodies and antigen-binding portions thereof that bind specifically to DLL3. As used herein, the term “antibody” encompasses, but is not limited to, whole immunoglobulin (z.e., an intact antibody) of any class. Native antibodies are usually heterotetrametric glycoproteins, composed of two identical light (L) chains and two identical heavy (H) chains. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH or VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL or VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains. The light chains of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (K) and lambda (X), based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes ofAttorney Docket No.: 090723-1514853-MDA23-109PCT immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. As used herein, the term antibody also encompasses an antibody fragment, for example, an antigen-binding fragment. Antigenbinding fragments comprise at least one antigen-binding domain. One example of an antigenbinding domain is an antigen-binding domain formed by a VH-VL dimer. Antibodies and antigen-binding fragments thereof can be described by the antigen to which they specifically bind. For example, as used herein, the terms “DLL3 antibody” and “anti-DLL3 antibody” both refer to an antibody or fragment thereof that specifically binds DLL3.

[0075] The term “variable” is used herein to describe certain portions of the antibody domains that differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a P-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the P-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity. Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding and confer antigen specificity and binding affinity to the antibody. (See Kabat et al. (1991) Sequences of Proteins of Immunological Interest 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD.) CDR sequences on the heavy chain (VH) may be designated as CDRH1, CDRH2, and CDRH3 (alternatively as VHCDR1, VHCDR2, and VHCDR3), while CDR sequences on the light chain (VL) may be designated as CDRL1, CDRL2, and CDRL3 (alternatively as VLCDR1, VLCDR2, and VLCDR3).

[0076] The term “epitope,” as used herein, means a component of an antigen capable of specific binding to an antibody or antigen binding fragment thereof. Such componentsAttorney Docket No.: 090723-1514853-MDA23-109PCT optionally comprise one or more contiguous amino acid residues and / or one or more noncontiguous amino acid residues. Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non- conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope can comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antigen binding protein binds can be determined using known techniques for epitope determination such as, for example, testing for antigen binding protein binding to antigen variants with different point mutations.

[0077] As used herein, the terms “binds specifically to,” “specifically binds to,” “specific for,” “targets,” “binds selectively to,” and “selective for” DLL3 or an isoform or an epitope of a DLL3 protein, and the like, mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0078] Provided herein are antibodies and antigen binding portions thereof that bind specifically to DLL3. The DLL3 antibodies and antigen binding portions thereof are polypeptides. As used herein, the terms “antigen binding portion” and “fragment” are used interchangeably to refer to a portion of an antibody polypeptide sequence that binds specifically to DLL3. DLL3 -specific antibodies were identified and tested as described in the Examples below. In some embodiments, the antibodies and antigen binding portions thereof provided herein may be a humanized antibody and antigen binding portions thereof.

[0079] In some embodiments, heavy chain variable region sequences and light chain variable region sequences of the isolated antibody or antibody fragment are one or more of the sequences as set forth in Table 1. The CDR sequences in the variable domains listed in Table 1 are indicated by bold text. In some embodiments, the heavy chain variable region is a polypeptide sequence having at least 90% identity (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 1-34, 38-51, 418, or 419. In certain embodiments, the heavy chain variable region is a polypeptide sequence having at least 90% identity (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 1-7. In some embodiments, the light chain variable region is a polypeptideAttorney Docket No.: 090723-1514853-MDA23-109PCT sequence having at least 90% identity (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, or 421. In certain embodiments, the light chain variable region is a polypeptide sequence having at least 90% identity (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 52-58.

[0080] In certain embodiments, the isolated antibody or antibody fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to any one of SEQ ID NOs: 1-34, 38-51, 418, or 419 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, or 421. In certain embodiments, the isolated antibody or antibody fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to any one of SEQ ID NOs: 1-7 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to any one of SEQ ID NOs: 52-58.Table 1. Variable region amino acid sequences of select DLL3-antibodies.Attorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCT

[0081] In some embodiments, the antibody or antigen binding fragment thereof as provided in this disclosure has a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences listed by row in Table 2. In some embodiments, the antibody or antigen binding fragment thereof has a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences listed by row in Table 2. In some embodiments, the antibody or antigen binding fragment thereof has a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences and a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences listed by row in Table 2.Table 2. Complementarity determining regions of select DLL3-antibodies.Attorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCTAttorney Docket No.: 090723-1514853-MDA23-109PCT

[0082] In some embodiments, provided is an isolated antibody or antigen binding fragment, comprising: (a) a heavy chain variable region comprising (i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, 106, 112, 115, 118, or 121; (ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, 107, 113, 116, 119, or 122; and (iii) VHCDR3 amino acid sequence comprising SEQ ID NOs: 105, 108, 111, 114, 117, 120, or 123; and (b) a light chain variable region comprising (i) a VLCDR1 amino acid sequence comprising SEQ ID NO: 256,259, 265, 268, 271, or 274; (ii) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257,260, 266, 269, 272, or 275; and (iii)a VLCDR3 amino acid sequence comprising SEQ ID NO: 258, 261, 267, 270, 273, or 276.

[0083] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 1 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ IDAttorney Docket No.: 090723-1514853-MDA23-109PCTNO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 52 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0084] In another aspect provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 2 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 53 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 259, a CDRL2 amino acid sequence comprising SEQ ID NO: 260, and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0085] In still another aspect provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 3 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 111; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 54 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 259, a CDRL2 amino acid sequence comprising SEQ ID NO: 260, and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0086] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 4 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 112, a CDRH2 amino acid sequence comprising SEQ ID NO: 113, and a CDRH3 amino acid sequence comprising SEQ ID NO: 114; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 55 and comprising a CDRL1Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequence comprising SEQ ID NO: 265, a CDRL2 amino acid sequence comprising SEQ ID NO: 266, and a CDRL3 amino acid sequence comprising SEQ ID NO: 267.

[0087] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 5 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 115, a CDRH2 amino acid sequence comprising SEQ ID NO: 116, and a CDRH3 amino acid sequence comprising SEQ ID NO: 117; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 56 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 268, a CDRL2 amino acid sequence comprising SEQ ID NO: 269, and a CDRL3 amino acid sequence comprising SEQ ID NO: 270.

[0088] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 6 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 118, a CDRH2 amino acid sequence comprising SEQ ID NO: 119, and a CDRH3 amino acid sequence comprising SEQ ID NO: 120; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 57 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 271, a CDRL2 amino acid sequence comprising SEQ ID NO: 272, and a CDRL3 amino acid sequence comprising SEQ ID NO: 273.

[0089] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 7 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 122, and a CDRH3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0090] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable regionAttorney Docket No.: 090723-1514853-MDA23-109PCT(VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 8 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 124, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 59 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0091] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 9 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 128, and a CDRH3 amino acid sequence comprising SEQ ID NO: 129; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0092] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 10 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 130, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 61 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 285.

[0093] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 11 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chainAttorney Docket No.: 090723-1514853-MDA23-109PCT variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 62 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0094] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 12 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 136, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 63 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0095] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 13 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 64 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0096] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 14 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 142, a CDRH2 amino acid sequence comprising SEQ ID NO: 143, and a CDRH3 amino acid sequence comprising SEQ ID NO: 144; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 65 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 295, a CDRL2 amino acid sequence comprising SEQ ID NO: 296, and a CDRL3 amino acid sequence comprising SEQ ID NO: 297.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0097] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 15 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 145, a CDRH2 amino acid sequence comprising SEQ ID NO: 146, and a CDRH3 amino acid sequence comprising SEQ ID NO: 147; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 66 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 298, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 300.

[0098] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 16 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 67 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 301, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0099] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 17 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 124, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 68 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0100] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 18 and comprising a CDRH1 amino acidAttorney Docket No.: 090723-1514853-MDA23-109PCT sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 69 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0101] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 19 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 158, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 70 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0102] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 20 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 71 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 313, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0103] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 21 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 163, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 72 and comprising a CDRL1Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0104] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 22 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 73 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0105] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 23 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 171; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 74 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0106] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 24 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 172, a CDRH2 amino acid sequence comprising SEQ ID NO: 173, and a CDRH3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 75 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 325, a CDRL2 amino acid sequence comprising SEQ ID NO: 326, and a CDRL3 amino acid sequence comprising SEQ ID NO: 327.

[0107] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable regionAttorney Docket No.: 090723-1514853-MDA23-109PCT(VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 25 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 175, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 76 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 328, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0108] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 26 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 178, a CDRH2 amino acid sequence comprising SEQ ID NO: 179, and a CDRH3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 77 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 331, a CDRL2 amino acid sequence comprising SEQ ID NO: 260, and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0109] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 27 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 181, a CDRH2 amino acid sequence comprising SEQ ID NO: 182, and a CDRH3 amino acid sequence comprising SEQ ID NO: 183; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 78 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 334, a CDRL2 amino acid sequence comprising SEQ ID NO: 335, and a CDRL3 amino acid sequence comprising SEQ ID NO: 336.

[0110] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 28 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chainAttorney Docket No.: 090723-1514853-MDA23-109PCT variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 79 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 337, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.[OHl] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 29 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 187, a CDRH2 amino acid sequence comprising SEQ ID NO: 188, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 80 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0112] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 30 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 81 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0113] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 31 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 145, a CDRH2 amino acid sequence comprising SEQ ID NO: 146, and a CDRH3 amino acid sequence comprising SEQ ID NO: 147; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 82 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 298, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 300.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0114] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 32 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 196, a CDRH2 amino acid sequence comprising SEQ ID NO: 197, and a CDRH3 amino acid sequence comprising SEQ ID NO: 198; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 83 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 349, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 351.

[0115] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 33 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 199, a CDRH2 amino acid sequence comprising SEQ ID NO: 200, and a CDRH3 amino acid sequence comprising SEQ ID NO: 201; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 84 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0116] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 34 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 85 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 337, a CDRL2 amino acid sequence comprising SEQ ID NO: 356, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.

[0117] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 1 and comprising a CDRH1 amino acidAttorney Docket No.: 090723-1514853-MDA23-109PCT sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 86 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0118] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 11 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 87 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0119] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 37 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 88 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 364, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0120] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 38 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 214, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 89 and comprising a CDRL1Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0121] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 39 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 218, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 90 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0122] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 40 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 172, a CDRH2 amino acid sequence comprising SEQ ID NO: 221, and a CDRH3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 91 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0123] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 41 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 218, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 92 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 271, a CDRL2 amino acid sequence comprising SEQ ID NO: 272, and a CDRL3 amino acid sequence comprising SEQ ID NO: 273.

[0124] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable regionAttorney Docket No.: 090723-1514853-MDA23-109PCT(VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 42 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 226, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 93 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 379, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.

[0125] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 43 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 122, and a CDRH3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0126] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 44 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 233, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 95 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0127] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 45 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 128, and a CDRH3 amino acid sequence comprising SEQ ID NO: 129; and a light chainAttorney Docket No.: 090723-1514853-MDA23-109PCT variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 96 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0128] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 46 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 238, a CDRH2 amino acid sequence comprising SEQ ID NO: 239, and a CDRH3 amino acid sequence comprising SEQ ID NO: 240; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 97 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 391, a CDRL2 amino acid sequence comprising SEQ ID NO: 392, and a CDRL3 amino acid sequence comprising SEQ ID NO: 393.

[0129] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 47 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 242, and a CDRH3 amino acid sequence comprising SEQ ID NO: 243; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 98 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0130] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 48 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 244, a CDRH2 amino acid sequence comprising SEQ ID NO: 245, and a CDRH3 amino acid sequence comprising SEQ ID NO: 246; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 99 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 397, a CDRL2 amino acid sequence comprising SEQ ID NO: 335, and a CDRL3 amino acid sequence comprising SEQ ID NO: 336.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0131] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 49 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 238, a CDRH2 amino acid sequence comprising SEQ ID NO: 248, and a CDRH3 amino acid sequence comprising SEQ ID NO: 240; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 100 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 391, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 402.

[0132] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 50 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 250, a CDRH2 amino acid sequence comprising SEQ ID NO: 251, and a CDRH3 amino acid sequence comprising SEQ ID NO: 252; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 101 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0133] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 51 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 218, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 102 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0134] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 418 and comprising a CDRH1 amino acidAttorney Docket No.: 090723-1514853-MDA23-109PCT sequence comprising SEQ ID NO: 426, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 420 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0135] In another aspect, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 419 and comprising a CDRH1 amino acid sequence comprising SEQ ID NO: 178, a CDRH2 amino acid sequence comprising SEQ ID NO: 179, and a CDRH3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 421 and comprising a CDRL1 amino acid sequence comprising SEQ ID NO: 435, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0136] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 1 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 52.

[0137] In other embodiments, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 2 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 53.

[0138] In yet other embodiments, provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 3 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 53.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0139] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 4 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 55.

[0140] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 5 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 56.

[0141] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 6 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 57.

[0142] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 7 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58.

[0143] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 8 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 59.

[0144] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 9 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58.

[0145] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 10 and a lightAttorney Docket No.: 090723-1514853-MDA23-109PCT chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 61.

[0146] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 11 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 62.

[0147] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 12 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 63.

[0148] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 13 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 64.

[0149] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 14 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 65.

[0150] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 15 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 66.

[0151] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 16 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 67.

[0152] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%,Attorney Docket No.: 090723-1514853-MDA23-109PCT91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 17 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 68.

[0153] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 18 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 69.

[0154] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 19 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 70.

[0155] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 20 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 71.

[0156] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 21 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 72.

[0157] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 22 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 73.

[0158] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 23 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 74.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0159] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 24 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 75.

[0160] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 25 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 76.

[0161] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 26 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 77.

[0162] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 27 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 78.

[0163] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 28 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 79.

[0164] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 29 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 80.

[0165] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 30 and a lightAttorney Docket No.: 090723-1514853-MDA23-109PCT chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 81.

[0166] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 31 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 82.

[0167] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 32 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 83.

[0168] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 33 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 84.

[0169] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 34 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 85.

[0170] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 1 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 86.

[0171] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 11 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 87.

[0172] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%,Attorney Docket No.: 090723-1514853-MDA23-109PCT91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 37 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 88.

[0173] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 38 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 89.

[0174] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 39 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 90.

[0175] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 40 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 91.

[0176] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 41 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 92.

[0177] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 42 and a light chain variable region (VL) having at least 90% identity (for example, at least 9042 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 93.

[0178] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 43 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0179] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 44 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 95.

[0180] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 45 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 96.

[0181] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 46 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 97.

[0182] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 47 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 98.

[0183] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 48 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 99.

[0184] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 49 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 100.

[0185] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 50 and a lightAttorney Docket No.: 090723-1514853-MDA23-109PCT chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 101.

[0186] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 51 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 102.

[0187] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 418 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 420.

[0188] In certain embodiments, the isolated antibody or antigen binding fragment comprises: a heavy chain variable region (VH) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical) to SEQ ID NO: 419 and a light chain variable region (VL) having at least 90% identity (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 421.

[0189] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 1 and a light chain variable region (VL) comprising SEQ ID NO: 52, for instance as found in antibody DLL3-2 as described herein.

[0190] In another embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 2 and a light chain variable region (VL) comprising SEQ ID NO: 53, for instance as found in antibody DLL3-8 as described herein.

[0191] In still another embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 3 and a light chain variable region (VL) comprising SEQ ID NO: 53, for instance as found in antibody DLL3-22 as described herein.

[0192] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 4 and a light chain variable region (VL) comprising SEQ ID NO: 55, for instance as found in antibody DLL3-48 as described herein.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0193] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 5 and a light chain variable region (VL) comprising SEQ ID NO: 56, for instance as found in antibody DLL3-68 as described herein.

[0194] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 6 and a light chain variable region (VL) comprising SEQ ID NO: 57, for instance as found in antibody DLL3-73 as described herein.

[0195] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 7 and a light chain variable region (VL) comprising SEQ ID NO: 58, for instance as found in antibody DLL3-79 as described herein.

[0196] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 8 and a light chain variable region (VL) comprising SEQ ID NO: 59, for instance as found in antibody DLL3-1 as described herein.

[0197] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 9 and a light chain variable region (VL) comprising SEQ ID NO: 58, for instance as found in antibody DLL3-3 as described herein.

[0198] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 10 and a light chain variable region (VL) comprising SEQ ID NO: 61, for instance as found in antibody DLL3-6 as described herein.

[0199] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 11 and a light chain variable region (VL) comprising SEQ ID NO: 62, for instance as found in antibody DLL3-7 as described herein.

[0200] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 12 and a light chain variable region (VL) comprising SEQ ID NO: 63, for instance as found in antibody DLL3-10 as described herein.

[0201] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VH) comprising SEQ ID NO: 13 and a light chain variable region (VL) comprising SEQ ID NO: 64, for instance as found in antibody DLL3-16 as described herein.

[0202] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 14 and a light chain variable region (VL) comprising SEQ ID NO: 65, for instance as found in antibody DLL3-17 as described herein.

[0203] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 15 and a light chain variable region (VL) comprising SEQ ID NO: 66, for instance as found in antibody DLL3-18 as described herein.

[0204] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 16 and a light chain variable region (VL) comprising SEQ ID NO: 67, for instance as found in antibody DLL3-19 as described herein.

[0205] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 17 and a light chain variable region (VL) comprising SEQ ID NO: 68, for instance as found in antibody DLL3-24 as described herein.

[0206] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 18 and a light chain variable region (VL) comprising SEQ ID NO: 69, for instance as found in antibody DLL3-27 as described herein.

[0207] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 19 and a light chain variable region (VL) comprising SEQ ID NO: 70, for instance as found in antibody DLL3-31 as described herein.

[0208] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 20 and a light chain variable region (VL) comprising SEQ ID NO: 71, for instance as found in antibody DLL3-32 as described herein.

[0209] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 21 and a light chain variable region (VL) comprising SEQ ID NO: 72, for instance as found in antibody DLL3-33 as described herein.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0210] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 22 and a light chain variable region (VL) comprising SEQ ID NO: 73, for instance as found in antibody DLL3-37 as described herein.

[0211] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 23 and a light chain variable region (VL) comprising SEQ ID NO: 74, for instance as found in antibody DLL3-39 as described herein.

[0212] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 24 and a light chain variable region (VL) comprising SEQ ID NO: 75, for instance as found in antibody DLL3-41 as described herein.

[0213] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 25 and a light chain variable region (VL) comprising SEQ ID NO: 76, for instance as found in antibody DLL3-45 as described herein.

[0214] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 26 and a light chain variable region (VL) comprising SEQ ID NO: 77, for instance as found in antibody DLL3-46 as described herein.

[0215] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 27 and a light chain variable region (VL) comprising SEQ ID NO: 78, for instance as found in antibody DLL3-51 as described herein.

[0216] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 28 and a light chain variable region (VL) comprising SEQ ID NO: 79, for instance as found in antibody DLL3-56 as described herein.

[0217] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 29 and a light chain variable region (VL) comprising SEQ ID NO: 80, for instance as found in antibody DLL3-57 as described herein.

[0218] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VH) comprising SEQ ID NO: 30 and a light chain variable region (VL) comprising SEQ ID NO: 81, for instance as found in antibody DLL3-66 as described herein.

[0219] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 31 and a light chain variable region (VL) comprising SEQ ID NO: 82, for instance as found in antibody DLL3-67 as described herein.

[0220] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 32 and a light chain variable region (VL) comprising SEQ ID NO: 83, for instance as found in antibody DLL3-69 as described herein.

[0221] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 33 and a light chain variable region (VL) comprising SEQ ID NO: 84, for instance as found in antibody DLL3-70 as described herein.

[0222] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 34 and a light chain variable region (VL) comprising SEQ ID NO: 85, for instance as found in antibody DLL3-78 as described herein.

[0223] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 1 and a light chain variable region (VL) comprising SEQ ID NO: 86, for instance as found in antibody DLL3-84 as described herein.

[0224] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 11 and a light chain variable region (VL) comprising SEQ ID NO: 87, for instance as found in antibody DLL3-90 as described herein.

[0225] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 37 and a light chain variable region (VL) comprising SEQ ID NO: 88, for instance as found in antibody DLL3-92 as described herein.

[0226] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 38 and a light chain variable region (VL) comprising SEQ ID NO: 89, for instance as found in antibody DLL3-93 as described herein.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0227] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 39 and a light chain variable region (VL) comprising SEQ ID NO: 90, for instance as found in antibody DLL3-99 as described herein.

[0228] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 40 and a light chain variable region (VL) comprising SEQ ID NO: 91, for instance as found in antibody DLL3-108 as described herein.

[0229] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 41 and a light chain variable region (VL) comprising SEQ ID NO: 92, for instance as found in antibody DLL3-114 as described herein.

[0230] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 42 and a light chain variable region (VL) comprising SEQ ID NO: 93, for instance as found in antibody DLL3-P6 as described herein.

[0231] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 43 and a light chain variable region (VL) comprising SEQ ID NO: 58, for instance as found in antibody DLL3-P7 as described herein.

[0232] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 44 and a light chain variable region (VL) comprising SEQ ID NO: 95, for instance as found in antibody DLL3-P15 as described herein.

[0233] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 45 and a light chain variable region (VL) comprising SEQ ID NO: 96, for instance as found in antibody DLL3-P21 as described herein.

[0234] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 46 and a light chain variable region (VL) comprising SEQ ID NO: 97, for instance as found in antibody DLL3-P25 as described herein.

[0235] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VH) comprising SEQ ID NO: 47 and a light chain variable region (VL) comprising SEQ ID NO: 98, for instance as found in antibody DLL3-P26 as described herein.

[0236] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 48 and a light chain variable region (VL) comprising SEQ ID NO: 99, for instance as found in antibody DLL3-P28 as described herein.

[0237] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 49 and a light chain variable region (VL) comprising SEQ ID NO: 100, for instance as found in antibody DLL3-P30 as described herein.

[0238] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 50 and a light chain variable region (VL) comprising SEQ ID NO: 101, for instance as found in antibody DLL3-P31 as described herein.

[0239] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 51 and a light chain variable region (VL) comprising SEQ ID NO: 102, for instance as found in antibody DLL3-P32 as described herein.

[0240] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 418 and a light chain variable region (VL) comprising SEQ ID NO: 420, for instance as found in antibody DLL3-57 as described herein.

[0241] In one embodiment provided herein is an isolated antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises: a heavy chain variable region (VH) comprising SEQ ID NO: 419 and a light chain variable region (VL) comprising SEQ ID NO: 421, for instance as found in antibody DLL3-109 as described herein.

[0242] In each case, where a specific amino acid sequence is recited, embodiments comprising a sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity to the recited sequence are also provided.

[0243] As with all peptides, polypeptides, and proteins, including fragments thereof, it is understood that additional modifications in the amino acid sequence of the DLL3 -specific antibodies or antigen binding fragments thereof described herein, for example, in the heavy chain variable region and / or light chain variable region, can occur that do not alter the nature or function of the antibodies or antigen binding fragments thereof. Such modifications includeAttorney Docket No.: 090723-1514853-MDA23-109PCT conservative amino acids substitutions, such that each recited sequence optionally contains one or more conservative amino acid substitutions. The list provided below identifies groups that contain amino acids that are conservative substitutions for one another; these groups are exemplary as other conservative substitutions are known to those of skill in the art:1) 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).

[0244] By way of example, when an aspartic acid at a specific residue is mentioned, also contemplated is a conservative substitution at the residue, for example, glutamic acid. Nonconservative substitutions, for example, substituting a proline with glycine or substituting a lysine with an asparagine, are also contemplated.

[0245] In some instances, the affinity of DLL3 -specific antibodies or antigen binding fragments thereof may be optimized through CRISPR or other site-directed mutagenesis methods to increase or decrease affinity as desired based on one or more of the known characteristics of the binding interaction with DLL3, the structure of either or both of the antibodies or antigen binding fragments thereof, or the DLL3 protein.

[0246] Methods of generating and screening for antibodies and antigen binding fragments thereof as provided in this disclosure are described in the Examples and are well-known in the art. Methods of further modifying antibodies for enhanced properties (e.g., enhanced affinity, chimerization, humanization) as well as generating antigen binding fragments, as described herein, are also well-known in the art.

[0247] In some embodiments, the heavy chain variable region and / or the light chain variable region of the isolated antibody or antigen binding fragment has an identical sequence to the heavy chain variable region and / or the light chain variable region of the antibody produced by the methods described herein and, in the Examples, below. In some embodiments, the heavy chain variable region and / or the light chain variable region of the isolated antibody or antigen binding fragments comprises one or more modifications, e.g., amino acid substitutions, deletions, or insertions.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0248] The present disclosure also provides chimeric antibodies. The term chimeric antibody refers to an antibody in which a component of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0249] A human antibody is one that possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources, genetically modified non-human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0250] Humanized forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies can also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications can be made to further refine antibody function. (See Jones et al. , 1986, Nature, 321 :522-25; Riechmann et al., 1988, Nature, 332:323-29; and Presta, 1992, Curr. Op. Struct. Biol., 2:593-96).

[0251] In some embodiments, the antibody or antigen binding fragment thereof provided herein can include a heavy (H) chain variable domain sequence (abbreviated herein as VH or VH), and a light (L) chain variable domain sequence (abbreviated herein as VL or VL). In some embodiments, an antibody molecule comprises or consists of a heavy chain and a light chain (sometimes referred to as a half antibody). In another example, and as described further below, an antibody molecule includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single chain antibodies (scFv, for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which may be produced by the modification of whole antibodies or synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to bind specifically to their respective antigen. Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, andAttorney Docket No.: 090723-1514853-MDA23-109PCT from any subclass (e.g., IgGl, IgG2, IgG3, and IgG4) of antibodies. The preparation of antibody molecules can be monoclonal or polyclonal. An antibody molecule can also be a human, humanized, CDR-grafted, or an in vitro generated antibody. The antibody can have a heavy chain constant region chosen from, e.g., IgGl, IgG2, IgG3, or IgG4. The antibody can also have a light chain chosen from either kappa or lambda light chains.

[0252] Antigen binding fragments of an antibody molecule are well known in the art, and include, for example, (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv) (See, e.g., Bird et al., 1988 Science 242:423-26; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-83); and (viii) a single domain antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0253] In some embodiments, the antibody is a monoclonal antibody. As used herein, the term monoclonal antibody refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are the same or substantially similar and that bind the same epitope(s), except for variants that can normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of yeast clones, phage clones, bacterial clones, mammalian cell clones, hybridoma clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target, for example, by affinity maturation, to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0254] In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a heavy chain variable region sequence and a light chain variable region sequence that are derived from an immunoglobulin producing human B cell, and further comprises a kappa or lambda light chain constant region. In some embodiments, the light chain constant region (kappa or lambda) is from the same type of light chain (i.e., kappa or lambda)Attorney Docket No.: 090723-1514853-MDA23-109PCT as the light chain variable region that was derived from the immunoglobulin producing human B cell; as a non-limiting example, if an IgE-producing human B cell comprises a kappa light chain, then the monoclonal antibody that is produced can comprise the light chain variable region from the IgE-producing B cell and further comprises a kappa light chain constant region.

[0255] In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a heavy chain variable region sequence and a light chain variable region sequence that are derived from an immunoglobulin-producing human B cell, and further comprises a heavy chain constant region having an IgG isotype (e.g., IgG4), an IgA isotype (e.g., IgAl), an IgM isotype, an IgD isotype, or that is derived from an IgG, IgA, IgM, or IgD isotype (e.g., is a modified IgG4 constant region). It will be appreciated by a person of ordinary skill in the art that the different heavy chain isotypes (IgA, IgD, IgE, IgG, and IgM) have different effector functions that are mediated by the heavy chain constant region, and that for certain uses it may be desirable to have an antibody that has the effector function of a particular isotype (e.g., IgG).

[0256] In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a native (i.e., wild-type) human IgG, IgA, IgM, or IgD constant region. In some embodiments, the monoclonal antibody comprises a native human IgGl constant region, a native human IgG2 constant region, a native human IgG3 constant region, a native human IgG4 constant region, a native human IgAl constant region, a native human IgA2 constant region, a native human IgM constant region, or a native human IgD constant region. In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a heavy chain constant region that comprises one or more modifications. It will be appreciated by a person of ordinary skill in the art that modifications such as amino acid substitutions can be made at one or more residues within the heavy chain constant region that modulate effector function. In some embodiments, the modification reduces effector function, e.g., results in a reduced ability to induce certain biological functions upon binding to an Fc receptor expressed on an effector cell that mediates the effector function. In some embodiments, the modification (e.g., amino acid substitution) prevents in vivo Fab arm exchange, which can introduce undesirable effects and reduce the therapeutic efficacy of the antibody. See, e.g., Silva et al., 2015, J. Biol. Chem. 280:5462-69.

[0257] In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a native (i.e., wild-type) human IgM constant region, human IgD constant region, human IgG constant region that is derived from IgGl, IgG2, IgG3, or IgG4, or human IgA constant region that is derived from IgAl or IgA2 and comprises one or moreAttorney Docket No.: 090723-1514853-MDA23-109PCT modifications that modulate effector function. In some embodiments, the antibody or antigen binding fragment, e.g., a monoclonal antibody, comprises a human IgM constant region, human IgD constant region, human IgG constant region that is derived from IgGl, IgG2, IgG3, or IgG4, or human IgA constant region that is derived from IgAl or IgA2.

[0258] In some embodiments the antibody with specified CDRs is an allotype other the allotype(s) found associated with the antibodies produced by the methods described herein and, in the Examples, below. The antibody may comprise an allotype selected from those listed in Table 3 below.Table 3. Human immunoglobulin allotypes.NB: Alphabetical notation given within brackets. From: Jefferis and Marie-Paule Lefranc, 2009, “Human immunoglobulin allotypes: Possible implications for immunogenicity” mAbs 1(4): 332-38, incorporated herein by reference .

[0259] In some embodiments, a humanized monoclonal antibody comprises CDR sequences, a heavy chain variable region, and / or a light chain variable region as described herein (e.g., as disclosed in Tables 1 and 2) and further comprises a heavy chain constant region and / or a light chain constant region that is heterologous to the antibody produced by the methods described herein and, in the Examples, below from which the CDR sequences and / or variable region sequences are derived. For example, in some embodiments, the humanized monoclonal antibody comprises the CDR sequences and / or variable region sequences of an antibodyAttorney Docket No.: 090723-1514853-MDA23-109PCT produced by the methods described herein and in the Examples below, and further comprises a heavy chain constant region and a light chain constant region that is heterologous to the antibody produced by the methods described herein and in the Examples below (e.g., the heavy chain constant region and / or light chain constant region is a wild-type or modified IgGl, IgG2, IgG3, or IgG4 constant region).

[0260] Antibody molecules can also be single domain antibodies. Single domain antibodies can include antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be any of the art, or any future single domain antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, rat, guinea, pig, human, camel, llama, fish, shark, goat, rabbit, and bovine. Single domain antibodies are described, for example, in International Application Publication No. WO 94 / 04678. For clarity reasons, this variable domain derived from a heavy chain antibody naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from antibodies raised in Camelidae species (e.g., camel, llama, dromedary, alpaca, and guanaco) or other species besides Camelidae.

[0261] In some embodiments, an antigen binding fragment can also be or can also comprise, e.g., a non-antibody, scaffold protein. These proteins are generally obtained through combinatorial chemistry-based adaptation of preexisting antigen-binding proteins. For example, the binding site of human transferrin for human transferrin receptor can be diversified using the system described herein to create a diverse library of transferrin variants, some of which have acquired affinity for different antigens. See, e.g., Ali et al., 1999, J. Biol. Chem. 274:24066-73. The portion of human transferrin not involved with binding the receptor remains unchanged and serves as a scaffold, like framework regions of antibodies, to present the variant binding sites. The libraries are then screened, as an antibody library is screened, and in accordance with the methods described herein, against a target antigen of interest to identify those variants having optimal selectivity and affinity for the target antigen. See, e.g., Hey et al., 2005, TRENDS Biotechnol. 23(10):514-522.

[0262] One of ordinary skill in the art would appreciate that the scaffold portion of the nonantibody scaffold protein can include, e.g., all or part of the Z domain of S. aureus protein A, human transferrin, human tenth fibronectin type III domain, kunitz domain of a human trypsinAttorney Docket No.: 090723-1514853-MDA23-109PCT inhibitor, human CTLA-4, an ankyrin repeat protein, a human lipocalin (e.g., anticalins, such as those described in, e.g., International Application Publication No. WO2015 / 104406), human crystallin, human ubiquitin, or a trypsin inhibitor from E. elaterium.

[0263] In some embodiments, provided are chimeric antibodies, bispecific antibodies (BsAbs), trispecific or other multi-specific antibodies, or bispecific T cell engager (BiTE), that comprise an anti-DLL3 antibody or antigen binding fragment thereof as described in this disclosure. In some embodiments, the DLL3-specific antibody or antigen binding fragment thereof is conjugated to a moiety that specifically binds to an immune cell. In some embodiments, provided is a bispecific antibody comprising an DLL3-specific antibody or antigen binding fragment thereof as described herein and an antibody or antigen binding fragment thereof that specifically binds to an immune cell. In some embodiments, the bispecific antibody comprises an DLL3-specific antibody or antigen-binding portion thereof and an antibody moiety that specifically binds to T cells. Such a molecule is referred to as a bispecific T cell engager and may induce T cell-mediated cytotoxicity of DLL3 expressing cancer cells (see, e.g., Zhou et al., 2021, Biomarker Research 9:38). In some embodiments, the bispecific antibody comprises an DLL3-specific antibody or antigen-binding portion thereof and an antibody moiety that specifically binds to natural killer cells (NK cells). Such a molecule is referred to as a NK cell engager and may induce NK cell-mediated cytotoxicity of DLL3- expressing cancer cells (see, e.g., Demaria et al., 2021, European Journal of Immunology 51(8)11934-1942).

[0264] In some embodiments, the antibody comprises a DLL3 -specific antibody or antigen binding fragment thereof as described in this disclosure and an anti-CD3 antibody (i.e. bispecific or multi-specific DLL3xCD3 antibodies). Such bispecific or multi-specific DLL3xCD3 antibodies act by simultaneous binding to a tumor-associated antigen (TAA) expressed on tumor cells (i.e. DLL3) and to CD3 on a T cell. Crosslinking of these two cell types by the antibody composition allows the formation of an immunological synapse, similar to that of a natural T-cell receptor (TCR) / peptide-major histocompatibility complex (MHC) complex. This synapse results in T-cell activation and thereby the secretion of inflammatory cytokines and cytolytic molecules that are able to kill the tumor cells in the process. It is generally thought that any T cell can serve as an effector cell, regardless of TCR specificity, as TCR signaling for such bispecific or multi-specific CD3 antibodies does not require engagement of the antigen-binding domain of the TCR, but is initiated via CD3 (see Middelburg J. et al., 2021, Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors, Cancers (Basel). Vol. 13, Issue 2, Article 287). In some embodiments, providedAttorney Docket No.: 090723-1514853-MDA23-109PCT are DLL3xCD3 bispecific antibodies comprising an anti-CD3 antibody, for example, an anti- CD3s antibody. In some embodiments, the anti-CD3 antibody has a sequence as set forth in SEQ ID NO: 409 below.EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRS KYNNYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCVRHGNFG DSYVSWFAYWGQGTLVTVSS / GKPGSGKPGSGKPGSGKPGSQAVVTQEPSLTVS PGGTVTLTCGSSTGAVTTSNYANWVQQKPGKSPRGLIGGTNKRAPGVPARFSGS LLGGKAALTISGAQPEDEADYYCALWYSNHWVFGGGTKLTV (SEQ ID NO: 409)

[0265] Any of the DLL3 -specific antibodies or antigen binding fragments thereof described herein can be modified with covalent and / or non-covalent modifications. Such modifications can be introduced into the antibodies or antigen binding fragments by, e.g., reacting targeted amino acid residues of the polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues. Suitable sites for modification can be chosen using any of a variety of criteria including, e.g., structural analysis or amino acid sequence analysis of the antibodies or antigen binding fragments. Recombinant techniques can be used to modify antibodies or antigen binding fragments thereof. For example, amino acids found to not contribute to either the activity or the binding specificity or affinity of the antibody can be deleted without a loss in the respective activity. Insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the antigen binding fragment is not significantly altered or impaired compared to the non-modified antibody, or antigen binding fragment thereof can be made. Such methods are readily apparent to a skilled practitioner in the art and can include site specific mutagenesis of the nucleic acid encoding the antibody or antigen binding fragment thereof. (Zoller et cd.. 1982, NucL Acids Res. 10:6487-500). In some instances, the DLL3-specific antibodies or antigen binding fragments may be labeled by a variety of means for use in diagnostic and / or pharmaceutical applications.

[0266] In some embodiments, the antibodies or antigen binding fragments thereof can be conjugated to a heterologous moiety. The heterologous moiety can be, e.g., a heterologous polypeptide, a therapeutic agent (e.g., a toxin or a drug), a photosensitizer, or a detectable label such as, but not limited to, a radioactive label, an enzymatic label, a fluorescent label, a heavy metal label, a luminescent label, or an affinity tag such as biotin or streptavidin. In some embodiments, the heterologous moiety is an antibody or antigen binding fragment thereof that specifically binds to a different target, and such a conjugated antibody is a type of antibody composition that can be referred to as a bispecific antibody. Additional suitable heterologous polypeptides include, e.g., an antigenic tag (e.g., FLAG (DYKDDDDK) (SEQ ID NO: 410),Attorney Docket No.: 090723-1514853-MDA23-109PCT polyhistidine (6-His; HHHHHH (SEQ ID NO: 411)), hemagglutinin (HA; YPYDVPDYA (SEQ ID NO: 412)), glutathione-S-transferase (GST), or maltose-binding protein (MBP)) for use in purifying the antibodies or antigen binding fragments. Heterologous polypeptides also include polypeptides (e.g., enzymes) that are useful as diagnostic or detectable markers, for example, luciferase, a fluorescent protein (e.g., green fluorescent protein (GFP)), or chloramphenicol acetyl transferase (CAT). A suitable photosensitizer (also referred to as a photoabsorber is, for example, IRDye700DX (IR700). Suitable radioactive labels include, e.g.,32P,33P,14C,125I,131I,35S, and3H. Suitable fluorescent labels include, without limitation, fluorescein, fluorescein isothiocyanate (FITC), green fluorescent protein (GFP), DyLight™ 488, phycoerythrin (PE), propidium iodide (PI), PerCP, PE-Alexa Fluor® 700, Cy5, allophycocyanin, and Cy7. Luminescent labels include, e.g., any of a variety of luminescent lanthanide (e.g., europium or terbium) chelates. For example, suitable europium chelates include the europium chelate of diethylene triamine pentaacetic acid (DTPA) or tetraazacyclododecane-l,4,7, 10-tetraacetic acid (DOTA). Enzymatic labels include, e.g., alkaline phosphatase, CAT, luciferase, and horseradish peroxidase. Another labeling technique which may result in greater sensitivity consists of coupling the antibodies to low molecular weight haptens. These haptens can then be specifically altered by means of a second reaction. For example, it is common to use haptens such as biotin, which reacts with avidin, or dinitrophenol, pyridoxal, or fluorescein, which can react with specific antihapten antibodies. Additional acceptable heterologous moieties are described below in Section VIII.

[0267] In some instances, the DLL3 -specific antibody or antigen binding fragment thereof may be conjugated to an imaging agent. For example, the DLL3-specific antibody or antigenbinding fragment thereof may be labelled for use in radionuclide imaging. In particular, the agent may be directly or indirectly labelled with a radioisotope. Examples of radioisotopes that may be used are:277Ac,211At,128Ba,131Ba,7Be,204Bi,205Bi,206Bi,76Br,77Br,82Br,109Cd,47Ca,nC,14C,36C1,48Cr,51Cr,62Cu,64Cu,67Cu,165Dy,155Eu,18F,153Gd,66Ga,67Ga,68Ga,72Ga,198Au,3H166HO,n iIn,113mIn,115mIn,1231,1251,1311,189Ir,191mIr,192Ir,194Ir,52Fe,55Fe,59Fe,177Lu,15O,191m’1910s,109Pd,32P,33P,42K,226Ra,186Re,188Re,82mRb,153Sm,46Sc,47Sc,72Se,75Se,105Ag,22Na,24Na,89Sr,35S,38S,177Ta,96Tc, "mTc,2O1T1,2O2T1,113Sn,117mSn,121Sn,166Yb,169Yb,175Yb,88Y,90Y,62Zn and65Zn. Preferably the radioisotope is131I,125I,123I,1 UI, "mTc,90Y,186Re,188Re,32P,153Sm,67Ga,2O1T1,77Br, or18F, and is imaged with a photoscanning device. Procedures for labeling biological agents with the radioactive isotopes are generally known in the art.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0268] Two proteins (e.g., an antibody and a heterologous moiety) can be cross-linked using any of a number of known chemical cross linkers. Examples of such cross linkers are those that link two amino acid residues via a linkage that includes a “hindered” disulfide bond. In these linkages, a disulfide bond within the cross-linking unit is protected (by hindering groups on either side of the disulfide bond) from reduction by the action, for example, of reduced glutathione or the enzyme disulfide reductase. One suitable reagent, 4- succinimidyloxycarbonyl-a-methyl-a(2 -pyridyldithio) toluene (SMPT), forms such a linkage between two proteins utilizing a terminal lysine on one of the proteins and a terminal cysteine on the other. Heterobifunctional reagents that cross-link by a different coupling moiety on each protein can also be used. Other useful cross-linkers include, without limitation, reagents which link two amino groups (e.g., N-5-azido-2-nitrobenzoyloxysuccinimide), two sulfhydryl groups (e.g., 1,4-bis-maleimidobutane), an amino group and a sulfhydryl group (e.g., m- maleimidobenzoyl-N-hydroxysuccinimide ester), an amino group and a carboxyl group (e.g., 4-[p-azidosalicylamido]butylamine), and an amino group and a guanidinium group that is present in the side chain of arginine (e.g., p-azidophenyl glyoxal monohydrate).

[0269] Techniques for conjugating a therapeutic moiety (e.g., any of those discussed in Section VIII) to an DLL3 -specific antibody or antigen binding fragment thereof as described herein are well known, see, for example, Amon et aL, 1985, Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56; Hellstrom et aL, 1987, Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53; Thorpe, 1985, Monoclonal Antibodies '84::Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506; “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy” In: Monoclonal Antibodies For Cancer Detection And Therapy, (Baldwin etal. eds.), pp. 303-316 (1985), and Thorpe et al., 1982, Immunol. Rev. 62: 119-158. Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate (e.g., a bispecific antibody) as described, for example, in U.S. Pat. No. 4,676, 980.

[0270] In some embodiments, a radioactive label can be directly conjugated to the amino acid backbone of the antibody. Alternatively, the radioactive label can be included as part of a larger molecule (e.g.,125I in meta-[125I]iodophenyl-N-hydroxysuccinimide ([125I]mIPNHS), which binds to free amino groups to form meta-iodophenyl (mIP) derivatives of relevant proteins (see, e.g., Rogers et al., 1997, J. Nucl. Med. 38: 1221-29) or chelate (e.g., to DOTA or DTP A), which is in turn bound to the protein backbone. Methods of conjugating the radioactive labels or larger molecules / chelates containing them to the antibodies or antigen bindingAttorney Docket No.: 090723-1514853-MDA23-109PCT fragments described herein are known in the art. Such methods involve incubating the proteins with the radioactive label under conditions (e.g., pH, salt concentration, and / or temperature) that facilitate binding of the radioactive label or chelate to the protein (see, e.g., U.S. Patent No. 6,001,329).

[0271] Methods for conjugating a fluorescent label (sometimes referred to as a fluorophore) or other heterologous moiety to a protein (e.g., an antibody) are known in the art of protein chemistry. For example, fluorophores can be conjugated to free amino groups (e.g., of lysines) or sulfhydryl groups (e.g., cysteines) of proteins using succinimidyl (NHS) ester or tetrafluorophenyl (TFP) ester moieties attached to the fluorophores. In some embodiments, the fluorophores can be conjugated to a heterobifunctional cross-linker moiety such as sulfo- SMCC. Suitable conjugation methods involve incubating an antibody protein or antigen binding fragment thereof with the fluorophore under conditions that facilitate binding of the fluorophore to the protein. See, e.g., Welch and Redvanly, (2003), Handbook of Radiopharmaceuticals: Radiochemistry and Applications, John Wiley and Sons.

[0272] In some embodiments, the antibodies or antigen binding fragments can be modified, e.g., with a moiety that improves the stabilization and / or retention of the antibodies in circulation, e.g., in blood, serum, or other tissues. For example, the antibody or antigen binding fragment can be PEGylated as described in, e.g., Lee et al.z1999, Bioconjug. Chem. 10(6): 973-78; Kinstler et al., 2002, Advanced Drug Deliveries Reviews 54:477-485; and Roberts et al., 2002, Advanced Drug Delivery Reviews 54:459-476, or HESylated (Fresenius Kabi, Germany) (see, e.g., Pavisic et al., 2010, Int. J. Pharm. 387(1-2): 110-119). The stabilization moiety can improve the stability, or retention of, the antibody (or antigen binding fragment) by at least 1.5 (e.g., at least 2, 5, 10, 15, 20, 25, 30, 40, or 50 or more) fold.

[0273] In some embodiments, the antibodies or antigen binding fragments thereof described herein can be glycosylated. In some embodiments, an antibody or antigen binding fragment thereof described herein can be subjected to enzymatic or chemical treatment, or produced from a cell, such that the antibody or antigen binding fragment has reduced or absent glycosylation. Methods for producing antibodies with reduced glycosylation are known in the art and described in, e.g., U.S. Patent No. 6,933,368; Wright etal., 1991, EMBO J. 10(10): 2717-2723; and Co et al., (1993), Mol. Immunol. 30: 1361. An altered glycosylation level may comprise altered fucosylation (See e.g. Golay et al. (2022), Frontiers Immunol. 13:929895, doi: 10.3389 / fimmu.2022.929895) to modulate antibody efficacy. Antibodies may also be partially glycosylated, e.g. partially fucosylated, i.e. having less glycosylation than fully glycosylatedAttorney Docket No.: 090723-1514853-MDA23-109PCT antibodies, with certain glycosylation sites being glycosylated and other (potential) glycosylation sites being non-glycosylated.IV. Chimeric antigen receptors

[0274] Also provided herein are chimeric antigen receptors comprising any of the antibodies or antigen binding fragments described herein. Chimeric antigen receptors (CARs, also known as chimeric T cell receptors) are designed to be expressed in host effector cells, e.g., T cells or NK cells, and to induce an immune response against a specific target antigen and cells expressing that antigen. Adoptive T cell immunotherapy, in which a patient’s own T lymphocytes are engineered to express CARs, has shown great promise in treating hematological malignancies. CARs can be engineered and used as described, for example, in Sadelain et al., 2013, Cancer Discov. 3:388-98. A CAR typically comprises an extracellular target-binding module, a transmembrane (TM) domain, and an intracellular signaling domain (ICD). The CAR domains can be joined via flexible hinge and / or spacer regions. The extracellular target-binding module generally comprises an antibody or antigen binding fragment thereof. In some instances, multiple binding specificities can be included in the extracellular target-binding module. For example, multiple antibodies or antigen binding fragments thereof that target different antigens can be included to produce bi-specific, tri- specific, or quad-specific CARs.

[0275] Provided herein are chimeric antigen receptors comprising: (a) an extracellular targetbinding domain comprising an DLL3 -specific antibody or antigen binding portion thereof; (b) a transmembrane domain; and (c) a signaling domain.

[0276] TM domains are primarily considered a structural requirement, anchoring the CAR in the cell membrane, and are most commonly derived from molecules regulating T cell function, such as CD8 and CD28. The intracellular module typically consists of the T cell receptor CD3(^ chain and one or more costimulatory domains from either the Ig (CD28-like) or TNF receptor (TNFR) superfamilies. CARs containing either CD28 or 4- IBB costimulatory domains have been widely used, to date, and both of them have yielded dramatic responses in clinical trials. CAR domains are discussed in more detail below.

[0277] The extracellular target-binding module of a CAR may comprise an antibody or an antigen binding fragment thereof that specifically binds a target antigen (e.g., DLL3). In certain embodiments, the extracellular target-binding domain can be a single-chain variable fragment derived from an antibody (scFv), a tandem scFv, a single-domain antibody fragment (VHHS or sdAbs), a single domain bispecific antibody, an intrabody, a nanobody, an immunokine in aAttorney Docket No.: 090723-1514853-MDA23-109PCT single chain format, Fab, Fab’, or (Fab’)2 in a single chain format. In other embodiments, the extracellular target-binding domain can be an antibody moiety that comprises covalently bound multiple chains of variable fragments. The antibody antigen binding fragment may alternatively comprise a VH-VL dimer that comprises such CDRs.

[0278] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0279] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 259, a CDRL2 amino acid sequence comprising SEQ ID NO: 260, and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0280] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 111; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 259, a CDRL2 amino acid sequence comprising SEQ ID NO: 260 and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0281] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 112, a CDRH2 amino acid sequence comprising SEQ ID NO: 113, and a CDRH3 amino acid sequence comprising SEQ ID NO: 114; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 265, a CDRL2 amino acid sequence comprising SEQ ID NO: 266, and a CDRL3 amino acid sequence comprising SEQ ID NO: 267.

[0282] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 115, a CDRH2 amino acid sequence comprising SEQ ID NO: 116, and a CDRH3 amino acid sequence comprising SEQ ID NO: 117; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 268, a CDRL2 amino acid sequence comprising SEQ ID NO: 269, and a CDRL3 amino acid sequence comprising SEQ ID NO: 270.

[0283] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 118, a CDRH2 amino acid sequence comprising SEQ ID NO: 119, and a CDRH3 amino acid sequence comprising SEQ ID NO: 120; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 271, a CDRL2 amino acid sequence comprising SEQ ID NO: 272, and a CDRL3 amino acid sequence comprising SEQ ID NO: 273.

[0284] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 122, and a CDRH3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0285] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 124, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0286] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 128, and a CDRH3 amino acid sequence comprising SEQ ID NO: 129; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0287] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 130, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 285.

[0288] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0289] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 136, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0290] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0291] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 142, a CDRH2 amino acid sequence comprising SEQ ID NO: 143, and a CDRH3 amino acid sequence comprising SEQ ID NO: 144; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 295, a CDRL2Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequence comprising SEQ ID NO: 296, and a CDRL3 amino acid sequence comprising SEQ ID NO: 297.

[0292] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 145, a CDRH2 amino acid sequence comprising SEQ ID NO: 146, and a CDRH3 amino acid sequence comprising SEQ ID NO: 147; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 298, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 300.

[0293] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 301, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0294] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 124, a CDRH2 amino acid sequence comprising SEQ ID NO: 125, and a CDRH3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0295] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0296] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 158, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 277, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.

[0297] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 106, a CDRH2 amino acid sequence comprising SEQ ID NO: 107, and a CDRH3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 313, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0298] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 163, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0299] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0300] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 139, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 171; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0301] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 172, a CDRH2 amino acid sequence comprising SEQ ID NO: 173,Attorney Docket No.: 090723-1514853-MDA23-109PCT and a CDRH3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 325, a CDRL2 amino acid sequence comprising SEQ ID NO: 326, and a CDRL3 amino acid sequence comprising SEQ ID NO: 327.

[0302] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 175, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0303] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 178, a CDRH2 amino acid sequence comprising SEQ ID NO: 179, and a CDRH3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 331, a CDRL2 amino acid sequence comprising SEQ ID NO: 260, and a CDRL3 amino acid sequence comprising SEQ ID NO: 261.

[0304] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 181, a CDRH2 amino acid sequence comprising SEQ ID NO: 182, and a CDRH3 amino acid sequence comprising SEQ ID NO: 183; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 334, a CDRL2 amino acid sequence comprising SEQ ID NO: 335, and a CDRL3 amino acid sequence comprising SEQ ID NO: 336.

[0305] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 337, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.

[0306] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 187, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0307] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0308] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 145, a CDRH2 amino acid sequence comprising SEQ ID NO: 146, and a CDRH3 amino acid sequence comprising SEQ ID NO: 147; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 298, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 300.

[0309] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 196, a CDRH2 amino acid sequence comprising SEQ ID NO: 197, and a CDRH3 amino acid sequence comprising SEQ ID NO: 198; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 349, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 351.

[0310] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 199, a CDRH2 amino acid sequence comprising SEQ ID NO: 200, and a CDRH3 amino acid sequence comprising SEQ ID NO: 201; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 279.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0311] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 337, a CDRL2 amino acid sequence comprising SEQ ID NO: 356, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.

[0312] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0313] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 133, a CDRH2 amino acid sequence comprising SEQ ID NO: 134, and a CDRH3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 286, a CDRL2 amino acid sequence comprising SEQ ID NO: 287, and a CDRL3 amino acid sequence comprising SEQ ID NO: 288.

[0314] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 103, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 258.

[0315] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 214, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0316] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 218, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0317] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 172, a CDRH2 amino acid sequence comprising SEQ ID NO: 221, and a CDRH3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0318] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 334, and a CDRH3 amino acid sequence comprising SEQ ID NO: 335; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 271, a CDRL2 amino acid sequence comprising SEQ ID NO: 272, and a CDRL3 amino acid sequence comprising SEQ ID NO: 273.

[0319] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 226, a CDRH2 amino acid sequence comprising SEQ ID NO: 104, and a CDRH3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 379, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 339.

[0320] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 122, and a CDRH3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0321] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 233, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0322] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 121, a CDRH2 amino acid sequence comprising SEQ ID NO: 128, and a CDRH3 amino acid sequence comprising SEQ ID NO: 129; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 274, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 276.

[0323] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 238, a CDRH2 amino acid sequence comprising SEQ ID NO: 239, and a CDRH3 amino acid sequence comprising SEQ ID NO: 283; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 391, a CDRL2 amino acid sequence comprising SEQ ID NO: 392, and a CDRL3 amino acid sequence comprising SEQ ID NO: 393.

[0324] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 242, and a CDRH3 amino acid sequence comprising SEQ ID NO: 243; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0325] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 244, a CDRH2 amino acid sequence comprising SEQ ID NO: 245,Attorney Docket No.: 090723-1514853-MDA23-109PCT and a CDRH3 amino acid sequence comprising SEQ ID NO: 246; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 397, a CDRL2 amino acid sequence comprising SEQ ID NO: 335, and a CDRL3 amino acid sequence comprising SEQ ID NO: 336.

[0326] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 238, a CDRH2 amino acid sequence comprising SEQ ID NO: 248, and a CDRH3 amino acid sequence comprising SEQ ID NO: 240; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 391, a CDRL2 amino acid sequence comprising SEQ ID NO: 299, and a CDRL3 amino acid sequence comprising SEQ ID NO: 402.

[0327] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 250, a CDRH2 amino acid sequence comprising SEQ ID NO: 251, and a CDRH3 amino acid sequence comprising SEQ ID NO: 252; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0328] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 217, a CDRH2 amino acid sequence comprising SEQ ID NO: 218, and a CDRH3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 256, a CDRL2 amino acid sequence comprising SEQ ID NO: 257, and a CDRL3 amino acid sequence comprising SEQ ID NO: 372.

[0329] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequence comprising SEQ ID NO: 426, a CDRH2 amino acid sequence comprising SEQ ID NO: 131, and a CDRH3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 283, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0330] In some embodiments, a CAR DLL3 antigen binding domain of this disclosure comprises a heavy chain variable region (VH) having a CDRH1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 178, a CDRH2 amino acid sequence comprising SEQ ID NO: 179, and a CDRH3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having a CDRL1 amino acid sequence comprising SEQ ID NO: 435, a CDRL2 amino acid sequence comprising SEQ ID NO: 278, and a CDRL3 amino acid sequence comprising SEQ ID NO: 294.

[0331] In some embodiments, the extracellular target-binding domain comprises any of the antibodies or antigen-binding portions thereof described herein. In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 52. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 1 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 52 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 258.

[0332] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 2 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 53. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 2 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 106, a VHCDR2 amino acid sequence comprising SEQ ID NO: 107, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 53 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 259, a VLCDR2 amino acid sequence comprising SEQ ID NO: 260, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0333] In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 3 (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 53. In other embodiments the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 3 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 106, a VHCDR2 amino acid sequence comprising SEQ ID NO: 107 and a VHCDR3 amino acid sequence comprising SEQ ID NO: 111; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 53 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 259, a VLCDR2, amino acid sequence comprising SEQ ID NO: 260, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

[0334] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 4 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 55. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 4 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 112, a VHCDR2 amino acid sequence comprising SEQ ID NO: 113, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 114; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 55 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 265, a VLCDR2 amino acid sequence comprising SEQ ID NO: 266, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 267.

[0335] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 5 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 56. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 5 and comprising a VHCDR1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 115, a VHCDR2 amino acid sequence comprising SEQ ID NO: 116, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 117; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 56 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 268, a VLCDR2 amino acid sequence comprising SEQ ID NO: 269, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 270.

[0336] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 57. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 6 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 118, a VHCDR2 amino acid sequence comprising SEQ ID NO: 119, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 120; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 57 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 271, a VLCDR2 amino acid sequence comprising SEQ ID NO: 272, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 273.

[0337] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 7 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 121, a VHCDR2 amino acid sequence comprising SEQ ID NO: 122, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 58 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 274, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0338] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%Attorney Docket No.: 090723-1514853-MDA23-109PCT identical) to SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 59. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 8 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 124, a VHCDR2 amino acid sequence comprising SEQ ID NO: 125, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 59 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 277, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 279.

[0339] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 9 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 9 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 121, a VHCDR2 amino acid sequence comprising SEQ ID NO: 128, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 129; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 58 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 274, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0340] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 10 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 61. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 10 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 130, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131 and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 61 and comprising a VLCDR1 aminoAttorney Docket No.: 090723-1514853-MDA23-109PCT acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 285.

[0341] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 11 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 62. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 11 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 133, a VHCDR2 amino acid sequence comprising SEQ ID NO: 134, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 135 and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 62 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 286, a VLCDR2 amino acid sequence comprising SEQ ID NO: 287, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 288.

[0342] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 12 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 63. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 12 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 136, a VHCDR2 amino acid sequence comprising SEQ ID NO: 125, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 63 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 277, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 279.

[0343] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 13 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 64. In other embodiments, the extracellularAttorney Docket No.: 090723-1514853-MDA23-109PCT target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 13 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 64 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0344] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 14 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 65. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 14 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 142, a VHCDR2 amino acid sequence comprising SEQ ID NO: 143, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 144; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 65 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 295, a VLCDR2 amino acid sequence comprising SEQ ID NO: 296, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 297.

[0345] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 15 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 66. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 15 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 145, a VHCDR2 amino acid sequence comprising SEQ ID NO: 146, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 147; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 66 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 298, a VLCDR2 amino acid sequence comprising SEQ ID NO: 299, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 300.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0346] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 16 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 67. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 16 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 67 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 301, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0347] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 17 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 68. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 17 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 124, a VHCDR2 amino acid sequence comprising SEQ ID NO: 125, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 126; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 68 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 277, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 279.

[0348] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 18 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 69. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 18 and comprising a VHCDR1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 69 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0349] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 70. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 19 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 158, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 70 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 277, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 279.

[0350] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 20 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 71. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 20 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 106, a VHCDR2 amino acid sequence comprising SEQ ID NO: 107, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 108; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 71 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 313, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0351] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%Attorney Docket No.: 090723-1514853-MDA23-109PCT identical) to SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 72. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 21 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 163, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 72 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0352] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 22 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 73. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 22 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 73 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0353] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 23 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 74. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 23 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 139, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 171; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 74 and comprising a VLCDR1 aminoAttorney Docket No.: 090723-1514853-MDA23-109PCT acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0354] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 24 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 75. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 24 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 172, a VHCDR2 amino acid sequence comprising SEQ ID NO: 173, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 75 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 325, a VLCDR2 amino acid sequence comprising SEQ ID NO: 326, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 327.

[0355] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 25 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 76. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 25 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 175, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 76 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0356] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 26 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 77. In other embodiments, the extracellularAttorney Docket No.: 090723-1514853-MDA23-109PCT target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 26 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 178, a VHCDR2 amino acid sequence comprising SEQ ID NO: 179, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 77 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 331 ,a VLCDR2 amino acid sequence comprising SEQ ID NO: 260, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

[0357] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 78. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 27 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 181, a VHCDR2 amino acid sequence comprising SEQ ID NO: 182, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 183; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 78 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 334, a VLCDR2 amino acid sequence comprising SEQ ID NO: 335, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 336.

[0358] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 28 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 79. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 28 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 79 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 337, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 339.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0359] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 29 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 80. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 29 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 187, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 156; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 80 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0360] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 30 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 81. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 30 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 133, a VHCDR2 amino acid sequence comprising SEQ ID NO: 134, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 81 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 286, a VLCDR2 amino acid sequence comprising SEQ ID NO: 287, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 288.

[0361] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 31 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 82. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 31 and comprising a VHCDR1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 145, a VHCDR2 amino acid sequence comprising SEQ ID NO: 146, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 147 and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 82 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 298, a VLCDR2 amino acid sequence comprising SEQ ID NO: 299, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 300.

[0362] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 32 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 83. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 32 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 196, a VHCDR2 amino acid sequence comprising SEQ ID NO: 197, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 198; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 83 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 349, a VLCDR2 amino acid sequence comprising SEQ ID NO: 299, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 351.

[0363] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 33 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 84. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 33 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 199, a VHCDR2 amino acid sequence comprising SEQ ID NO: 200, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 201; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 84 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 279.

[0364] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%Attorney Docket No.: 090723-1514853-MDA23-109PCT identical) to SEQ ID NO: 34 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 85. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 34 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 85 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 337, a VLCDR2 amino acid sequence comprising SEQ ID NO: 356, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 339.

[0365] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 83. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 1 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 86 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256 a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 258.

[0366] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 11 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 87. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 11 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 133, a VHCDR2 amino acid sequence comprising SEQ ID NO: 134, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 135; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 87 and comprising a VLCDR1 aminoAttorney Docket No.: 090723-1514853-MDA23-109PCT acid sequence comprising SEQ ID NO: 286, a VLCDR2 amino acid sequence comprising SEQ ID NO: 287, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 288.

[0367] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 37 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 88. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 37 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 103, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 88 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 258.

[0368] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 38 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 89. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 38 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 214, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 89 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0369] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 39 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 90. In other embodiments, the extracellularAttorney Docket No.: 090723-1514853-MDA23-109PCT target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 39 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 217, a VHCDR2 amino acid sequence comprising SEQ ID NO: 218, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 90 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 372.

[0370] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 40 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 91. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 40 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 172, a VHCDR2 amino acid sequence comprising SEQ ID NO: 221, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 174; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 283 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 278, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0371] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 41 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 92. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 41 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 217, a VHCDR2 amino acid sequence comprising SEQ ID NO: 218, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 92 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 271, a VLCDR2 amino acid sequence comprising SEQ ID NO: 272, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 273.Attorney Docket No.: 090723-1514853-MDA23-109PCT

[0372] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 42 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 93. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 42 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 226, a VHCDR2 amino acid sequence comprising SEQ ID NO: 104, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 93 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 379 a VLCDR2 amino acid sequence comprising SEQ ID NO: 257 and a VLCDR3 amino acid sequence comprising SEQ ID NO: 339.

[0373] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 43 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 58. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 43 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 121. a VHCDR2 amino acid sequence comprising SEQ ID NO: 122, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 123; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 58 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 274, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0374] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 44 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 95. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 44 and comprising a VHCDR1 amino acid sequenceAttorney Docket No.: 090723-1514853-MDA23-109PCT comprising SEQ ID NO: 217, a VHCDR2 amino acid sequence comprising SEQ ID NO: 233, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 95 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256 a VLCDR2 amino acid sequence comprising SEQ ID NO: 257 and a VLCDR3 amino acid sequence comprising SEQ ID NO: 372.

[0375] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 45 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 96. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 45 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 121, a VHCDR2 amino acid sequence comprising SEQ ID NO: 128, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 129; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 96 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 274, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

[0376] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 46 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 97. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 46 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 238, a VHCDR2 amino acid sequence comprising SEQ ID NO: 239, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 240; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 97 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 391, a VLCDR2 amino acid sequence comprising SEQ ID NO: 392, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 393.

[0377] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%Attorney Docket No.: 090723-1514853-MDA23-109PCT identical) to SEQ ID NO: 47 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 98. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 47 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 217, a VHCDR2 amino acid sequence comprising SEQ ID NO: 242, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 243; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 98 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 372.

[0378] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 48 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 99. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 48 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 244, a VHCDR2 amino acid sequence comprising SEQ ID NO: 245, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 246; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 99 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 397, a VLCDR2 amino acid sequence comprising SEQ ID NO: 335, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 336.

[0379] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 49 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 100. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 49 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 238, a VHCDR2 amino acid sequence comprising SEQ ID NO: 248, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 240; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 100 and comprising a VLCDR1 aminoAttorney Docket No.: 090723-1514853-MDA23-109PCT acid sequence comprising SEQ ID NO: 391, a VLCDR2 amino acid sequence comprising SEQ ID NO: 299, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 402.

[0380] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 50 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 101. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 50 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 250, a VHCDR2 amino acid sequence comprising SEQ ID NO: 251, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 252; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 101 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283, a VLCDR2 amino acid sequence comprising SEQ ID NO: 278, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0381] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 51 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 102. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 51 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 217, a VHCDR2 amino acid sequence comprising SEQ ID NO: 218, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 219; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 102 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 256, a VLCDR2 amino acid sequence comprising SEQ ID NO: 257, and a VLCDR3 amino acid sequence comprising SEQ ID NO: 372.

[0382] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 418 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 420. In other embodiments, the extracellularAttorney Docket No.: 090723-1514853-MDA23-109PCT target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 418 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 426, a VHCDR2 amino acid sequence comprising SEQ ID NO: 131, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 132; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 420 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 283 a VLCDR2 amino acid sequence comprising SEQ ID NO: 278 and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0383] In some embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 419 and a light chain variable region comprising an amino acid sequence that is at least 90% identical (for example, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical) to SEQ ID NO: 421. In other embodiments, the extracellular target-binding domain comprises a scFv comprising a heavy chain variable region (VH) having at least 90% identity to SEQ ID NO: 419 and comprising a VHCDR1 amino acid sequence comprising SEQ ID NO: 178, a VHCDR2 amino acid sequence comprising SEQ ID NO: 179, and a VHCDR3 amino acid sequence comprising SEQ ID NO: 180; and a light chain variable region (VL) having at least 90% identity to SEQ ID NO: 421 and comprising a VLCDR1 amino acid sequence comprising SEQ ID NO: 435 a VLCDR2 amino acid sequence comprising SEQ ID NO: 278 and a VLCDR3 amino acid sequence comprising SEQ ID NO: 294.

[0384] In some embodiments, the CAR protein comprises: (1) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 1; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 52; (2) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 2; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53; (3) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 3; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53; (4) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 4; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 55; (5) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 5; and a light chain variableAttorney Docket No.: 090723-1514853-MDA23-109PCT region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 56; (6) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 6; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 57; (7) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 7; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 58; (8) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 8; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 59; (9) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 9; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 58; (10) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 10; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 61; (11) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 11; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 62; (12) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 12; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 63; (13) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 13; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 64; (14) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 14; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 65; (15) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 15; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 66; (16) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 16; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ IDAttorney Docket No.: 090723-1514853-MDA23-109PCTNO: 67; (17) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 17; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 68; (18) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 18; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 69; (19) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 19; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 70; (20) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 20; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 71; (21) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 21; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 72; (22) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 22; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 73; (23) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 23; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 74; (24) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 24; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 75; (25) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 25; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 76; (26) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 26; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 77; (27) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 27; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 78; (28) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3Attorney Docket No.: 090723-1514853-MDA23-109PCT amino acid sequences derived from SEQ ID NO: 28; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 79; (29) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 29; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 80; (30) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 30; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 81; (31) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 31; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 82; (32) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 32; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 83; (33) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 33; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 84; (34) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 34; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 85; (35) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 35; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 83 ; (36) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 36; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 87; (37) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 37; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 88; (38) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 38; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 89; (39) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 39; and a light chain variable region (VL)Attorney Docket No.: 090723-1514853-MDA23-109PCT comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 90; (40) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 40; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 91; (41) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 41; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 92; (42) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 42; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 93; (43) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 43; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 58; (44) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 44; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 95; (45) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 45; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 96; (46) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 46; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 97; (47) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 47; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 98; (48) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 48; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 99; (49) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 49; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 100; (50) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 50; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ IDAttorney Docket No.: 090723-1514853-MDA23-109PCTNO: 101; (51) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 51; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 102; (52) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 418; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 420; or (53) a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 419; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 421.

[0385] In some embodiments, the scFv comprises a linker polypeptide between the heavy chain and light chain sequences (e.g., as seen within the CAR amino acid sequence of SEQ ID NO: 413-415 or 438; disclosed below) or any of the other linkers described herein.

[0386] In some embodiments, the extracellular target-binding domains of the CARs provided herein further comprise one or more additional antigen-binding domains (z.e., in addition to the DLL3-specific antibody or antigen binding portion thereof, as described above). In some embodiments, the extracellular target-binding domain comprises one additional antigenbinding domain. CARs comprising such an extracellular target-binding domain can be referred to as bi-specific CARs. In some embodiments, the extracellular target-binding domain comprises two additional antigen-binding domains. CARs comprising such an extracellular target-binding domain can be referred to as tri-specific CARs. In some embodiments, the extracellular target-binding domain comprises three additional antigen-binding domain. CARs comprising such an extracellular target-binding domain can be referred to as quad-specific CARs. Each of the one or more additional antigen-binding domains may comprise an antibody or antigen binding portion thereof. In some embodiments, the one or more additional antigenbinding domains specifically bind to CD3e, CD16, CD28, CD32, CD64, CD137, or any combination thereof.

[0387] The transmembrane (TM) domain of a CAR provided herein may be derived from either a natural or from a synthetic source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In some embodiments, the transmembrane domain is derived from (z.e., comprises at least the transmembrane region(s) of) the a, P, 5, y, or C, chain of the T-cell receptor, CD28, CD3s, CD3(^, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD30, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154. In some embodiments, a transmembrane domain can be chosen based on, for example, the natureAttorney Docket No.: 090723-1514853-MDA23-109PCT of the various other proteins or trans-elements that bind the transmembrane domain or the cytokines induced by the transmembrane domain. In some embodiments, the transmembrane domain comprises a transmembrane domain (e.g., CD8a transmembrane domain). Exemplary transmembrane domains are found within each of SEQ ID NOs: 413-415 and 438 although others may also be utilized. In one embodiment, the transmembrane domain is a CD8a transmembrane domain having the sequence set forth in SEQ ID NO: 440 (IWAPLAGTCGVLLLSLVITLYC). When a transmembrane domain is synthetic, it may comprise predominantly hydrophobic residues such as leucine and valine. In some embodiments, a triplet of phenylalanine, tryptophan, and valine may be found at each end of a synthetic transmembrane domain. In some embodiments, a short oligo- or polypeptide linker, having a length of, for example, between about 2 and about 10 (such as about any of 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids in length may form the linkage between the transmembrane domain and the intracellular signaling domain of a CAR described herein. In some embodiments, the short oligo- or polypeptide linker is a glycine-serine doublet.

[0388] The intracellular signaling domain of the CAR is responsible for activation of at least one of the normal effector functions of the immune cell in which the CAR has been placed in or is designed to be placed in. An effector function of a T cell may be, for example, cytolytic activity or helper activity, including the secretion of cytokines. Thus, the term “intracellular signaling domain” refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal. The term “intracellular signaling sequence” is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal.

[0389] Examples of intracellular signaling domains for use in the CARs provided herein include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the same functional capability.

[0390] It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary or costimulatory signal is also required. Thus, T cell activation can be said to be mediated by two distinct classes of intracellular signalingAttorney Docket No.: 090723-1514853-MDA23-109PCT sequence: those that initiate antigen-dependent primary activation through the TCR (primary signaling sequences) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (costimulatory signaling sequences).

[0391] Primary signaling sequences regulate primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way. Primary signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or IT AMs. In some embodiments, the CARs described herein comprise one or more IT AMs.

[0392] Examples of IT AM containing primary signaling sequences that are of particular use in the CARs include those derived from TCR^, FcRy, FcRP, CD3y, CD35, CD3s, CD3(^, CD5, CD22, CD79a, CD79b, and CD66d.

[0393] In some embodiments, the CAR comprises a primary signaling sequence derived from CD3(^. For example, the intracellular signaling domain of the CAR can comprise the CD3(^ intracellular signaling sequence by itself or combined with any other desired intracellular signaling sequence(s) useful in the context of the CAR disclosed herein. In some embodiments, the intracellular signaling domain of a CAR provided herein comprises a CD3(^ primary intracellular signaling sequence and a 4- IBB costimulatory signaling sequence. An exemplary CD3(^ sequence is set forth in SEQ ID NO: 441. An exemplary 4-1BB costimulatory signaling sequence is set forth in SEQ ID NO: 442.RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALP PR (SEQ ID NO: 441)KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 442)

[0394] The CARs provided herein may include additional elements, such as a signal peptide to ensure proper export of the fusion protein to the cells surface, a leader sequence (e.g., CD8 leader sequence), and a hinge domain (e.g., CD8 hinge domain) that imparts flexibility to the recognition region and allows strong binding to the targeted moiety. In some embodiments, the CARs provided herein comprise a CD8 hinge domain. An exemplary CD8 hinge domain sequence is set forth in SEQ ID NO: 443 (TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY). In some embodiments, a spacer domain may be present between any of the domains of the CAR. The spacer domain can be any polypeptide that functions to link two parts of the CAR. A spacer domain may comprise up to about 300 amino acids, including for example about 5 to aboutAttorney Docket No.: 090723-1514853-MDA23-109PCT200, about 10 to about 100, or about 25 to about 50 amino acids. Methods of identifying and selecting suitable spacer domains are known in the art.

[0395] In some embodiments, the CAR comprises the following amino acid sequence:MRLPAQLLGLLMLWVSGSSGDIQMTQSPSTLSASVGDRVTITCRASQSISSWL AWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYY CQQYNTYSPTFGQGTKLEIKRGGGGGSGGGGGSGGGGSEVQLVESGGGLVQ PGGSLRLSCAASGFTYSSYWMSWVRQAPGKGLEWVANIKEDGSEKDYVDSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWGYLDYWGQGTLVTV SSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPL AGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEE EGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM GGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 413; DLL3-2-4-1BB CAR sequence)

[0396] In some embodiments, the CAR comprises the following amino acid sequence:MRLPAQLLGLLMLWVSGSSGEIVMTQSPATLSVSPGERATLSCRASQSVLNN LAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVY YCQQSNNWPYTFGQGTKLEIKRGGGGGSGGGGGSGGGGSQVQLQESGPGLV RPSGTLSLTCAVSGGSISSINWWTWVRQPPGKGLEWIGEILYSGSTNYNPSLK SRVTISVDKSKNQFSLKLNSVTAADTAVYYCARDITAGAFDIWGQGTTVTVS STTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLA GTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEE GGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM GGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR (SEQ ID NO: 414; DLL3-8-4-1BB CAR sequence)

[0397] In some embodiments, the CAR comprises the following amino acid sequence:MRLPAQLLGLLMLWVSGSSGEIVMTQSPATLSVSPGERATLSCRASQSVLNN LAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVY YCQQSNNWPYTFGQGTKLEIKRGGGGGSGGGGGSGGGGSQVQLQESGPGLV RPSGTLSLTCAVSGGSISSINWWTWVRQPPGKGLEWIGEILYSGSTNYNPSLK SRVTIS VDKSKNQF SLKLNS VT AADTAVYYC ARDITTGAFDIWGQGTTVT VS S TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAG TCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEG GCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMG GKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTA TKDTYDALHMQALPPR (SEQ ID NO: 415; DLL3 -22-4- IBB CAR sequence)

[0398] In some embodiments, the CAR comprises the following amino acid sequence:MRLPAQLLGLLMLWVSGSSGDIQMTQSPSTLSASVGDRVTITCRASQSISIWL AWYQQKPGKAPKLLISKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATFY CQQYNSYSTFGQGTKLEIKRGGGGGSGGGGGSGGGGSQVQLQESGPGLVKP SGTLSLTCAVSNGSINSNNWWSWVRQPPGKELEWIGDIHHSGSTNYNPSLKS RLTISVDKSKNHFSLKLSSVTAADTAVYYCARELGGYFDLWGRGTLVTVSST TTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTAttorney Docket No.: 090723-1514853-MDA23-109PCTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG CELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGG KPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTAT KDTYDALHMQALPPR (SEQ ID NO: 438; DLL3-48-4-1BB CAR sequence)V. Antibody Expression and Purification, Nucleic Acids, Vectors, and Cells

[0399] The DLL3 antibodies and antigen binding fragments thereof and molecules comprising such antibodies and antigen binding fragments thereof discussed above (e.g., CARs) may be produced by recombinant expression in a human or non-human cell. Antibodyproducing cells include non-human cells expressing heavy chains, light chains, or both heavy and light chains; human cells that are not immune cells expressing heavy chains, light chains, or both heavy and light chains; and human B cells that produce heavy chains or light chains, but not both heavy and light chains. The antibodies and antigen binding fragments thereof of this disclosure may be heterologously expressed, in vitro or in vivo, in cells other than human B cells, such as non-human cells and human cells other than B cells, optionally other than immune cells, and optionally in cells other than cells in a B cell lineage.

[0400] The DLL3 antibodies and antigen binding fragments thereof and molecules comprising them described herein can be produced using a variety of techniques known in the art of molecular biology and protein chemistry. For example, a nucleic acid encoding the antibody or antigen binding fragment thereof can be inserted into an expression vector that contains transcriptional and translational regulatory sequences, which include, e.g., promoter sequences, ribosomal binding sites, transcriptional start and stop sequences, translational start and stop sequences, transcription terminator signals, polyadenylation signals, and enhancer or activator sequences. The regulatory sequences include a promoter and transcriptional start and stop sequences. In addition, the expression vector can include more than one replication system, such that it can be maintained in two different organisms, for example, in mammalian or insect cells for expression and in a prokaryotic host for cloning and amplification.

[0401] Several possible vector systems are available for the expression of cloned heavy chain and light chain polypeptides from nucleic acids in mammalian cells. One class of vectors relies upon the integration of the desired gene sequences into the host cell genome. Cells that have stably integrated DNA can be selected by simultaneously introducing drug resistance genes such as E. coli gpt (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072) or Tn5 neo (Southern and Berg, 1982, Mol. AppL Genet. 1 :327). The selectable marker gene can be either linked to the DNA gene sequences to be expressed or introduced into the same cell by cotransfection (Wigler et al., 1979, Cell 16:77). A second class of vectors utilizes DNA elementsAttorney Docket No.: 090723-1514853-MDA23-109PCT that confer autonomously replicating capabilities to an extrachromosomal plasmid. These vectors can be derived from animal viruses, such as bovine papillomavirus (Sarver et al. , 1982, Proc. Natl. Acad. Sci. USA, 79:7147), CMV, polyoma virus (Deans et al., 1984, Proc. Natl. Acad. Sci. USA 81 : 1292), or SV40 virus (Lusky & Botchan, 1981, Nature 293:79).

[0402] The expression vectors can be introduced into cells in a manner suitable for subsequent expression of the nucleic acid. The method of introduction is largely dictated by the targeted cell type, discussed below. Exemplary methods include CaPCU precipitation, liposome fusion, cationic liposomes, electroporation, nucleoporation, viral infection, dextran- mediated transfection, polybrene-mediated transfection, protoplast fusion, and direct microinjection.

[0403] Appropriate host cells for the expression of antibodies or antigen binding fragments thereof include yeast, bacteria, insect, plant, and mammalian cells. Of particular interest are bacteria such as E. coli, fungi such as Saccharomyces cerevisiae and Pichia pastoris, insect cells such as SF9, mammalian cell lines (e.g., human cell lines), as well as primary cell lines. Also provided herein are populations of any such cells.

[0404] In some embodiments, an antibody or antigen binding fragment thereof can be expressed in, and purified from, transgenic animals (e.g., transgenic mammals). For example, an antibody can be produced in transgenic non-human mammals (e.g., rodents) and isolated from milk as described in, e.g., Houdebine, 2002, Curr. Opin. Biotechnol. 13(6):625-29; van Kuik-Romeijn et al., 2000, Transgenic. Res. 9(2): 155-59; and Pollock etal., 1999, J. Immunol. AfetAotA 231(1-2): 147-57.

[0405] The antibodies and antigen binding fragments thereof can be produced from the cells by culturing a host cell transformed with the expression vector containing nucleic acid encoding the antibodies or antigen binding fragments, under conditions, and for an amount of time, sufficient to allow expression of the proteins. Such conditions for protein expression vary with the choice of the expression vector and the host cell and are easily ascertained by one skilled in the art through routine experimentation. For example, antibodies expressed in A. coli can be refolded from inclusion bodies (see, e.g., Hou et al., 1998, Cytokine 10:319-30). Bacterial expression systems and methods for their use are known in the art (see Ausubel et al., 1988, Current Protocols in Molecular Biology, Wiley & Sons; and Green and Sambrook, 2012, Molecular Cloning— A Laboratory Manual, 4th Ed., Cold Spring Harbor Laboratory Press, New York (2001)). The choice of codons, suitable expression vectors, and suitable host cells vary depending on a number of factors and may be easily optimized as needed. An antibody (or antigen binding fragment thereof) described herein can be expressed inAttorney Docket No.: 090723-1514853-MDA23-109PCT mammalian cells or in other expression systems including but not limited to yeast, baculovirus, and in vitro expression systems (see, e.g., Kaszubska el al., 2000, Protein Expression and Purification 18:213-20). Additional discussion of expression vectors for use in eukaryotic cells (e.g., for treating a subject with cancer), along with suitable delivery systems, is provided in Section VIII, below.

[0406] Also provided ...

Claims

1. Attorney Docket No.: 090723-1514853-MDA23-109PCTWHAT IS CLAIMED IS:

1. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NOs: 103, 106,112, 115, 118, or 121;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NOs: 104, 107,113, 116, 119, or 122; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 105, 108, 111, 114, 117, 120, or 123; and(b) a light chain variable region comprising:(i) a VLCDR1 amino acid sequence comprising SEQ ID NOs: 256, 259,265, 268, 271, or 274;(ii) a VLCDR2 amino acid sequence comprising SEQ ID NOs: 257, 260,266, 269, 272, or 275; and(iii) a VLCDR3 amino acid sequence comprising SEQ ID NOs: 258, 261,267, 270, 273, or 276.

2. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 103;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 104; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NO: 105; and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 256;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 258.

3. An isolated antibody or antigen-binding fragment, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 106;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 107; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 108;Attorney Docket No.: 090723-1514853-MDA23-109PCT and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 259;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 260; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

4. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 106;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 107; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 111; and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 259;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 260; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 261.

5. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 112;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 113; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 114; and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 265;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 266; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 267.

6. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 115;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 116; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 117; and(b) a light chain variable region comprising:Attorney Docket No.: 090723-1514853-MDA23-109PCT(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 268;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 269; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 270.

7. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 118;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 119; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 120; and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 271;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 272; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 273.

8. An isolated antibody or antigen-binding fragment thereof, comprising:(a) a heavy chain variable region comprising:(i) a VHCDR1 amino acid sequence comprising SEQ ID NO: 121;(ii) a VHCDR2 amino acid sequence comprising SEQ ID NO: 122; and(iii) a VHCDR3 amino acid sequence comprising SEQ ID NOs: 123; and(b) a light chain variable region comprising:(iv) a VLCDR1 amino acid sequence comprising SEQ ID NO: 274;(v) a VLCDR2 amino acid sequence comprising SEQ ID NO: 257; and(vi) a VLCDR3 amino acid sequence comprising SEQ ID NO: 276.

9. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: a. the heavy chain variable region comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NOs: 1-34, and 38-51, 418, or 419, and b. the light chain variable region comprises an amino acid sequence having at least 90% identity to any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, or 421.Attorney Docket No.: 090723-1514853-MDA23-109PCT10. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: a. the heavy chain variable region comprises an amino acid sequence comprising any one of SEQ ID NOs: 1-34, and 38-51, 418, or 419, and b. the light chain variable region comprises an amino acid sequence comprising any one of SEQ ID NOs: 52-59, 61-62, 64-69, 71-73, 75, 77-93, 69-102, 420, or 421.

11. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 1 and the light chain variable region comprises SEQ ID NO: 52.

12. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 2 and the light chain variable region comprises SEQ ID NO: 53.

13. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 3 and the light chain variable region comprises SEQ ID NO: 53.

14. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 4 and the light chain variable region comprises SEQ ID NO: 55.

15. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 5 and the light chain variable region comprises SEQ ID NO: 56.

16. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 6 and the light chain variable region comprises SEQ ID NO: 57.

17. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein: the heavy chain variable region comprises SEQ ID NO: 7 and the light chain variable region comprises SEQ ID NO: 58.

18. The isolated antibody or antigen-binding fragment of any one of claims 1-17, wherein the antigen-binding fragment is a monovalent scFv (single chain fragmentAttorney Docket No.: 090723-1514853-MDA23-109PCT variable) antibody, divalent scFv, Fab fragment, F(ab’)2 fragment, F(ab’)3 fragment, Fv fragment, or single chain antibody.

19. The isolated antibody or antigen-binding fragment of any one of claims 1-17, wherein the antibody or antigen-binding fragment is a chimeric antibody, bispecific antibody, trispecific antibody, or other multi-specific antibody.

20. The isolated antibody or antigen-binding fragment of any one of claims 1-19, wherein the antibody is an IgG antibody or a recombinant IgG antibody or antibody fragment.

21. The isolated antibody or antigen-binding fragment of any one of claims 1-20, wherein the antibody or antigen-binding fragment is conjugated or fused to an imaging agent, a cytotoxic agent, a metal, a photosensitizer, or a radioactive moiety.

22. The isolated antibody or antigen-binding fragment of claim 21, wherein the antibody or antigen-binding fragment is conjugated or fused to an imaging agent, and wherein the imaging agent is a fluorophore.

23. The isolated antibody or antigen-binding fragment of claim 21, wherein the antibody or antiantigen-binding body fragment is conjugated or fused to a radioactive moiety, and wherein the radioactive moiety is Zr-89, Cu-64, F-18, Y-90, Lu-177, At-211, Ac-225, or Pb-212.

24. The isolated antibody or antigen-binding fragment of any one of claims 1-20, wherein the antibody is an immune conjugate.

25. The isolated antibody or antigen-binding fragment of any one of claims 1-20, wherein the antibody is an antibody-drug conjugate.

26. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment of any one of claims 1-25 and a pharmaceutically acceptable carrier.

27. An isolated nucleic acid encoding the antibody heavy and / or light chain variable region of the antibody or antigen-binding fragment of any one of claims 1-17.

28. An expression vector comprising the isolated nucleic acid of claim 27.Attorney Docket No.: 090723-1514853-MDA23-109PCT29. A hybridoma or engineered cell comprising a nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 1-17.

30. A hybridoma or engineered cell comprising the nucleic acid of claim 27.

31. A method of making an isolated antibody or antigen-binding fragment, comprising culturing the hybridoma or engineered cell of claim 29 or 30 under conditions that allow expression of the antibody or antigen-binding fragment and, optionally, isolating the antibody or antigen-binding fragment from the culture.

32. A chimeric antigen receptor (CAR) comprising: a. an extracellular target-binding domain comprising an antibody or an antigenbinding fragment of any one of claims 1-17; b. a transmembrane domain; and c. a signaling domain.

33. A chimeric antigen receptor (CAR) protein comprising: a CDRH1 comprising SEQ ID NO: 103, a CDRH2 comprising SEQ ID NO: 104, and a CDRH3 comprising SEQ ID NO: 105; and comprising a CDRL1 comprising SEQ ID NO: 256, a CDRL2 comprising SEQ ID NO: 257, and a CDRL3 comprising SEQ ID NO: 258; or a CDRH1 comprising SEQ ID NO: 106, a CDRH2 comprising SEQ ID NO: 107, and a CDRH3 comprising SEQ ID NO: 108; and comprising a CDRL1 comprising SEQ ID NO: 259, a CDRL2 comprising SEQ ID NO: 260, and a CDRL3 comprising SEQ ID NO: 261; or a CDRH1 comprising SEQ ID NO: 106, a CDRH2 comprising SEQ ID NO: 107, and a CDRH3 comprising SEQ ID NO: 111; and comprising a CDRL1 comprising SEQ ID NO: 259, a CDRL2 comprising SEQ ID NO: 260, and a CDRL3 comprising SEQ ID NO: 261; or a CDRH1 comprising SEQ ID NO: 112, a CDRH2 comprising SEQ ID NO: 113, and a CDRH3 comprising SEQ ID NO: 114; and comprising a CDRL1 comprising SEQ ID NO: 265, a CDRL2 comprising SEQ ID NO: 266, and a CDRL3 comprising SEQ ID NO: 267; orAttorney Docket No.: 090723-1514853-MDA23-109PCT a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 116, and a CDRH3 comprising SEQ ID NO: 117; and comprising a CDRL1 comprising SEQ ID NO: 268, a CDRL2 comprising SEQ ID NO: 269, and a CDRL3 comprising SEQ ID NO: 270; or a CDRH1 comprising SEQ ID NO: 118, a CDRH2 comprising SEQ ID NO: 119, and a CDRH3 comprising SEQ ID NO: 120; and comprising a CDRL1 comprising SEQ ID NO: 271, a CDRL2 comprising SEQ ID NO: 272, and a CDRL3 comprising SEQ ID NO: 273 ; or a CDRH1 comprising SEQ ID NO: 121, a CDRH2 comprising SEQ ID NO: 122, and a CDRH3 comprising SEQ ID NO: 123; and comprising a CDRL1 comprising SEQ ID NO: 274, a CDRL2 comprising SEQ ID NO: 257, and a CDRL3 comprising SEQ ID NO: 276.

34. The CAR protein of claim 33, wherein the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 1; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 52; or the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 2; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53; or the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 3; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 53; or the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 4; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 55; or the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 5; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 56; orAttorney Docket No.: 090723-1514853-MDA23-109PCT the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 6; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 57; or the antigen binding domain comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 7; and a light chain variable region (VL) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences derived from SEQ ID NO: 58.

35. The CAR protein of any one of claims 32-34, wherein the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 1 and a light chain variable sequence set forth in SEQ ID NO: 52; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 2 and a light chain variable sequence set forth in SEQ ID NO: 53; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 3 and a light chain variable sequence set forth in SEQ ID NO: 53; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 4 and a light chain variable sequence set forth in SEQ ID NO: 55; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 5 and a light chain variable sequence set forth in SEQ ID NO: 56; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 6 and a light chain variable sequence set forth in SEQ ID NO: 57; or the antigen binding domain comprises a heavy chain variable sequence set forth in SEQ ID NO: 7 and a light chain variable sequence set forth in SEQ ID NO: 58.

36. The CAR protein of any one of claims 32-35, wherein the antigen binding domain specifically binds delta-like ligand 3 (DLL3).

37. The CAR of any one of claims 33-36, further comprising a hinge domain, a transmembrane domain, and an intracellular signaling domain.

38. The CAR of claim 37, wherein the hinge domain is a CD8a hinge domain or an IgG4 hinge domain.

39. The CAR of claim 32 or 37, wherein the transmembrane domain is a CD8a transmembrane domain or a CD28 transmembrane domain.Attorney Docket No.: 090723-1514853-MDA23-109PCT40. The CAR of claim 32 or 37, wherein the intracellular signaling domain comprises a CD3z intracellular signaling domain.

41. A nucleic acid molecule encoding the CAR of any one of claims 32- 40.

42. The nucleic acid molecule of claim 41, wherein the nucleic acid sequence encoding the CAR is operatively linked to an expression control sequence.

43. An expression vector comprising the nucleic acid molecule of claim 41 or 42.

44. An engineered cell comprising the nucleic acid molecule of claim 41 or 42.

45. The cell of claim 44, wherein the cell is a T cell.

46. The cell of claim 44, wherein the cell is an NK cell.

47. The cell of claim 44, wherein the nucleic acid is integrated into a genome of the cell.

48. The cell of any one of claims 44-47, wherein the cell is a human cell.

49. A pharmaceutical composition comprising a population of cells in accordance with any one of claims 44-48 and a pharmaceutically acceptable carrier.

50. A method of treating cancer in a subject, comprising administering to the subject therapeutically effective amount of the pharmaceutical composition of claim 26 or 49.

51. The method of claim 50, wherein the composition comprises the pharmaceutical composition of claim 49, and wherein the cells are allogeneic cells.

52. The method of claim 50, wherein the composition comprises the pharmaceutical composition of claim 49, and wherein the cells are autologous cells.Attorney Docket No.: 090723-1514853-MDA23-109PCT53. The method of claim 50, wherein the composition comprises the pharmaceutical composition of claim 49, and wherein the cells are HLA matched to the subject.

54. The method of claim 50, wherein the pharmaceutical composition comprises the isolated antibody or antigen-binding fragment of claim 18 conjugated to a therapeutic agent.

55. The method of claim 54, wherein the therapeutic agent is at least one of a cytotoxic agent, a photosensitizer, a chemotherapeutic agent, or an immunosuppressive agent.

56. The method of claim 54 or 55, wherein the therapeutic agent is a moiety that specifically binds to an immune cell.

57. The method of claim 56, wherein the immune cell is a T cell.

58. The method of claim 56, wherein the immune cell is a natural killer cell.

59. The method of any one of claims 50-58, wherein the cancer has been determined to express an elevated level of DLL3 relative to a healthy tissue.

60. The method of any one of claims 50-59, wherein the cancer is a small cell lung cancer (SCLC), prostate cancer, or a neuroendocrine cancer.

61. The method of any one of claims 50-60, wherein the patient has previously failed to respond to at least one of: an immune checkpoint inhibitor, chemotherapy, or radiation therapy.

62. The method of claim 61, wherein the subject has relapsed cancer or recurrent cancer.

63. The method of claim 55, wherein the therapeutic agent is a photosensitizer, and wherein the method further comprises administration of near infrared photoimmunotherapy to the subject.Attorney Docket No.: 090723-1514853-MDA23-109PCT64. The method of any one of claims 50-63, further comprising administering at least a second anti-cancer therapy.

65. The method of claim 64, wherein the second anti-cancer therapy is a chemotherapy, molecular targeted therapy, immunotherapy, radiotherapy, radioimmunotherapy, phototherapy, gene therapy, surgery, hormonal therapy, epigenetic modulation, anti-angiogenic therapy or cytokine therapy.

66. A method of detecting the presence of DLL3 in a biological sample comprising:(a) contacting a biological sample with the isolated antibody or antigen-binding fragment thereof of any one of claims 1-25, and(b) detecting an amount of binding of the isolated antibody or antigen-binding fragment thereof as a determination of the presence of DLL3 in the biological sample.

67. The method of claim 66, wherein the biological sample comprises cancer cells.

68. The method of claim 66, wherein the biological sample comprises a sample from a tumor from a patient.

69. A method of imaging a tumor in a subject with an DLL3 expressing cancer, the method comprising:(a) administering to the subject an isolated antibody or antigen-binding fragment thereof of any one of claims 1-21 conjugated to an imaging label, and(b) detecting the imaging label in the subject to obtain an image of the tumor.

70. A method of monitoring response of a subject with a DLL3 expressing cancer to cancer therapy, comprising:(a) administering to the subject the isolated antibody or antigen-binding fragment thereof of any one of claims 1-22 conjugated to an imaging label at a first time point before the subject receives cancer therapy;(b) detecting the imaging label in the subject to obtain a first image of a tumor;(c) administering to the subject an isolated antibody or antigen-binding fragment thereof of any one of claims claims 1-22 conjugated to an imaging label at a second time point after the subject receives cancer therapy;Attorney Docket No.: 090723-1514853-MDA23-109PCT(d) detecting the imaging label in the subject to obtain a second image of the tumor; and(e) comparing the first image to the second image to determine whether a change in tumor size has occurred.

71. The method of claim 70, wherein steps (c) to (e) are repeated at a third time point after the subject receives cancer therapy.

72. The method of any claim 70 or 71, wherein the imaging label comprises a radioisotope, a bioluminescent label, a chemiluminescent label, or a paramagnetic compound.

73. A method of assessing the likelihood of responsiveness of a subject with cancer to treatment with a DLL3 targeted therapy, comprising:(a) measuring in a tumor sample from a subject an amount of expression of DLL3; and(b) determining if the subject has a cancer characterized as having a high level of DLL3 expression.

74. The method of claim 73, wherein the amount of DLL3 expression in the tumor sample is measured using the isolated antibody or antigen-binding fragment thereof of any one of claims 1-23.

75. The method of claim 73, wherein the DLL3 targeted therapy comprises administration of the pharmaceutical composition of claim 26 or claim 49.

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