Methods of treating cancer with DLL3 targeting radioimmunoconjugates

Abstract

Described herein is a method of treating a tumor or cancer of an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 531.

Description

METHODS OF TREATING CANCER WITH DLL3 TARGETINGRADIOIMMUNOCONJUGATESCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional App. No. 63 / 650,768 filed May 22, 2024, and U.S. Provisional App. No. 63 / 672,535 filed on July 17, 2024, both of which are incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing in XML format with a file name 60924-734_601_SL.xml, created on May 21, 2025, and with a file size of 210,735 bytes which is hereby incorporated by reference in its entirety.BACKGROUND

[0003] High-grade neuroendocrine cancer represents 15% of all lung cancer cases (SCLC 14%; LCNEC 1%). SCLC and LCNEC share similar clinicopathologic traits characterized by higher mitotic rates with extensive necrosis, high tumor mutational burden, neuroendocrine gene expression, and strong association with environmental exposures such as smoking, see Andrini E, et al., Large Cell Neuroendocrine Carcinoma of the Lung: Current Understanding and Challenges. J Clin Med. 2022;! 1(5): 1461. Nearly 70% of patients at initial diagnosis have tumors that have spread beyond the supraclavicular areas and are said to have extensive-stage disease. Regardless of stage, the prognosis is unsatisfactory despite improvements in diagnosis and therapies developed over the past 25 years, see Siegel RL, etal., Cancer statistics, 2023. CA Cancer J Clin. 2023; 73(1): 17-48; Gong J, et al, Managing patients with relapsed small-cell lung cancer. J Oncol Pr act. 2018; 14(6): 359-366; Jackman DM, et al, Small-cell lung cancer. Lancet. 2005;366(9494): 1385-1396.

[0004] Delta-like canonical Notch ligand 3 (DLL3) is an inhibitory ligand of the Notch pathway that is confined to the Golgi apparatus and cytoplasmic vesicles. Therefore, it is minimally expressed on the surface of healthy cells. However, in neuroendocrine carcinomas, such as SCLC and LCNEC, DLL3 is upregulated and expressed on the surface of tumor cells, driving cell proliferation and differentiation. Indeed, DLL3 overexpression is reported in up to 80 to 90% of SCLCs and aberrantly expressed in 50% to 60% of LCNEC. The differential expression profile of DLL3 in normal vs. cancerous cells makes this target well suited for DLL3-directed therapies. Nevertheless, DLL3 -directed antibodies have not been observed tohave therapeutic benefit in preclinical tumor models without a cytotoxic payload, see Saunders LR, et al., A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor -initiating cells in vivo. Sci TranslMed. 2015;7(302):302ral36; Tully KM, etal, Radioimmunotherapy targeting delta-like ligand 3 in small cell lung cancer exhibits antitumor efficacy with low toxicity. Clin Cancer Res. 2022;28(7): 1391 -1401. Hence, DLL3 antigen targeting has been exploited to deliver a cytotoxic payload or redirect immune cells to tumors using ADCs, T-cell engagers, or chimeric antigen receptor T-cell therapy, including rovalpituzumab tesirine, AMG757, and AMG 119, see Cortinovis DL, etal, Harnessing DLL3 inhibition: From old promises to new therapeutic horizons. Front Med (Lausanne).2022;9:989405. More recently, new investigational DLL3 -targeting agents, including ADC and bispecific T-cell engagers, have shown to be show some activity in the treatment of SCLC and other neuroendocrine carcinomas, see Rudin CM, etal, Emerging therapies targeting the deltalike ligand 3 (DLL3) in small cell lung cancer. JHematol Oncol. 2023; 16(1 ):66. Despite recent advances, patients with recurrent SCLC and LCNEC have few therapeutic options and existing approved treatments to date have been demonstrated to provide limited benefit.SUMMARY

[0005] What is needed is further development of other DLL3 -targeting agents that can provide a new approach in the treatment of SCLC, LCNEC, and other neuroendocrine carcinomas, in particular those that can provide the opportunity to specifically target lung neuroendocrine tumor cells by delivering radiation directly to the primary tumor and metastatic sites.

[0006] Described herein are methods for treating individuals with DLL3 expressing tumors, including neuroendocrine tumors, using DLL3 radioimmunoconjugates. The description herein provide for radioimmunoconjugates and dosages of radioimmunoconjugates that deliver a maximum amount of radiation to a tumor or cancer, while reducing toxicity allowing for more potent therapy and increased patient compliance.

[0007] Described herein is a method of treating a tumor or cancer of an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence setforthin any oneof SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ IDNO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512, and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 531, wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to that set forth in any one of SEQ ID NO: 101 to 106, 201 to 206, 301 to 306, 401 to 306, and 501 to 506. In some embodiments, the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ IDNO: 131. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 101 to SEQ ID NO: 106. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence of any one of SEQ ID NO: 101 to SEQ ID NO: 106. In some embodiments, the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any oneof SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206. In some embodiments, the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 313 to SEQ ID NO: 315. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence setforthin any one of SEQ ID NO: 301 to SEQ ID NO: 306. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 303. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 303. In someembodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 304. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 304. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 305. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 305. In some embodiments, the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 403. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 403. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406. In some embodiments, the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region,wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506. In some embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506. In some embodiments, the DLL3 antigen binding region is humanized. In some embodiments, the DLL3 antigen binding region does not comprise an immunoglobulin light chain. In some embodiments, the DLL3 antigen binding region comprises or consists of a VHH. In some embodiments, the radioimmunoconjugate comprises an immunoglobulin heavy chain constant region. In some embodiments, the immunoglobulin heavy chain constant region comprises a CH2 domain of an immunoglobulin, CH3 domain of an immunoglobulin, or a CH2 domain and a CH3 domain of an immunoglobulin. In some embodiments, the immunoglobulin heavy chain constant region comprises a CH2 domain anda CH3 domain of an immunoglobulin. In some embodiments, the immunoglobulin heavy chain constant region is an IgA, IgGl, IgG2, IgG3, or IgG4 isotype. In some embodiments, the immunoglobulin heavy chain constant region is an IgGl isotype. In some embodiments, the immunoglobulin heavy chain constant region is an IgG4 isotype. In some embodiments, the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region or alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn). In some embodiments, the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region and alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn). In some embodiments, the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region. In some embodiments, the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn). In some embodiments, the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is an alteration that reduces complement dependent cytotoxicity (CDC), antibody -dependent cell-cytotoxicity (ADCC), antibody-dependent cell-phagocytosis ADCP, or a combination thereof . In some embodiments, the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is selected from the list consisting of: (a) 297 A, 297Q, 297G, or 297D, (b) 279F, 279K, or 279L, (c) 228P, (d) 235A, 235E, 235G, 235Q, 235R, or235S, (e) 237A, 237E, 237K, 237N, or237R, (f) 234A, 234V, or 234F, (g) 233P, (h) 328A,(i) 327Q or 327T, (j) 329A, 329G, 329Y, or 329R (k) 33 IS, (1) 236F or 236R, (m) 238A, 238E, 238G, 238H, 2381, 238V, 238W, or 238Y, (n) 248A, (o) 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, or 254V, (p) 255N, (q) 256H, 256K, 256R, or 256V, (r) 264 S, (s) 265H, 265K, 265 S, 265 Y, or 265 A, (t) 267G, 267H, 2671, or 267K, (u) 268K, (v) 269N or 269Q, (w) 270 A, 270G, 270M, or 270N, (x) 27 IT, (y) 272N, (z) 292E, 292F, 292G, or 2921, (aa) 293 S, (bb) 301 W, (cc) 304E, (dd) 31 IE, 311G, or 311 S, (ee) 316F, (ff) 328V, (gg) 33 OR, (hh) 339E or 339L, (ii) 3431 or 343 V, (jj) 373 A, 373G, or 373S, (kk) 376E, 376W, or 376Y, (11) 380D, (mm) 382D or 382P, (nn) 385P, (oo) 424H, 424M, or 424V, (pp) 4341, (qq) 438G, (rr) 439E, 439H, or 439Q, (ss) 440 A, 440D, 440E, 440F, 440M, 440T, or 440V, (tt) K322A, (uu) L235E, (vv) L234A and L235A, (ww) L234A, L235A, and G237A, (xx) L234A, L235A, and P329G, (yy) L234F, L235E, and P33 I S, (zz) L234A, L235E, and G237A, (aaa), L234A, L235E, G237A, and P331 S (bbb) L234A, L235A, G237A, P238S, H268A, A33 OS, andP331 S, (ccc) L234A, L235A, and P329A, (ddd) G236R and L328R, (eee) G237A, (fff) F241A, (ggg) V264A, (hhh) D265A, (iii) D265 A and N297A, (jjj) D265 A and N297G, (kkk) D270A, (111) A330L, (mmm) P331 A or P331 S, (nnn) E233P, (ooo) L234A, L235E, G237A, A330S, P33 I S, and (ppp) any combination of (a) - (ppp), per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region comprises L234A, L235E, G237A, A330S, and P331 S per EU numbering. In some embodiments, the amino acid alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) reduces the serum halflife of the radioimmunuconjugate. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 251, 252, 253, 254, 255, 288, 309, 310, 312, 385, 386, 388, 400, 415, 433, 435, 436, 439, 447, and combinations thereof per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 253, 254, 310, 435, 436 and combinations thereof per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 1253 A, I253D, I253P, S254A, H310A, H310D, H310E, H310Q, H435A, H435Q, Y436A, and combinations thereof perEU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: I253A, S254A, H310A, H435Q, Y436A and combinations thereof perEU numbering. In some embodiments, the alteration to theone or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 1253 A, H310A, H435Q, and combinations thereof per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises 1253 A per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises H310A per EU numbering. In some embodiments, the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises H435Q per EU numbering. In some embodiments, the DLL3 antigen binding region further comprises a linker amino acid sequence or a human IgG hinge region. In some embodiments, the human IgG hinge region comprises an amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, the DLL3 antigen binding region is coupled to the immunoglobulin heavy chain constant region by a human IgG hinge region. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120, SEQ ID NO: 216 to SEQ ID NO: 220, SEQ ID NO: 316 to SEQ ID NO: 320, SEQ ID NO: 416 to SEQ ID NO: 420, and SEQ ID NO: 516 to SEQ ID NO: 520. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120, SEQ ID NO: 216 to SEQ ID NO: 220, SEQ ID NO: 316 to SEQ ID NO: 320, SEQ ID NO: 416 to SEQ ID NO: 420, and SEQ ID NO: 516 to SEQ ID NO: 520. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 216 to SEQ ID NO: 220. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 216 to SEQ ID NO: 220. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 316 to SEQ ID NO: 320. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 317. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 317. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%,85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 318. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 318. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 319. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 319. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 316 to SEQ ID NO: 320. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 416 to SEQ ID NO: 420. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 417. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 417. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 416 to SEQ ID NO: 420. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 516 to SEQ ID NO: 520. In some embodiments, the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 516 to SEQ ID NO: 520. In some embodiments, the radioimmunoconjugate binds DLL3 at a KDof 10 nanomolar or less. In some embodiments, the radioimmunoconjugate binds DLL3 at a KDof 5 nanomolar or less. In some embodiments, the radioimmunoconjugate binds DLL3 at a KDof 2 nanomolar or less. In some embodiments, the radioimmunoconjugate binds DLL3 at a KDof 1 nanomolar or less. In some embodiments, the radioimmunoconjugate further comprises a chelating agent. In some embodiments, the radioimmunoconjugate is between 60 and 110 kDa. In some embodiments, the radioimmunoconjugate has a serum half-life of less than 15 days. In some embodiments, the radioimmunoconjugate has a serum half-life of less than 10 days. In some embodiments, the radioimmunoconjugate has a serum half-life of less than 120 hours. In some embodiments, the radioimmunoconjugate has a serum half-life of less than 72 hours. In some embodiments, the chelating agent is a radioisotope chelating agent. In some embodiments, the chelating agent is an alpha emitter chelating agent. In some embodiments, the chelating agent is a beta-emitter or gamma-emitter chelating agent. In some embodiments, the chelating agent is selected from the list consisting of: DOTA, DO3A, DOTAGA, DOTAGA anhydride, Py4Pa, Py4Pa-NCS, Crown, Macropa, Macropa-NCS, HEHA, CHXoctapa, Bispa, Noneunpa, and combinations thereof. In some embodiments, the chelating agent is selected from the list consisting of: DOTMA, DOTPA, DO3 AM-acetic acid, DOTP, DOTMP, DOTA-4AMP, CB- TE2A, NOTA, NOTP, TETPA, TETA, PEPA, H40ctapa, H2Dedpa, DO2P, EDTA, DTPA-BMA, 3,2,3-LI(HOPO), 3,2-HOPO, Neunpa, Neunpa-NCS, Octapa, PyPa, Porphyrin, Deferoxamine, DFO*, and combinations thereof. In some embodiments, the chelating agent is DOTA. In some embodiments, the chelating agent is DOTAGA. In some embodiments, the chelating agent is Py4Pa. In some embodiments, the chelating agent is directly coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region. In some embodiments, the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region by a linker. In some embodiments, the linker is selected from: 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine -citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl ( PAB), and those resulting from conjugation with linker reagents: N-Succinimidyl 4-(2 -pyridylthio) pentanoate forming linker moiety 4-mercaptopentanoic acid (SPP), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l- carboxylate (SMCC), N-Succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-Succinimidyl (4- iodo-acetyl) aminobenzoate (SIAB), polyethylene glycol (PEG), a polyethylene glycol polymer (PEGn), and S-2-(4-Isothiocyanatobenzyl) (SCN). In some embodiments, the linker is selected from: polyethylene glycol (PEG), a polyethylene glycol polymer (PEGn), and 4-benzyl. In some embodiments, the chelating agent comprises a linker-chelator resulting from conjugation with:some embodiments, the chelating agent comprises a linker-chelator resulting from conjugation with:some embodiments, the chelating agent comprises a linker-chelator resulting from conjugation with:some embodiments, the chelating agent comprises a linker-chelator resulting from conjugation with:some embodiments, the chelating agent comprises a linker-chelator selected from:chelating agent comprises a linker-chelator that is:some embodiments, the chelating agent comprises a linker-chelator that is:some embodiments, the chelating agent comprises a linker-chelator that is:, elating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 1 :1 to 8:1. In some embodiments, the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 1 :1 to 6:1. In some embodiments, the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region ata ratio of 2:1 to 6:1. In some embodiments, the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 4:1. In some embodiments, the radioisotope is an alpha emitter. In some embodiments, the radioisotope is an alpha emitter selected from the list consisting of 225-Ac, 223-Ra, 224-Ra, 227-Th, 212-Pb, 212-Bi, and 213- Bi. In some embodiments, the radioisotope is 225-Ac. In some embodiments, the radioisotope is a beta emitter. In some embodiments, the radioisotope is a beta emitter selected from 177-Lu, 90-Y, 67-Cu, and 153-Sm. In some embodiments, the radioisotope is a gamma emitter. In some embodiments, the radioisotope is a gamma emitter selected from 111-In, 89-Zn, 123-1, 99m-Tc, and 68-Ga. In some embodiments, the molecular weight of the radioimmunoconjugate is between 60 and 100 kDa. In some embodiments, the molecular weight of the radioimmunoconjugate is between 60 and 90 kDa. In some embodiments, the molecular weight of the radioimmunoconjugate is between 65 and 90 kDa. In some embodiments, the molecular weight of the radioimmunoconjugate is between 70 and 90 kDa. In some embodiments, theradioimmunoconjugate forms a dimer with another radioimmunoconjugate. In some embodiments, the radioimmunoconjugate is included in a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and the radioimmunoconjugate. In some embodiments, the radioimmunoconjugate is administered intravenously. In some embodiments, the tumor or cancer comprises a solid tissue tumor or cancer. In some embodiments, the tumor or cancer expresses DLL3. In some embodiments, the tumor or cancer comprises lung cancer cell, breast cancer, ovarian cancer, or neuroendocrine cancer. In some embodiments, the neuroendocrine cancer comprises a carcinoma. In some embodiments, the lung cancer comprises a non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer comprises small cell lung cancer (SCLC). In some embodiments, the lung cancer comprises a large-cell neuroendocrine carcinoma (LCNEC) or a pulmonary LCNEC. In some embodiments, the individual has previously received a platinum based chemotherapeutic. In some embodiments, the platinum based chemotherapeutic is selected from the list consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, and combinations thereof. In some embodiments, the tumor or cancer is refractory to treatment with at least one previous anti -neoplastic agent. In some embodiments, the individual has adequate renal function or adequate hepatic function. In some embodiments, the individual has adequate renal function. In some embodiments, the individual has adequate hepatic function. In some embodiments, the tumor or cancer is a locally advanced cancer. In some embodiments, the tumor or cancer is a metastatic cancer. In some embodiments, the tumor or cancer is an extensive stage cancer. In some embodiments, the method is associated with a lower incidence of gastrointestinal side -effects. In some embodiments, the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In some embodiments, the method further comprising selecting the individual based on a positive result from an assay of a prior administration of a DLL3 -binding reagent coupled or complexed to a gamma-emitting radionuclide, wherein the positive result from the assay indicates binding of the DLL3 -binding reagent to a tumor or cancer of the individual. In some embodiments, the gamma-emitting radionuclide comprises 111 -In. In some embodiments, the gamma-emitting radionuclide is administered at a dose of about 5 mCi. In some embodiments, the assay comprises Single-Photon Emission Computed Tomography combined with Computed Tomography (SPECT / CT). In some embodiments, the DLL3 -binding reagent comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2(HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512, and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 531. In some embodiments, the DLL3 -binding reagent comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506. In some embodiments, the gamma-emitting radionuclide is complexed to the DLL3 -binding reagent by a linker-chelator.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The novel features described herein are set forth with particularity in the appended claims. A better understanding of the features and advantages of the features described herein will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the features described herein are utilized, and the accompanying drawings of which:

[0009] FIG. 1 illustrates internalization of VHHFcl47 and ABD147 following target engagement in human SHP-77 SCLC cells with conjugate (ABD147) or without (VHHFcl47) compared to isotype control (hlgG).

[0010] FIGs. 2A-2C show female athymic nude mice challenged with xenografted SHP-77 tumors after receiving a single IV dose of cold ABD 147 (without radioisotope conjugation; control) or Ac225-ABD147 at the indicated doses. FIG. 2 A shows individual mouse body weight change. FIG. 2B shows individual mouse tumor volume. FIG. 2C shows Kaplan-Meier survival curve, with a log-rank test comparing treatment to vehicle (*p<0.05, **p<0.01, ***p<0.001).

[0011] FIGs. 3A-3C show female athymic nude mice challenged with xenografted NCL- H82 tumors after receiving a single IV dose of cold ABD 147 (control) or Ac225-ABD147 at the indicated doses. FIG. 3 A shows individual mouse body weight change. FIG. 2B shows individual mouse tumor volume. FIG. 3C shows Kaplan-Meier survival curve, with a log-rank test comparing treatment to vehicle (*p<0.05, **p<0.01, ***p<0.001).

[0012] FIG. 4 illustrates the clearance of Inin-ABD147 from the blood of hFcRn transgenicmice after a single IV dose at 3 MBq and 0.3 mg / kg protein. FIG. 4 shows plasma activity concentration vs. time. Error bars show mean ± SD.

[0013] FIGs. 5A-5B illustrate the plasma concentration vs. time in naive Cynomolgus Monkeys after receiving a single dose of cold ABD147 at dose levels of 6 and 30 mg / kg, measured by ELISA. FIG. 5A shows plasma concentration after terminal sacrifice, n = 3 animals / sex at 6 mg / kg and n = 5 animals / sex at 30 mg / kg. FIG. 5B shows recovery sacrifice, n=5 animals / sex up to 48 hours andn = 2 animals / sex from 72 hours to 384 hours at 30 mg / kg. Error bars show mean ± SD.

[0014] FIG. 6 illustrates the plasma concentration vs. time in male and female Cynomolgus Monkeys (n=3 / sex) after receiving a single dose of Inni-ABD147 at a target mass dose of 0.3 mg / kg, measured by gamma counter. Error bars show mean ± SD (n=3 / sex).

[0015] FIG. 7 illustrates the plasma concentration vs. time in male and female Cynomolgus Monkeys after receiving a single dose of Inin-ABD147 at a target mass dose of 3 mg / kg, measured by gamma counter. Error bars show mean ± SD (n=3 / sex).

[0016] FIG. 8 shows biodistribution of In1H-ABD147 into normal tissue in naive hFcRn mice after receiving a single dose of 0.3 mg / kg. For each tissue, columns from left to right represent tissue activity concentrations at defined time points (lOmin, 24h, 72h, 168h, and 336h respectively).

[0017] FIG. 9 shows whole-body clearance of In1H-ABD147 from naive female and male Cynomolgus Monkeys after receiving a single dose of Inin-ABD147 at a fixed mass dose of either 0.3 or 3 mg / kg (n=3 / sex / dose).

[0018] FIG. 10 illustrates predominant liver biodistribution of In1H-ABD147, as shown by representative SPECT / CT images from a naive male Cynomolgus Monkey between 1 hour and 240 hours post-injection of 0.3mg / kg Inni-ABD147.

[0019] FIGs. 11A-11B illustrate tissue activity concentration calculated by SPECT / CT in male Cynomolgus Monkeys after receiving a single dose of 0.3 mg / kg (FIG. 11A), or 3 mg / kg (FIG. 11B) of Inin-ABD147. For each tissue, columns from left to right represent tissue activity concentrations at defined time points (Ih, 24h, 72h, 144h, and 240h respectively). Error bars show ± SEM, n=3 animals / dose.

[0020] FIGs. 12A-12B illustrate tissue activity concentration calculated by SPECT / CT in female Cynomolgus Monkeys after receiving a single dose of 0.3 mg / kg (FIG. 12A) or 3 mg / kg (FIG. 12B) of In111-ABD147. For each tissue, columns from left to right represent tissue activity concentrations at defined time points (Ih, 24h, 72h, 144h, and 240h respectively). Error bars show mean ± SEM, n=3 animals / dose.

[0021] FIG. 13 shows liver update (%ID) 1 hour to 240 hours post injection of indicateddoses of Ini n-ABD147. Error bars show mean ± SEM, n=3 animals / sex / dose.

[0022] FIGs. 14A-14B show extrapolated radiation absorbed doses and total body effective dose for Ac225-ABD147 in human. Ac225-ABD147 doses in human (mean ± standard error of the mean) were extrapolated from cynomolgus monkeys receiving 0.3 mg / kg (FIG. 14A), or 3 mg / kg (FIG. 14B) In1 H-ABD147. Total body effective dose applies an RBE of 5.

[0023] FIGs. 15A-15B show extrapolated radiation absorbed doses and total body effective dose for Ini n-ABD147 in human. In1 H-ABD147 doses in human (mean ± standard error of the mean) were extrapolated from cynomolgus monkeys receiving 0.3 mg / kg (FIG. 15A) or 3 mg / kg (FIG. 15B) In1 H-ABD147. Total body effective dose applies an RBE of 1.

[0024] FIG. 16 illustrates the tissue biodistribution of In1 H-ABD147 in mice bearing SHP- 77 SCLC Xenografts 72 hours after a single dose of 0.3 mg / Kg. Error bars show mean ± SEM, n=4.

[0025] FIG. 17 illustrates the tissue biodistribution of 111 In-ABD147 in mice bearing NCL-H82 SCLC Xenografts 96 hours after a single dose of 0.3 mg / Kg. Mean ± SEM, n=7.

[0026] FIGs. 18A-18C illustrate predominant tumor biodistribution and liver clearance of Inn i-ABD147 over time. FIG. 18A shows representative SPECT / CT images from mice with xenografted NCL-H82 tumors post-injection of 1 mg / kg In11^ABD 147. FIG. 18B shows timecourse tissue activity concentrations of In1 H-ABD147 determined by SPECT / CT image quantification 24, 72, and 144 h. FIG. 18C shows tissue activity concentrations of In111- ABD147 as determined by gamma counting at 144 h post -injection (error bars show mean ± SEM, n = 3 mice).

[0027] FIGs. 19A-19B show effects of mass dose on Inn i-ABD147 distribution to tumors and normal tissues in SHP-77 tumor-bearing mice after a single indicated dose. FIG. 19A shows tissue activity concentration of Ini n-ABD147 at 24 h. FIG. 19B shows time-course tissue activity concentrations of Ini n-ABD147 at24, 72, and 168. Mean ± SEM, n=4 mice / time point in blood, plasma, kidney, liver, spleen, and tumor tissues.

[0028] FIG. 20 shows tissue biodistribution of Ac225-ABD147 in mice bearing NCI-H82 SCLC Xenografts 7 days after a single dose of 1.0 mg / kg. Mean ± SEM, n=5 mice.

[0029] FIG. 21 A shows whole-blood gamma pharmacokinetics in counts per minute per gram (cpm / g) at timepoints 15 minutes post end-of-irradiation (EOI) to 96 hours post EOI for Patients 1-3.

[0030] FIG. 2 IB shows whole-blood gamma pharmacokinetics in %ID / mL values at timepoints 15 minutes post EOI to 96 hours post EOI for Patients 1 -3.

[0031] FIGs. 22A-22C show two-compartment model curve fitting for observed and predicted cpm / g for Patient 1 (FIG. 22 A), Patient 2 (FIG. 22B), and Patient 3 (FIG. 22C).

[0032] FIGs. 23A-23C show two-compartment model curve fitting for observed and predicted CMaxfor Patient 1 (FIG. 23 A), Patient 2 (FIG. 23B), and Patient 3 (FIG. 23C).

[0033] FIG. 24 shows representative whole body planar images from Patient 2 at 1 hour post EOI, 4 hours post EOI, 24 hours post EOI, 48 hours post EOI, and 96 hours post EOI, in anterior and posterior views.

[0034] FIG. 25 shows SPECT / CT measurements of average absorbed dose (MBq / mL) in liver, spleen, pelvis, and kidney in Patients 1 -3 at 15 minutes post EOI to 72 hours post EOI.

[0035] FIGs. 26A-26D show representative SPECT / CT scan images of a lung lesion in Patient 2, 48 hours post EOI. FIG. 26A shows a CT scan image of the lung lesion in the axial plane. FIG. 26B shows a corresponding SPECT image of the CT scan (FIG. 26A), exhibiting localization ofniIn-ABD147 to the lung lesion. FIG. 26C shows a CT scan image of the lung lesion in the sagittal plane. FIG. 26D shows a corresponding SPECT image of the CT scan (FIG. 26C), exhibiting localization of1HIn-ABD147 to the lung lesion.

[0036] FIGs. 27A-27C show comparisons of average %ID / mL (FIG. 27A), CMax(FIG.27B), and %ID (FIG. 27C) in blood of Patients 1-3 dosed with 0.2 mg / kgmIn-ABD147, NHPs dosed with 0.3 mg / kg or 3 mg / kginIn-ABD147, male hFcRn mice dosed with 1 mg / kgU1ln- ABD147, and female hFcRn mice dosed with 0.3 mg / kgluIn-ABD147.

[0037] FIGs. 28A-28C show WBC count, neutrophil count (NEUT), and lymphocyte count (LYM) for Patient 1 at baseline, 72 hours post -EOI with1HIn-ABD147, at Day 1 of infusion with225Ac-ABD147, at Day 8 post-EOI with225Ac-ABD147, at Day 15 post-EOI with225Ac- ABD147, at Day 22 post-EOI with225Ac-ABD147, at Day 29 post EOI with225Ac-ABD147, and at Day 36 post-EOI with225Ac-ABD147 (FIG. 28A), for Patient 2 at baseline, 72 hours post-EOI withniIn-ABD147, atDay 1 of infusion with225Ac-ABD147, atDay 8 post-EOI with225Ac-ABD147, and at Day 15 post-EOI with225Ac-ABD147 (FIG. 28B), and for Patient 3 at baseline, at a timepoint post-EOI withinIn-ABD147 (as denotedby *), at Day 8 post-EOI with225Ac-ABD147, and at Day 15 post-EOI with225Ac-ABD147 (FIG. 28C).

[0038] FIGs. 29A-29C show platelet counts for Patient 1 (FIG. 29A), Patient 2 (FIG. 29B), and Patient 3 (FIG. 29C), at the timepoints discussed in FIGs. 28A-28C.

[0039] FIGs. 30A-30C show platelet counts for Patient 1 (FIG. 30A), Patient 2 (FIG. 30B), and Patient 3 (FIG. 30C), at the timepoints discussed in FIGs. 28A-28C.DETAILED DESCRIPTIONDefinitions

[0040] In the following description, certain specific details are set forth in order to provide athorough understanding of various embodiments. However, one skilled in the art will understand that the embodiments provided may be practiced without these details. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0041] As used herein the term “about” refers to an amount that is near the stated amount by 10% or less.

[0042] As used herein the term “individual,” “patient,” or “subject” refers to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease for which the described compositions and method are useful for treating. In certain embodiments the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. In certain embodiments, the individual is a human.

[0043] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and / or non -natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0044] Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2,ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequencesbeing compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN -2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0045] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0046] The immunoconjugates and radioimmunoconjugates described herein comprise antigen binding regions. These antigen binding regions can be derived from an “antibody.” The term “antibody” herein is used in the broadest sense and includes monoclonal antibodies, and includes intact antibodies and functional (antigen -binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. An antibody fragment retains at least some of the binding specificity of the parental antibody. Typically, an antibody fragment retains at least 10% of the parental binding activity. Preferably, an antibody fragment retains atleast20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the parental antibody's binding affinity for the target. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies,peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD. The antibody can comprise a human IgGl constant region. The antibody can comprise a human IgG4 constant region.

[0047] The terms “complementarity determining region,” and “CDR,” which are synonymous with “hypervariable region” or “HVR,” are known in the art to refer to noncontiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each variable domain (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR -LI, CDR-L2, CDR-L3). “Framework regions” and “FR” are known in the art to refer to the non- CDR portions of the VHH variable regions of the heavy and light chains. In general, there are fourFRs in each full-length variable domain (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927- 948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody -antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pluckthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modelling antibodies on the WEB,” Protein Eng. 2000 Dec;13(12):819-24 (“AbM’ numbering scheme. In certain embodiments, the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[0048] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertionsaccommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[0049] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The VHH variable domains of the heavy chain and light chain (VHand VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g. , Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)). A single Vn or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VHor VLdomain from an antibody that binds the antigen to screen a library of complementary VLor VH domains, respectively (5eee.g.,Portolanoet al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0050] The term “VHH polypeptide” as used herein encompasses natural and synthetic compositions and refers to a polypeptide constituting a VHH fragment as it is known in the art, i.e., a polypeptide that constitutes a single domain heavy chain only antigen binding variable domain fragment, or a polypeptide that structurally and functionally resembles a VHH fragment, as such structure is further described below and has the ability to specifically bind antigen is described below, as both are known in the art. In some embodiments, the VHH polypeptides comprise a variable domain comprising three heavy chain CDR’s; in one embodiment the VHH polypeptide is derived from a camelid; in another embodiment the VHH polypeptide is derived from a library or camelid antibodies; VHH polypeptides bind to antigens with specificity and high affinity. In some embodiment, the VHH polypeptide is a single variable domain comprising the arrangement: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. VHH polypeptides may be obtained, for example, as the antigen binding fragments of heavy chain only antibodies generated in vivo (e.g., in cam elids). VHH polypeptides may also be obtained from synthetic libraries, e.g., phage display libraries. For example, see McMahon et al., Nature Structural & Molecular Biology | VOL 25 | MARCH 2018 | 289-296 Yeast surface display platform for rapid discovery of conformationally selective nanobodies,' Moutel et al., eLife 2016;5:el6228 NaLi- H1 : A universal synthetic library of humanized nanobodies providing highly functional antibodies and intrabodies. De Genst E, Saerens D, Muyldermans S, Conrath K. Antibody repertoire development in camelids. Dev Comp Immunol. 2006;30(l -2):187-98. doi:10.1016 / j dci.2005.06.010. PMID: 16051357. Vincke C, Gutierrez C, Wemery U, Devoogdt N, Hassanzadeh-Ghassabeh G, Muyldermans S. Generation of single domain antibody fragmentsderived from camelids and generation of manifold constructs. Methods Mol Biol. 2012;907:145- 76. doi: 10.1007 / 978-l-61779-604-7_8. PMID: 22907350. Arbabi Ghahroudi M, Desmyter A, Wyns L, Hamers R, Muyldermans S. Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett. 1997 Sep 15 ;414(3 ): 521 -6. doi: 10.1016 / s0014-5793(97)01062-4. PMID: 9323027.

[0051] For VHH humanization, see, for example, Vincke C, Loris R, Saerens D, Martinez - Rodriguez S, Muyldermans S, Conrath K. General strategy to humanize a camelid single - domain antibody and identification of a universal humanized nanobody scaffold. J Biol Chem. 2009 Jan 30;284(5):3273-84. doi: 10.1074 / jbc.M806889200. Epub 2008 Nov 14. PMID: 19010777.

[0052] For VHH stability, see, for example, Kunz P, Flock T, Soler N, Zaiss M, Vincke C, Sterckx Y, Kastelic D, Muyldermans S, Hoheisel JD. Exploiting sequence and stability information for directing nanobody stability engineering. Biochim Biophys Acta Gen Subj . 2017 Sep;1861(9):2196-2205. doi: 10.1016 / j.bbagen.2017.06.014. Epub 2017 Jun 20. PMID: 28642127; PMCID: PMC5548252; Kunz P, Zinner K, Miicke N, BartoschikT, Muyldermans S, Hoheisel JD. The structural basis of nanobody unfolding reversibility and thermoresistance. Sci Rep. 2018 May 21 ;8(1 ):7934. doi: 10.1038 / s41598-018-26338-z. PMID: 29784954; PMCID: PMC5962586.

[0053] The antibodies of the immunoconjugates described herein may comprise an Fc domain. An Fc domain generally encompasses and / or refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region, such as an immunoglobulin CH2 and CH3 domain. Fc fragments generally exclude a CHI domain and in some instances an immunoglobulin hinge region. The term includes native sequence Fc regions and variant Fc regions. For example, a human IgG heavy chain Fc region extends from Cy s226, or from Pro230, to the carboxyl -terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. In certain embodiments, the Fc region include IgG and sub -classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and / or IgD heavy chain constant regions and / or heavy chain constant regions derived from IgG and sub-classes thereof (e.g., IgGl and IgG4), IgM, IgE, IgA, and IgD. Generally, the antibodies described herein have the format variable domain - hinge - Fc domain, wherein the hinge sequence is included as part of the Fc domain sequence.

[0054] A “humanized” antibody refers to an antibody having a sequence that differs fromthe sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0055] The “specificity” of an amino acid sequence, in particular an antibody fragment, such as a VHH, or functional fragments thereof as disclosed herein can be determined based on affinity and / or avidity and is generally derived from the CDR regions without contribution from other parts of the antibody such as constant regions. In some embodiments, the amino acid sequences as disclosed herein will bind to a target protein of interest with a dissociation constant (KD) of less than about 1 micromolar (1 pM). A KDvalue greater than about 1 millimolar is indicates non-binding or non-specific binding. Binding affinities may be determined by means or methods known to the person skilled in the art, for example ELISA methods, isothermal titration calorimetry, surface plasmon resonance, fluorescence -activated cell sorting analysis, and the like.

[0056] The terms “specific binding”, “specifically binds” or “specifically binding” and other related terms, as used herein in the context of an antibody or antigen binding protein or antibody fragment, refer to non-covalent or covalent preferential binding to an antigen relative to other molecules or moieties (e.g., an antibody specifically binds to a particular antigen relative to other available antigens). The antibody, or antigen binding polypeptide is capable of binding antigen with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeuticagent in targeting that antigen. The antigen binding polypeptides described herein specifically bind DLL3 if the KDis 1 millimolar of less.

[0057] In some embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. A variant typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and / or using any of a number of known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

[0058] The nucleic acids encoding the antibodies described herein can be used to infect, transfect, transform, or otherwise render a suitable cell transgenic for the nucleic acid, thus enabling the production of antibodies for commercial or therapeutic uses. Standard cell lines and methods for the production of antibodies from a large-scale cell culture are known in the art. See e.g., Li et al., “Cell culture processes for monoclonal antibody production.” Mabs. 2010 Sep- Oct; 2(5): 466-477. In certain embodiments, the cell is a Eukaryotic cell. In certain embodiments, the Eukaryotic cell is a mammalian cell. In certain embodiments, the mammalian cell is a cell line useful for producing antibodies is a Chines Hamster Ovary cell (CHO) cell, an NS0 murine myeloma cell, or a PER.C6® cell. In certain embodiments, the nucleic acid encoding the antibody is integrated into a genomic locus of a cell useful for producing antibodies. In certain embodiments, described herein is a method of making an antibody comprising culturing a cell comprising a nucleic acid encoding an antibody under conditions in vitro sufficient to allow production and secretion of said antibody.

[0059] Also described herein are methods of making an antibody described herein. Such methods comprise incubating a cell or cell -line comprising a nucleic acid encoding the antibody in a cell culture medium under conditions sufficient to allow for expression and secretion of the antibody, and further harvesting the antibody from the cell culture medium. The harvesting can further comprise one or more purification steps to remove live cells, cellular debris, non- antibody proteins or polypeptides, undesired salts, buffers, and medium components. In certainembodiments, the additional purification step(s) include centrifugation, ultracentrifugation, protein A, protein G, protein A / G, or protein L purification, and / or ion exchange chromatography.

[0060] As used herein, the term “DLL-3” or “DLL3” refers to Delta-like protein 3 protein of any species. In some instances, DLL3 refers to human DLL3 and is encoded by DLL3 delta like canonical Notch ligand 3 (homo sapiens) gene. This protein plays a role in the formation of somite boundaries during segmentation of the paraxial mesoderm. The sequence can be found from Uniprot (Q9NYJ7.DLL3 HUMAN).

[0061] As used herein, the term “immunoconjugate” refers to a molecular complex comprising an at least one antigen binding region derived from an antibody (e.g., variable regions or complementarity determining regions) further coupled to at least one non -antibody derived molecule, such as a chelator or cytotoxic agent. Non-antibody derived molecules may for example be conjugated to one or more lysine or cysteine resides of the antigen binding region or to a constant region coupled (by peptide linkage or otherwise) to the antigen binding region. In some embodiments, the immunoconjugate further comprises a chelating moiety (interchangeably, “chelator”). In one embodiment, an immunoconjugate comprises an antibody construct of this disclosure linked directly or indirectly to a cytotoxic agent or radioisotope.

[0062] As used herein, the term “linker” refers to a moiety that attaches one molecule to another molecule (e.g., attaches a radioisotope to an antibody fragment such as a VHH or functional fragment thereof). The linker may be a chemical linker, a nucleotide linker, a peptide linker, or any combination thereof.

[0063] As used herein, the term “chelator” or “chelating moiety” refers to a chemical compound to which a metal, preferably a radiometal, can be chelated via coordinate bonding.

[0064] A “radioimmunoconjugate” and related terms used herein refers to a radioactive substance that carries radiation directly to cancer cells. A radioimmunoconjugate is made bycoupling a radioactive isotope (e.g., 225 Ac) to an antigen binding molecule (e.g., monoclonal antibody or fragment thereof, VHH, etc.), that can bind an antigen of interest. The coupling maybe via a molecular linker, spacer, stretcher, chelator or combination thereof. Radioimmunoconjugates may also for imaging or treatment of diseases.

[0065] An “isolated” antibody or immunoconjugate or radioimmunoconjugate is one which has been separated from a component of its natural environment or artificial production. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). Routine methods for assessment of antibody purity in a composition are known to the skilled worker, see e.g.,Flatman et al., J. Chromatogr . B 848:79-87 (2007). In particular, unwanted components (contaminants) to be purified away from are such components that would interfere with desired uses for the antibody, such as, e.g., a therapeutic use, and may include, inter alia, bacterial factors, enzymes, hormones, and other proteinaceous or non -proteinaceous solutes.

[0066] The term “administering”, “administered” and grammatical variants refers to the physical introduction of an agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracap sular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation. Other non -parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Any of the radioimmunoconjugates or antigen binding polypeptides thereof described herein can be administered to a subject using art -known methods and delivery routes.

[0067] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, radioimmunoconjugates of this disclosure are used to delay development of a disease or to slow the progression of a disease.

[0068] A “therapeutically effective amount” is at least the minimum concentration required to affect a measurable improvement or prevention of a particular disorder. A therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of a composition of this disclosure to elicit a desired response in the individual. A therapeutically effective amount is also one in which toxic or detrimental effects of the composition of this disclosure are outweighed by the therapeuticallybeneficial effects.

[0069] The terms “predictive” and “prognostic” as used herein are interchangeable. In one sense, the methods for prediction or prognostication are to allow the person practicing a predictive / prognostic method of this disclosure to select patients that are deemed (usually in advance of treatment, but not necessarily) more likely to respond to treatment with an immunoconjugate of the present invention or a composition of the aforementioned (e.g., a pharmaceutical composition).

[0070] The term “detecting” is used in the broadest sense to include both qualitative and quantitative measurements of a target antigen molecule. In one aspect, the detecting method as described herein is used to identify the mere presence of the antigen of interest in a biological sample. In another aspect, the methodis used to test whether the antigen of interest in a sample is present at a detectable level. In yet another aspect, the method can be used to quantify the amount of the antigen of interest in a sample and further to compare the antigen levels from different samples. In another aspect, the method can be used in vivo to determine the location of a target cell, for example, using a targeted imaging complex of this disclosure.

[0071] The term “tumor” as used herein refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0072] The terms “cancer” and “cancerous” as used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), skin cancer, melanoma, lung cancer including small -cell lung cancer, non-small cell lung cancer (“NSCLC”), small cell neuroendocrine lung cancer, large cell neuroendocrine lung cancer, pulmonary large cell neuroendocrine carcinoma (LCNEC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), glioblastoma, cervical cancer, ovarian cancer (e.g., high grade serous ovarian carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC)), bladder cancer (e.g., urothelial bladder cancer), testicular (germ cell tumor) cancer, hepatoma, breast cancer, brain cancer (e.g., astrocytoma), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (e.g., renal cell carcinoma, nephroblastoma or Wilms’ tumor), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. Additional examples of cancer include, without limitation, retinoblastoma, thecomas, arrhenoblastomas, hepatoma, hematologicmalignancies including non-Hodgkins lymphoma (NHL), multiple myeloma and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi’s sarcoma, melanoma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, anaplastic astrocytoma, basal cell carcinoma (basal cell epithelioma), bile duct cancer, small cell bladder cancer, metastatic breast cancer, metastatic colorectal cancer, epithelial ovarian cancer, fallopian tube cancer, gastric adenocarcinoma, glioblastoma multiforme (GBM), recurrent glioblastoma multiforme (GBM), gliomas, gliosarcoma, head and neck squamous cell carcinoma (HNSCC), recurrent head and neck cancer squamous cell carcinoma, malignant pleural mesothelioma head and neck cancer, Hodgkin lymphoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma, squamous non-small cell lung cancer, squamous carcinoma of the lung, relapsed or refractory small -cell lung cancer, treatment-resistant melanoma, metastatic melanoma, Merkel cell carcinoma, neuroendocrine cancer, large cell neuroendocrine cancer, neuroendocrine tumors (NETS), ovarian carcinoma, papillary carcinoma, peritoneal cancer, neuroendocrine prostate cancer, hormone-refractory prostate cancer, castration-resistant prostate cancer, soft tissue sarcoma, and squamous cell carcinoma.

[0073] As used herein, an individual or patient with adequate renal function is an individual or patient that has a creatine clearance of > 60 mL / min based on the Cockcroft-Gault glomerular filtration rate estimate. As used herein, an individual or patient with adequate hepatic function has an aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level of < 2.5 upper limit of normal (ULN), a direct bilirubin level of < 0.6 mg / dL or < 10.3 pmol / L, and a total serum bilirubin level of 0.2 to 1.3 mg / dL or 3.4 to 22 pmol / L.

[0074] The term “locally advanced cancer” as used herein is a cancer that has spread from its original location to nearby tissue or lymph nodes but has not yet spread to other parts of the body.

[0075] The term “metastatic cancer” means the state of cancer where the cancer cells of a tissue of origin are transmitted from the original site to one or more sites elsewhere in the body, by the blood vessels or lymphatics, to form one or more secondary tumors in one or more organs besides the tissue of origin. A prominent example is a metastatic breast cancer.

[0076] The term “extensive stage cancer” as used herein is a cancer that has spread beyond a single area that can still be treated with radiotherapy.DLL3 Binding molecules

[0077] The methods of treatment described herein utilize delivery of radioisotopes to cancers and tumors that express DLL3. The delivery of the radioisotopes can be achieved by antigen binding polypeptides that incorporate DLL3 antigen binding regions. In certain embodiments, the antigen binding polypeptide comprises an antibody or antigen binding fragment thereof. In certain embodiments, the DLL3 antigen binding region is humanized. In certain embodiments, the DLL3 antigen binding region does not comprise an immunoglobulin light chain. In certain embodiments, the DLL3 antigen binding region comprises or consists of a VHH.

[0078] In certain embodiments, the radioimmunoconjugates described herein may bind DLL3 at a KD of 10 nanomolar or less, 5 nanomolar or less, 2 nanomolar or less, or 1 nanomolar or less.

[0079] In certain embodiments, radioimmunoconjugates further comprises a chelating agent and the molecular weight of the immunoconjugate is between 60 and 110 kDa, 60 and 90 kDa, 65 and 90 kDa, or 70 and 90kDa.

[0080] In certain embodiments, the radio immunoconjugate is characterized by a half-life less than about 15 days, 10 days, 120 hours, or 72 hours.

[0081] In certain embodiments, the immunoconjugate forms a dimer with another immunoconjugate.

[0082] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b)a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53. Wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical set to that set forth in any one of SEQ ID NO: 101 to 106, 201 to 206, 301 to 306, 401 to 306, and 501 to 506.

[0083] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 101 to SEQ ID NO: 106. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO: 101 to SEQ ID NO: 106.

[0084] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO: 201 to SEQ ID NO: 206.

[0085] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 313 to SEQ ID NO: 315, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%,85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306. Alternatively, DLL3 antigen bindingregion comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO: 301 to SEQ ID NO: 306.

[0086] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 303. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:303.

[0087] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 304. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:304.

[0088] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 305. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:305.

[0089] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth inany one of SEQ ID NO: 401 to SEQ ID NO: 406.

[0090] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 403. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 403.

[0091] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406.

[0092] In certain embodiments, the DLL3 binding molecule comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506. Alternatively, DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.

[0093] The present disclosure provides in various embodiments the radioimmunoconjugate comprising a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region does not comprise an immunoglobulin light chain.

[0094] The present disclosure provides in various embodiments the radioimmunoconjugate comprising a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises or consists of a VHH.

[0095] The present disclosure provides in various embodiments the radioimmunoconjugate comprising an immunoglobulin heavy chain constant region. In certain embodiments, the immunoglobulin heavy chain constant region comprises an Fc region. In certain embodiments, the immunoglobulin heavy chain constant region comprises CH2 domain. In certainembodiments, the immunoglobulin heavy chain constant region comprises CH3 domain. In certain embodiments, the immunoglobulin heavy chain constant region comprises CH2 and a CH3 domain. In certain embodiments, the immunoglobulin heavy chain constant region comprises hinge region and a CH2 and a CH3 domain. In certain embodiments, the immunoglobulin heavy chain constant region does not comprise a CHI domain.Fc modifications

[0096] The present disclosure also encompasses fragments, analogs, mutants, variants, and / or derivatives of the antigen binding polypeptides, disclosed herein. Such fragments, analogs, mutants, variants, and / or derivatives according to the disclosure are generally functional. In some embodiments, such fragments, analogs, mutants, variants, and / or derivatives according to the disclosure are considered functional if they are capable of specifically binding to DLL3.

[0097] The antigen binding polypeptides can be further coupled or fused to immunoglobulin polypeptides that impart function other than antigen binding, such as immune effector function or binding to the neonatal Fc Receptor (FcRn). The immunoglobulin polypeptides of the present disclosure may be characterized by reduced effector function (e.g., ADCC, CDC ADCP). The immunoglobulin polypeptides of the present disclosure may be characterized by reduced FcRn binding. This reduced FcRn binding may result is a shorter half-life in the circulation of a human individual compared to an antibody with a wild-type Fc region. The shorter half-life may be less than 24, 48, 72, 96, 120, 144, or 168 hours. The shorter half-life may be less than 1 week. The shorter half-life may be less than 2 weeks.

[0098] For example, the antigen binding polypeptides described herein may further comprise an immunoglobulin heavy chain constant region. In certain embodiments, the immunoglobulin heavy chain constant region comprises a CH2 domain of an immunoglobulin, CH3 domain of an immunoglobulin, or a CH2 and a CH3 domain of an immunoglobulin. In certain embodiments, the immunoglobulin heavy chain constant region comprise a CH2 domain. In certain embodiments, the immunoglobulin heavy chain constant region comprise a CH3 domain.

[0099] For example, the disclosure also encompasses the antigen binding polypeptide comprising an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region is an IgA, IgGl, IgG2, IgG3, or IgG4 isotype. In certain embodiments, the immunoglobulin heavy chain constant region comprises an IgG4 isotype. In certain embodiments, the immunoglobulin heavy chain constant region comprises an IgGl . In certain embodiments, the immunoglobulin heavy chain constant region comprises a human IgG4 isotype. In certain embodiments, the immunoglobulin heavy chain constant region comprises ahuman IgGl .

[0100] In some embodiments of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region or alters binding of the polypeptide to the neonatal Fc receptor (FcRn).

[0101] In some embodiments of any one of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region and alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn).

[0102] In some embodiments of any one of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region.

[0103] In some embodiments of any one of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn).

[0104] In some embodiments of any one of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is an alteration that reduces complement dependent cytotoxicity (CDC), antibody -dependent cellcytotoxicity (ADCC), antibody-dependent cell-phagocytosis ADCP, or a combination thereof. The alteration to one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is selected from the list consisting of: (a) 297 A, 297Q, 297G, or 297D, (b) 279F, 279K, or 279L, (c) 228P, (d) 235A, 235E, 235G, 235Q, 235R, or 235S, (e) 237A, 237E, 237K, 237N, or237R, (f) 234A, 234V, or 234F, (g) 233P, (h) 328A, (i) 327Q or 327T, (j) 329A, 329G, 329Y, or 329R (k) 33 IS, (1) 236F or 236R, (m) 238A, 238E, 238G, 238H, 2381, 238V, 238W, or 238Y, (n) 248A, (o) 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, or 254V, (p) 255N, (q) 256H, 256K, 256R, or 256V, (r) 264S, (s) 265H, 265K, 265 S, 265 Y, or 265 A, (t) 267G, 267H, 2671, or 267K, (u) 268K, (v) 269N or 269Q, (w) 270 A, 270G, 270M, or 270N, (x) 27 IT, (y) 272N, (z) 292E, 292F, 292G, or 2921, (aa) 293 S, (bb) 301 W, (cc) 304E, (dd) 31 IE, 311G, or 311 S, (ee) 316F, (ff) 328V, (gg) 33 OR, (hh) 339E or339L, (ii) 3431 or 343 V, (jj) 373 A, 373G, or 373S, (kk) 376E, 376W, or 376Y, (11) 380D, (mm) 382D or 382P, (nn) 385P, (oo) 424H, 424M, or 424V, (pp) 4341, (qq) 438G, (rr) 439E, 439H, or 439Q, (ss) 440A, 440D, 440E, 440F, 440M, 440T, or 440V, (tt) K322A, (uu) L235E, (vv) L234A and L235A, (ww) L234A, L235A, and G237A, (xx) L234A, L235A, and P329G, (yy) L234F, L235E, and P33 I S, (zz) L234A, L235E, and G237A, (aaa), L234A, L235E, G237A, and P331 S (bbb) L234A, L235A, G237A, P238S, H268A, A330S, andP331 S, (ccc) L234A, L235A, and P329A, (ddd) G236R and L328R, (eee) G237A, (fff) F241A, (ggg) V264A, (hhh) D265A, (iii) D265 A and N297A, (jjj) D265 A and N297G, (kkk) D270A, (111) A330L, (mmm) P331 A or P331 S, or (nnn) E233P, (ooo) L234A, L235E, G237A, A330S, and P331 S or (ppp) any combination of (a) - (ppp), per EU numbering. Alternatively, the alteration to one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region comprises L234A, L235E, G237A, A330S, and P33 I S per EU numbering.

[0105] In some embodiments of any one of the methods provided, the antigen binding polypeptide comprises an immunoglobulin heavy chain constant region, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) which reduces the serum half-life of the polypeptide. The alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 251, 252, 253, 254, 255, 288, 309, 310, 312, 385, 386, 388, 400, 415, 433, 435, 436, 439, 447, and combinations thereof per EU numbering. Alternatively, the alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 253, 254, 310, 435, 436 and combinations thereof per EU numbering. In certain embodiments, the alteration to one or more amino acid residues is selected from the list consisting of: I253A, I253D, I253P, S254A, H310A, H310D, H310E, H310Q, H435A, H435Q, Y436A, and combinations thereof per EU numbering. Alternatively, the alteration to one or more amino acid residues is selected from the list consisting of: 1253 A, S254A, H310A, H435Q, Y436A and combinations thereof perEU numbering. Alternatively, the alteration to one or more amino acid residues is selected from the list consisting of : 1253 A, H310A, H435Q, and combinations thereof per EU numbering. In certain embodiments, the alteration to one or more amino acid residues comprises 1253 A per EU numbering. In certain embodiments, the alteration to one or more amino acid residues comprises H310A per EU numbering. In certain embodiments, the alteration to one or more amino acid residues comprises H435Q per EU numbering.

[0106] In certain embodiments, the radioimmunoconjugate further comprises a linker aminoacid sequence or a human IgG hinge region, In certain embodiments, the human IgG hinge region comprising the amino acid sequence set forth in SEQ ID NO: 41 .

[0107] The present disclosure provides in some embodiments the radioimmunoconjugate comprising a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region is coupled to the immunoglobulin heavy chain constant region by a human IgG hinge region.Methods of Treatment

[0108] High-grade neuroendocrine cancer represents 15% of all lung cancer cases (SCLC 14%; LCNEC 1%). The global incidence, representing approximately 375,000 patients, is expected to grow 4% annually through 2029. SCLC and LCNEC share similar, clinicopathologic traits characterized by higher mitotic rates with extensive necrosis, high tumor mutational burden, neuroendocrine gene expression, and strong association with environmental exposures such as smoking. Nearly 70% of patients at initial diagnosis have tumors that have spread beyond the supraclavicular areas and are said to have extensive- stage disease. Regardless of stage, the prognosis is unsatisfactory despite improvements in diagnosis and therapie s developed over the past 25 years. Because SCLC and LCNEC tend to be widely disseminated by the time of diagnosis, despite being more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; cure is difficult to achieve. Without treatment, SCLC and LCNEC have the most aggressive clinical course of any type of pulmonary tumor, with a median survival from diagnosis of only 2 to 4 months. With treatment, the overall survival (OS) rate at 5 years is 5% to 10% for SCLC and 15% to 25% for LCNEC. Newer investigational DLL3 -targeting agents, including ADC and bispecific T-cell engagers, have shown to be active in the treatment of SCLC and other neuroendocrine carcinomas and targeting of DLL3 may provide a new approach in the treatment of SCLC, LCNEC, and other neuroendocrine carcinomas (Rudin 2023). These agents capitalize on the differential expression and localization of DLL3 in normal and tumor cells. Normally, DLL3 transmembrane protein and ligand of the Notch receptor family is minimally expressed on the cell surface and confined to the Golgi apparatus and cytoplasmic vesicles. However, in neuroendocrine carcinomas, such as SCLC and LCNEC, DLL3 is upregulated and expressed on the surface of tumor cells, driving cell proliferation and differentiation. Indeed, DLL3 overexpression is reported in up to 80 to 90% of SCLCs and aberrantly expressed in 50% to 60% of LCNEC (Ali 2021 ; Hermans.

[0109] Patients with recurrent SCLC and LCNEC have few therapeutic options and existing approved treatments provide limited benefit. Such patients are suitable for clinical studies. 225Ac-ABD147 proposes a different therapeutic approach by DLL3 targeting, providing theopportunity to specifically target lung neuroendocrine tumor cells by delivering radiation directly to the primary tumor and metastatic sites. The antibody -based delivery of the chelated 225Ac as described in this application is engineered and optimized to enable a predictable PK profile with a shorter half-life and blood circulation (NHP terminal t’ of 38 hours), and to minimize kidney exposure, while favoring tumor accumulation and maximizing the absorbed dose deposited to DLL3 expressing cancer cells (enabled by the VHH binding domain resulting in approximately 20 to 35% ID / g tumor uptake and improved efficacy as shown in preclinical murine models).

[0110] In certain embodiments, disclosed herein, are antibodies, DLL3 binding molecules, and radioimmunoconjugates of DLL3 binding molecules useful for the treatment of a cancer or tumor. Treatment refers to a method that seeks to improve or ameliorate the condition being treated. With respect to cancer, treatment includes, but is not limited to, reduction of tumor volume, reduction in growth of tumor volume, increase in progression-free survival, or overall life expectancy. In certain embodiments, treatment will affect remission of a cancer being treated. In certain embodiments, treatment encompasses use as a prophylactic or maintenance dose intended to prevent reoccurrence or progression of a previously treated cancer or tumor. It is understood by those of skill in the art that not all individuals will respond equally or at all to a treatment that is administered, nevertheless these individuals are considered to be treated.

[0111] In certain embodiments, the antibodies can be administered to a subject in need thereof by any route suitable for the administration of antibody -containing pharmaceutical compositions, such as, for example, subcutaneous, intraperitoneal, intravenous, intramuscular, intratumoral, or intracerebral, etc. In certain embodiments, the antibodies are administered intravenously. In certain embodiments, the antibodies are administered subcutaneously. In certain embodiments, the antibodies are administered intratumoral. In certain embodiments, the antibodies are administered on a suitable dosage schedule, for example, weekly, twice weekly, monthly, twice monthly, once every two weeks, once every three weeks, or once a month etc. In certain embodiments, the antibodies are administered once every three weeks.

[0112] In certain embodiments, disclosed herein, are radioimmunoconjugates useful for the treatment of a cancer or tumor. In certain embodiments, the cancer or tumor comprises lung cancer cell, breast cancer, ovarian cancer, and neuroendocrine cancer. In certain embodiments, the cancer or tumor comprises a carcinoma. In certain embodiments, the cancer or tumor comprises non-small cell lung cancer (NSCLC). In certain embodiments, the cancer or tumor comprise small cell lung cancer (SCLC). In certain embodiments, the cancer or tumor comprises large-cell neuroendocrine carcinoma (LCNEC). In certain embodiments, the cancer or tumor comprises pulmonary large cell neuroendocrine carcinoma (LCNEC). In certain embodiments,the tumor or cancer expresses DLL3.

[0113] In certain embodiments, the cancer or tumor is a solid cancer or tumor. In certain embodiments, the cancer or tumor is a blood cancer or tumor. In certain embodiments, the cancer is any cancer or tumor that expresses DLL3 extracellularly. In certain embodiments, the cancer comprises neuroendocrine prostate cancer, or Merkel cell carcinoma, or small cell urinary cancer, or melanoma or a neuroendocrine cancer or neuroendocrine cancer of unknown origin. In other embodiments, the cancer is a GBM or glioma cancer or an endometrial cancer or a GI neuroendocrine cancer. In some embodiments, the tumor or cancer is a locally advanced cancer. In some embodiments, the tumor or cancer is a metastatic cancer. In some embodiments, the tumor or cancer is an extensive stage cancer.

[0114] The methods described herein can be used to deliver consistent dosages of radiation to individuals and tumors of individuals in need thereof, by administering to the patients a radioimmunoconjugate described herein. Such consistent dosages can be measured by a low coefficient of variation amongst a plurality of patients as relating to absorbed dose or an area under the curve (AUC) of an absorbed dose. This can be measured with respect to individual tissues (e.g., liver, kidney, bone marrow, etc.) In some embodiments, the dosages of the radiation delivered are absorbed by a tissue of the patients in need thereof. In some embodiments, the absorbed dose has a coefficient of variation (CV) of less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% amongst a plurality of patients. Consistent dosages may also be measured using AUC values that that vary by less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% amongst a plurality of patients.

[0115] The methods described herein can be used to treat individuals with a prior history of treatment. In certain embodiments, the individual to be treated may be selected for treatment with the DLL3 binding radioimmunoconjugates based upon a prior treatment history. In certain embodiments, the individual to be treated may have been previously treated with a different DLL3 targeting drug.

[0116] 225Ac-ABD147, as disclosed herein, can be used for the treatment of patients withSCLC LCNEC, or other DLL3 -expressing tumors or cancers. In some embodiments,225Ac- ABD147 can be administered to a patient following platinum -based chemotherapy.225Ac- ABD147 is a targeted radioligand therapy product with potent anticancer activity thatincorporates 225Ac, an alpha-emitting radionuclide, coordinated to the mAh ABD147, as described herein. 225 Ac is an alpha emitter with a half-life (tl / 2) of 9.9 days. It decays via a cascade of 6 short-lived progeny to stable bismuth 209 (209Bi). The decay path of225Ac yields net 4 alpha particles with energies ranging from 5.8 to 8.4 MeV with the alpha particles travelling between 47 to 85 pm in tissue.225Ac-ABD147 comprises an engineered humanized mAb designed to target with high affinity the DLL3 receptor and a linker chelator conjugated to the antibody that coordinates the radionuclide225Ac. The linker chelator is covalently attached to the antibody through nonspecific lysine conjugation that produces a distribution of chelators, with an average chelator-to-antibody ratio of 4.

[0117] Described herein are methods of treating cancers and / or tumors using radioimmunoconjugates targeting DLL3. Described herein is a method of treating a tumor or cancer of an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53 , wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0118] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 toSEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0119] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0120] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0121] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0122] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementaritydetermining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0123] In some embodiments described herein, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53, wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0124] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope,wherein the DLL3 antigen binding region comprises: a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical set to that set forth in any one of SEQ ID NO: 101 to 106, 201 to 206, 301 to 306, 401 to 306, and 501 to 506.

[0125] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0126] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0127] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0128] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0129] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0130] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementaritydetermining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0131] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0132] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 101 to SEQ ID NO: 106.

[0133] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO: 101 to SEQ ID NO: 106.

[0134] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein theradioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0135] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0136] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to the individual peradministration, thereby treating the tumor or cancer of the individual.

[0137] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0138] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0139] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effectiveamount of the radioimmunoconjugate delivers from about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0140] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0141] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206.

[0142] In some embodiment, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206.

[0143] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising anamino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0144] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0145] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0146] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0147] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0148] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0149] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; (b) a heavy chain complementarity determining region 2(HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence setforthin any one of SEQ ID NO: 313 to SEQ ID NO: 315. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0150] In some embodiments, the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306.

[0151] In some embodiments, the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306.

[0152] In certain embodiments, the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 303, wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments,the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0153] In some embodiment, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 303.

[0154] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 304, wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0155] In some embodiment, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope,wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 304.

[0156] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 305, wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0157] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 305.

[0158] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementaritydetermining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0159] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0160] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0161] In some embodiments, the method comprises administering to the individual atherapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0162] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0163] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprisingan amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0164] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0165] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406.

[0166] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 403 , wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi of radiation to the individual per administration, thereby treating the tumor orcancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual. In particular embodiments, the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0167] In some embodiment, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth set forth in SEQ ID NO: 403.

[0168] In some embodiment, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406.

[0169] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0170] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein theradioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

[0171] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0172] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0173] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0174] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

[0175] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531. wherein the radioisotope comprises 225 -Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.172 mCi to the individual peradministration, thereby treating the tumor or cancer of the individual.

[0176] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.

[0177] In some embodiments, the method comprises administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.Dosages of DLL3 Radioimmunoconjugates and pharmaceutical compositions

[0178] In a further aspect, the present disclosure provides the radioimmunoconjugate that comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120, any one of SEQ ID NO: 216 to SEQ ID NO: 220, any one of SEQ ID NO: 316 to SEQ ID NO: 320, SEQ ID NO: 317, SEQ ID NO: 318, SEQ ID NO: 319, SEQ ID NO: 416 to SEQ ID NO: 420, SEQ ID NO: 417, and any one of SEQ ID NO: 516 to SEQ ID NO: 520.

[0179] In one aspect, this disclosure provides a method of treating a disease, disorder, or condition in a patient in need thereof, the method comprises administering to a subject in need thereof a pharmaceutically effective amount of an immunoconjugate or radioimmunoconjugate or composition of the present invention. For some further embodiments, the method is for inhibiting the growth and / or the killing of a cancer cell or tumor. In another aspect, this disclosure provides for the use of an immunoconjugate described herein for the preparation and / or manufacture of a medicament for treating a disease, disorder, or condition in a subject, such as, e.g., cancer.

[0180] Pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented). The quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient’s disease, although appropriate dosages may be determined by clinical trials.

[0181] For the prevention or treatment of disease, the dosage and mode of administration may be chosen by the physician according to known criteria. The appropriate dosage of immunoconjugate or radioimmunoconjugate or composition of this disclosure will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the immunoconjugate or radioimmunoconjugate or composition of this disclosure is administered for preventive or therapeutic purposes, previous therapy, the patient’s clinical history and response to the immunoconjugate or radioimmunoconjugate or composition, and the discretion of the attending physician. The immunoconjugate or radioimmunoconjugate or composition of this disclosure is suitably administered to the patient at one time or over a series of treatments. Preferably, the immunoconjugate or radioimmunoconjugate or composition is administered by intravenous infusion or by subcutaneous injections.

[0182] The dose and administration schedule may be selected and adjusted based on the level of disease, or tolerability in the subject, which may be monitored during the course of treatment. The conjugates of the present invention may be administered once per day, once per week, multiple times per week, but less than once per day, multiple times per month but less than once per day, multiple times per month but less than once per week, once per month, once per five weeks, once per six weeks, once per seven weeks, once per eight weeks, once per nine weeks, once per ten weeks, or intermittently to relieve or alleviate symptoms of the disease. Administration may continue at any of the disclosed intervals until remission of the tumor or symptoms of the cancer being treated. Administration may continue after remission or relief of symptoms is achieved where such remission or relief is prolonged by such continued administration.

[0183] The present disclosure describes the protocol and the rational for treating subjects, e.g., to select the starting dose for treatment and subsequently treating the selected subjects with escalated dose. Preclinical pharmacology, Pharmacokinetics, biodistribution, dosimetry and toxicology studies in both rodents and NHPs inform and guide the choice of a safe and appropriate starting dose for the initial study of225Ac-ABD147 in humans. The recommended starting dose of225Ac-ABD147 is 1.6 MBq and that dose is projected to deliver 25% of the lowest absorbed dose limit from preclinical animal studies. The maximum dose is projected to be 6.4 MBq based on dosimetry extrapolation from NHP studies and established EBRT dose limits. The present disclosure describes dosages of225Ac-ABD147 which may be used for an initial starting dose of treatment, and subsequent doses according to Table 1.

[0184] This design is constructed to avoid exposing patients to ineffective dose levels, and instead rapidly escalating to emission levels that are predicted to provide antitumor activity. This design will also reduce the chance of escalating the dose when the probability of dose-limiting toxicity (DLT) is high, and instead increases the chance of escalating the dose when the probability of DLT is low.

[0185] The dosages of a radioimmunoconjugate described herein are administered to deliver from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the administration delivers at least about 0.02 mCi, at least about 0.04 mCi, at least about 0.06 mCi, at least about 0.07 mCi, at least about 0.08 mCi, at least about 0.09 mCi, at least about 0.10 mCi, at least about 0.12 mCi, at least about 0.14 mCi, or at least about 0.16 mCi. In certain embodiments, the administration delivers about 0.02 mCi, at most about 0.04 mCi, at most about 0.06 mCi, at most about 0.07 mCi, at most about 0.08 mCi, at most about 0.09 mCi, at most about 0.10 mCi, at most about 0.12 mCi, at most about 0.14 mCi, or at most about 0.16 mCi. In certain embodiments, the administration delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the administration delivers about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the administration delivers about 0.043 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In certain embodiments, the administration delivers at least about O.035 mCi, atleast about 0.036 mCi, at least about 0.037 mCi, at least about 0.038 mCi, at least about 0.039 mCi, atleast about 0.040 mCi, at least about 0.041 mCi, at least about 0.042 mCi, at least about 0.043 mCi, at least about 0.044 mCi, atleast about 0.045 mCi, at least about 0.046 mCi, at least about 0.047 mCi, at least about 0.048 mCi, at least about 0.049 mCi, at least about 0.050 mCi, at least about 0.051 mCi, at least about 0.052 mCi, or at least about 0.053 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In certain embodiments, the administration delivers at most about 0.035 mCi, at most about 0.036 mCi, at most about 0.037 mCi, at most about 0.038 mCi, at most about 0.039 mCi, atmost about O.040 mCi, atmost about 0.041 mCi, at most about 0.042 mCi, at most about 0.043 mCi, at most about 0.044 mCi, at most about 0.045 mCi, at most about 0.046 mCi, at most about 0.047 mCi, at most about 0.048 mCi, at most about 0.049 mCi, at most about 0.050 mCi, atmost about 0.051 mCi, at most about 0.052 mCi, or at most about 0.053 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In some embodiments, the administration delivers about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the administration delivers at least about 0.076 mCi, at least about 0.077 mCi, at least about 0.078 mCi, at least about 0.079 mCi, at least about 0.080 mCi, at least about 0.081 mCi, at least about 0.082 mCi, at least about 0.083 mCi, at least about 0.084 mCi, at least about 0.085 mCi, at least about 0.086 mCi, at least about 0.087 mCi, at least about 0.088 mCi, at least about 0.089 mCi, atleast about 0.090 mCi, at least about 0.091 mCi, at least about 0.092 mCi, at least about 0.093 mCi, or at least about 0.094 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In certain embodiments, the administration delivers atleast about 0.076 mCi, at most about 0.077 mCi, at most about 0.078 mCi, at most about 0.079 mCi, at most about 0.080 mCi, at most about 0.081 mCi, at most about 0.082 mCi, at most about 0.083 mCi, at most about 0.084 mCi, atmost about 0.085 mCi, at most about 0.086 mCi, at most about 0.087 mCi, at most about 0.088 mCi, at most about 0.089 mCi, at most about 0.090 mCi, at most about 0.091 mCi, at most about 0.092 mCi, at most about 0.093 mCi, or at most about 0.094 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In some embodiments, the administration delivers about 0.129 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In certain embodiments, the administration delivers at least about 0.119 mCi, at least about 0.120 mCi, at least about 0.121 mCi, at least about 0.122 mCi, at least about 0.123 mCi, at least about 0.124 mCi, at least about 0.125 mCi, at least about 0.126 mCi, at least about 0.127 mCi, at least about 0.128 mCi, at least about 0.129 mCi, at least about 0.130 mCi, atleast about 0.131 mCi, atleast about 0.132 mCi, atleast about 0.133 mCi, at leastabout O.134 mCi, atleast about O.135 mCi, at least about 0.136 mCi, or at least about 0.137 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In certain embodiments, the administration delivers at most about 0.119 mCi, at most about 0.120 mCi, at most about 0.121 mCi, at most about 0. 122 mCi, at most about 0.123 mCi, at most about 0.124 mCi, at most about 0. 125 mCi, at most about 0.126 mCi, at most about 0. 127 mCi, at most about 0.128 mCi, at most about 0.129 mCi, at most about 0.130 mCi, at most about 0.131 mCi, at most about 0.132 mCi, at most about 0.133 mCi, at most about 0. 134 mCi, at most about 0.135 mCi, at most about 0.136 mCi, or at most about 0. 137 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In some embodiments, the administration delivers about 0.172 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In certain embodiments, the administration delivers at least about O.162 mCi, at least about 0.163 mCi, at least ab out 0.164 mCi, at least about 0.165 mCi, at least about 0.166 mCi, at least about 0.167 mCi, at least about 0.168 mCi, at least about 0.169 mCi, at least about 0.170 mCi, or at least about 0.171 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the administration delivers at most about 0.162 mCi, at most about 0.163 mCi, at most about 0.164 mCi, at most about 0.165 mCi, at most about 0.166 mCi, at most about 0.167 mCi, atmost about 0.168 mCi, at most about 0.169 mCi, at most about 0.170 mCi, at most about 0.171 mCi, or at most about 0. 172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, an individual receives one dose at the disclosed dosage amount, or one or more subsequent doses. In certain embodiments, an individual receives 1, 2, 3, 4, 5, 6, 7, 8 or more subsequent doses. In certain embodiments, a subsequent dose received after an initial dose may be less than the initial dose. In certain embodiments, a subsequent dose received after an initial dose may be the same as the initial dose. In certain embodiments, a subsequent dose received after an initial dose may be more than the initial dose. In certain embodiments, an individual may receive a first induction dose to deliver a selected amount of radiation, and may receive subsequent maintenance doses at a lower amount of radiation. In certain embodiments, an individual may receive sub sequent maintenance doses at a same amount of radiation as the first induction dose. In certain embodiments, subsequent doses may be separated by atleast 3, 4, 5, 6, 7, or 8 weeks. In certain embodiments, subsequent doses may be separated by at most 12, 11, 10, 9, 8, 7, 6, 5, or 4 weeks. In certain embodiments, subsequent doses may be delivered at a time chosen by a physician based upon recovery of radiosensitive organs, such as bone marrow.

[0186] Described herein are methods of treating cancers and tumors using with a therapeutically effective amount of a radioimmunoconjugate. In certain embodiments, treatmentmay be achieved after a single dose. In certain embodiments, a patient may be administered one or more subsequent doses at an interval selected by an attending physician to achieve treatment. In certain embodiments, the one or more subsequent doses may be less than a first dose. In certain embodiments, the one or more subsequent doses may be higher than a first dose. In certain embodiments, the one or more subsequent doses may be the same as a first dose . In certain embodiments, the one or more subsequent doses may deliver from about 0.02 mCi to about 0. 172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the one or more subsequent doses may deliver about 0.02 mCi, at least about 0.04 mCi, at least about 0.06 mCi, at least about 0.07 mCi, at least about 0.08 mCi, at least about 0.09 mCi, at least about 0. 10 mCi, at least about 0.12 mCi, at least about 0.14 mCi, or at least about 0.16 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver about 0.02 mCi, at most about 0.04 mCi, at most about 0.06 mCi, at most about 0.07 mCi, at most about 0.08 mCi, at most about 0.09 mCi, at most about 0.10 mCi, at most about 0.12 mCi, at most about 0.14 mCi, or at most about 0.16 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the one or more subsequent doses may deliver about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of an individual. In certain embodiments, the one or more subsequent doses may deliver about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at least about 0.035 mCi, at least about 0.036 mCi, at least about 0.037 mCi, at least about 0.038 mCi, at least about 0.039 mCi, at least about 0.040 mCi, at least about 0.041 mCi, at least about 0.042 mCi, at least about 0.043 mCi, at least about 0.044 mCi, at least about 0.045 mCi, at least about 0.046 mCi, at least about 0.047 mCi, at least about 0.048 mCi, at least about 0.049 mCi, atleast about 0.050 mCi, at least about 0.051 mCi, at least about 0.052 mCi, or at least about 0.053 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at most about 0.035 mCi, at most about 0.036 mCi, at most about 0.037 mCi, at most about 0.038 mCi, at most about 0.039 mCi, atmost about 0.040 mCi, at most about 0.041 mCi, at most about 0.042 mCi, at most about 0.043 mCi, atmost about 0.044 mCi, at most about 0.045 mCi, at most about 0.046 mCi, at most about 0.047 mCi, at most about 0.048 mCi, at most about 0.049 mCi, at most about 0.050 mCi, at most about 0.051 mCi, at most about 0.052 mCi, or at most about 0.053 mCi to the individual peradministration, thereby treating the tumor or cancer of the individual . In some embodiments, the one or more subsequent doses may deliver about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more sub sequent doses may deliver at least about 0.076 mCi, at least about 0.077 mCi, at least about 0.078 mCi, at least about 0.079 mCi, at least about 0.080 mCi, atleast about 0.081 mCi, at least about 0.082 mCi, at least about 0.083 mCi, at least about 0.084 mCi, at least about 0.085 mCi, at least about 0.086 mCi, at least about 0.087 mCi, at least about 0.088 mCi, at least about 0.089 mCi, at least about 0.090 mCi, at least about 0.091 mCi, at least about 0.092 mCi, at least about 0.093 mCi, or at least about 0.094 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at least about 0.076 mCi, at most about 0.077 mCi, at most about 0.078 mCi, at most about 0.079 mCi, at most about 0.080 mCi, at most about 0.081 mCi, at most about 0.082 mCi, at most about 0.083 mCi, at most about 0.084 mCi, at most about 0.085 mCi, atmost about 0.086 mCi, atmost about 0.087 mCi, atmost about 0.088 mCi, at most about 0.089 mCi, atmost about 0.090 mCi, atmost about 0.091 mCi, at most about 0.092 mCi, at most about 0.093 mCi, or at most about 0.094 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In some embodiments, the one or more subsequent doses may deliver about 0. 129 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at least about 0.119 mCi, atleast about 0.120 mCi, at least about 0.121 mCi, atleast about 0. 122 mCi, at least about O.123 mCi, at least about 0. 124 mCi, at least about 0. 125 mCi, at least about 0.126 mCi, at least about 0.127 mCi, at least about 0.128 mCi, at least about 0.129 mCi, at least about 0.130 mCi, at least about 0.131 mCi, at least about 0.132 mCi, at least about 0.133 mCi, at least about 0.134 mCi, atleast about 0.135 mCi, atleast about 0.136 mCi, or at least about 0.137 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In certain embodiments, the one ormore subsequent doses may deliver at most about 0.119 mCi, at most about 0.120 mCi, at most about 0.121 mCi, at most about 0.122 mCi, at most about 0.123 mCi, at most about 0.124 mCi, at most about 0.125 mCi, at most about 0.126 mCi, at most about 0.127 mCi, at most about 0.128 mCi, atmost about 0. 129 mCi, at most about 0.130 mCi, atmost about 0. 131 mCi, atmost about 0.132 mCi, at most about 0.133 mCi, at most about 0.134 mCi, at most about 0.135 mCi, at most about 0.136 mCi, or at most about 0.137 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In some embodiments, the one or more subsequent doses may deliver about 0.172 mCi to the individual per administration, thereby treatingthe tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at least about 0.162 mCi, at least about 0.163mCi, at least about 0.164 mCi, at least about 0.165 mCi, at least about 0.166 mCi, at least about 0.167 mCi, at least about 0.168 mCi, at least about 0.169 mCi, at least about 0.170 mCi, or at least about 0.171 mCi to the individual per administration, thereby treating the tumor or cancer of the individual. In certain embodiments, the one or more subsequent doses may deliver at most about 0.162 mCi, at most about 0.163 mCi, at most about 0.164 mCi, at most about 0.165 mCi, at most about 0.166 mCi, at most about 0.167 mCi, at most about 0. 168 mCi, at most about 0.169 mCi, atmost about 0.170 mCi, at most about 0.171 mCi, or at most about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual . In some embodiments, a subject may be administered a single dose or one or more subsequent doses based on tolerability or physician discretion to achieve a response of stable disease or better. In some embodiments, a response or stable disease or better is defined per RECIST vl .1 . In some embodiments, the single and one or more subsequent doses provides for up to a maximum total dose of 6.4 MBq (0.172 mCi).

[0187] In other embodiments, a subject is treated at a selected dose level that has been demonstrated to be tolerable and efficacious until radiation tolerance has been met or until radiographic disease progression, occurrence of unacceptable toxicity, or loss of clinical benefit. In certain embodiments, a subject is treated at a selected dose level that has been demonstrated to reduce or eliminate severe adverse events (SAEs). In certain embodiments, a subject is treated at a selected dose level that has been demonstrated to reduce or eliminate infusion-related reactions (IRRs). In certain embodiments, a subject is treated at a selected dose level that has been demonstrated to reduce or eliminate dose-limiting toxicity (DLT). In certain embodiments, SAEs are gastrointestinal side-effects. In certain embodiments, DLT is gastrointestinal sideeffects. In certain embodiments, the selected dose level is associated with a lower incidence of gastrointestinal side-effects, wherein the gastrointestinal side-effects comprise one or more comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver from about 0.02 mCi to about 0.172 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side -effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certainembodiments, the selected dose level may deliver about 0.02 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver about 0.04 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver about 0.043 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver about 0.086 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver about 0.129 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas. In certain embodiments, the selected dose level may deliver about 0.172 mCi of radiation to the individual per administration, wherein the selected dose level is associated with a lower incidence of gastrointestinal side-effects, and wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas.

[0188] The radioimmunoconjugates described herein may in certain cases be administered once if the individual responds to the therapy. Subsequent doses may be administered if an individual does not respond, partially responds, or at physician discretion. Individuals may be administered the therapeutics described herein until remission, a complete response, a partial response, or stable diseaseis achieved. Subsequent doses maybe increased in order to increase a therapeutic response. Subsequent doses may be decreased in order to reduce toxicities. Subsequent doses may be administered on physician approved schedule or 1, 2, 3, 4, 5, or 6 months after a first dose. In some embodiments a patient does not receive greater than 6.4 MBq(0.172 mCi) over all administrations.

[0189] The methods described herein may include dosing an individual with a gammaemitting radionuclide or a beta-emitting coupled to DLL3 -binding reagent to determine the suitability of an individual for treatment or for selecting the individual for treatment with the radioimmunoconjugates of the present disclosure. In certain embodiments, the patient selected has been previously treated for a cancer or a tumor. In certain embodiments, the patient selected has been treated with a prior treatment selected from the group consisting of a chemotherapeutic agent, a surgery, a radiation therapy, an immunotherapy, a photodynamic therapy, a stem cell therapy, a hyperthermia therapy, and any combinations thereof. In certain embodiments, the radiation therapy is external beam radiation therapy (EBRT), stereotactic body radiation therapy (SBRT), or any combination thereof. In certain embodiments, the prior treatment is a checkpointinhibitor. In certain embodiments, the check-point inhibitor is anti-PD-1 therapy, an anti- CTLA-4 therapy, or any combination thereof. In certain embodiments, the prior treatment is selected from the group consisting of palifosfamide, 5 -fluorouracil, capecitabine, pemetrexed, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafenib, and any combinations thereof. In certain embodiments, the patient selected has previously received a platinum based chemotherapeutic. In certain embodiments, the platinum based chemotherapeutic is selected from the list consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, and combinations thereof. In certain embodiments, the patient is afflicted with a tumor or cancer that is refractory to treatment with at least one previous anti-neoplastic agent. In certain embodiments, the patient selected has adequate renal function or adequate hepatic function. In some embodiments, the patient selected as adequate renal function. In some embodiments, the patient selected has adequate hepatic function.

[0190] 111In-ABD147, as described herein, can be used as an imaging agent to be used as a surrogate for225Ac-ABD147 to enable the dosimetry assessment of225Ac-ABD147 in patients with SCLC, LCNEC, or other DLL3 -expressing tumors or cancers.n iIn-ABD147 is an imaging agent that incorporates 111 -In, a gamma emitting radionuclide with a tl / 2 of 2.8 days, conjugated to the mAb ABD 147. 111 -In decays via electron capture to stable cadmium- 111. The decay yields 2 gamma-ray emissions with energies of 171 keV and 245 keV that allow for SPECT imaging of the patient.n iIn-ABD147 comprises an engineered humanized mAb designed to target with high affinity the DLL3 receptor and a linker chelator conjugated to the antibody that coordinates the radionuclide 111 -In, as described herein. The linker chelator is covalently attached to the antibody through nonspecific lysine conjugation that produces a distribution of chelators, with an average chelator-to-antibody ratio of 4.

[0191] Described herein are methods for selecting an individual for receiving treatmentusing the DLL3 binding radioimmunoconjugates described herein. The individual may be selected for receiving treatment by using an antibody, or an antibody fragment thereof, coupled or complexed to a beta-emitting or a gamma-emitting radionuclide to assess antibody uptake and absorption of beta-emitting or gamma-emitting radiation in a tumor or cancer of the patient. In certain embodiments, the individual is selected based on a positive result from an assay of a prior administration of an antibody, or an antibody fragment thereof, complexed to a betta- emitting or gamma-emitting radionuclide, wherein the positive result from the assay indicates binding of the antibody, or the antibody fragment thereof, to a tumor or cancer of the individual. In certain embodiments, the beta-emitting radionuclide is selected from the group consisting of 177-Lu, 90-Y, 67-Cu, and 153-Sm. In certain embodiments, the gamma-emitting radionuclide is selected from the group consisting of 111-In, 89-Zn, 123-1, 99m-Tc, and 68 -Ga. In certain embodiments, the gamma-emitting radionuclide is 111 -In. In certain embodiments, the assay is selected from the group consisting of one or more of positron emission tomography (PET), Single-Photon Emission Computed Tomography (SPECT), and SPECT combined with computed tomography (CT). In certain embodiments, the assay is SPECT. In certain embodiments, the assay is SPECT combined with CT (SPECT / CT). In certain embodiments, the antibody, or the antibody fragment thereof, binds a tumor associated antigen. In certain embodiments, the tumor associated antigen is DLL3. In certain embodiments, the antibody, or the antibody fragment thereof, is a DLL3 -binding reagent. In certain embodiments, the DLL3 - binding reagent comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512, and / or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53 . In certain embodiments, the DLL3 -binding reagent comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512, and (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53. In certain embodiments, the DLL3 -binding reagent comprises a DLL3 antigen binding region, wherein the DLL3 antigen binding region comprises: (a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509, (b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512, or (c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131, SEQ ID NO: 231, SEQ ID NO: 431, or SEQ ID NO: 53 . In certain embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206. In certain embodiments, the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206. In certain embodiments, the antibody, or antibody fragment thereof, is administered to the patient at a dose of about 5 mCi. In certain embodiments, the DLL3 -binding reagent is administered to the patient at a dose of about 5 mCi. In certain embodiments, the beta-emitting or the gamma-emitting radionuclide is complexed to the DLL3-binding reagent by any linker-chelator disclosed herein.Chelating agents

[0192] The radioimmunoconjugates of the present disclosure comprise a chelating agent ormoiety which allows for the tumor targeting moieties to be loaded with an appropriate radioisotope, such as a beta emitter or an alpha emitter. The chelator can be coupled to the antigen binding region, the heavy chain constant region, the immunoglobulin Fc region, or any combination thereof. Such coupling can suitably be by a covalent attachment to one or more amino acids of the immunoconjugate, the antigen binding region, the heavy chain constant region, the immunoglobulin Fc region, or any combination thereof. In certain embodiments, the chelator is not attached to a variable region.

[0193] In certain embodiments, a radioimmunoconjugate further comprises a chelating agent, wherein the chelating agent is a radioisotope chelating agent. The chelating agents can be an alpha emitter chelating agent, a beta- or gamma-emitter chelating agent. In particular, but non-limiting embodiments, the chelating agent is selected from the list consisting of: DOTA, DO3A, DOTAGA, DOTAGA anhydride, Py4Pa, Py4Pa-NCS, Crown, Macropa, Macropa-NCS, HEHA, CHXoctapa, Bispa, Noneunpa, and combinations thereof. Alternatively, the chelating agent can be selected from the list consisting of: DOTMA, DOTPA, DO3 AM-acetic acid, DOTP, DOTMP, DOTA-4AMP, CB-TE2A, NOTA, NOTP, TETPA, TETA, PEPA, H4Octapa, H2Dedpa, DO2P, EDTA, DTPA-BMA, 3,2,3-LI(HOPO), 3,2-HOPO, Neunpa, Neunpa-NCS, Octapa, PyPa, Porphyrin, Deferoxamine, DFO*, and combinations thereof. In certain embodiments, the chelating agent is DOTA. In particular embodiments, the chelating agent is DOTAGA. In some embodiments, the chelating agent is Py4Pa.Linkers

[0194] The present disclosure provides the chelating agent coupled to the antigen binding region and / or the immunoglobulin heavy chain constant region. Alternatively, the chelating agent is coupled to the antigen binding region and / or the immunoglobulin heavy chain constant region by a linker. In some embodiments, the chelating agent is covalently linked to the antigen binding region through a linker that is covalently linked to the chelating agent and covalently linked to the antigen binding region. In some embodiments, the linker is hydrophilic (e.g., a PEG chain). In some embodiments, the linker is hydrophobic (e.g., an alkyl or alkene chain). Other linkers that can be used to covalently link the chelating agent to the antigen binding region are disclosed in U.S. Patent App. No. 19 / 104559, U.S. Patent App. No. 19 / 104942, and U.S. Patent App. No. 19 / 104953, all of which are incorporated by reference herein in their entirety. Chelators may be linked or coupled to the immunoconjugates as described in Sadiki, A. et al. “Site-specific conjugation of native antibody.” Antibody Therapeutics 2020, 3, 271-284.

[0195] In some embodiments, the linker is selected from: 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyl oxy carbonyl ( PAB), and those resulting from conjugation with linker reagents: N - Succinimidyl 4-(2 -pyridylthio) pentanoate forming linker moiety 4 -mercaptopentanoic acid (SPP), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l -carboxylate (SMCC), N- Succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB), polyethylene glycol (PEG), a polyethylene glycol polymers (PEGn), and S-2-(4-Isothiocyanatobenzyl) (SCN). Alternatively, the linker is selected from: polyethylene glycol (PEG), a polyethylene glycol polymers (PEG), and S-2-(4-isothiocyanatobenzyl) (SCN). In certain embodiments, the linker comprises PEG5. In some embodiments, the linker comprises SCN.

[0196] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker in a site-specific manner, directed into a specific amino acid orglycan residue. In some embodiments, the site-specific conjugation involves directed functionalization of a specific lysine residue in the framework region with the chelator-linker. In other embodiments, this residue may be functionalized with a different reactive functional group which then reacts in a second step with chelator-linker to furnish the immunoconjugate. In some embodiments, this reactive functional group is thiopropionate.

[0197] For example, the resulting chelating agent comprises a linker-chelator selected from the list consisting of: TFP-Ad-PEG5-DOTAGA, p-SCN-Bn-DOTA, p-SCN-Ph-Et-Py4Pa, and TFP-Ad-PEG5-Ac-Py4Pa. In certain embodiments, the resulting chelating agent comprises TFP- Ad-PEG5-DOTAGA, p-SCN-Bn-DOTA, p-SCN-Ph-Et-Py4Pa, or TFP-Ad-PEG5-Ac-Py4Pa.

[0198] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker in a site-specific manner, directed into a specific amino acid orglycan residue, to the antigen binding region and / or the immunoglobulin heavy chain constant region, wherein the amino acid is a lysine and antigen binding region and / or the immunoglobulin heavy chain constant region is reacted with:DOTAGA),

[0199] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker to a lysine residue of the antigen binding region and / or the immunoglobulin heavy chain constant region, using:DOTAGA),

[0200] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker usingDOTAGA).

[0201] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker using

[0202] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker using

[0203] In some embodiments, the immunoconjugate comprises a linker-chelator selected from:

[0204] In some embodiments, the immunoconjugate comprises a linker-chelator that is:

[0205] In some embodiments, the immunoconjugate comprises a linker-chelator that is:

[0206] In some embodiments, the immunoconjugate comprises a linker-chelator that is:

[0207] In some embodiments, the immunoconjugate comprises a linker-chelator that is:

[0208] In some embodiments, the immunoconjugate is formed through the attachment of the chelator-linker to a lysine residue of the antigen binding region and / or the immunoglobulin heavy chain constant region, via a thiourea to the para position of the benzyl of -p-Bn-DOTAformed from the isothiocyanate of p-SCN-Bn-DOTA:

[0209] In general, the chelating agent is coupled to the antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 1 :1 to 8:1, 1 :1 to 6:1, 4:1, or 2:1 to 6:1. For example, the linker chelator is covalently attached to the antibody through nonspecific lysine conjugation that produces a distribution of chelators, with an average chelate-to antibody ratio of 4.Radioisotopes

[0210] In some embodiments, the radioisotope in the immunoconjugates described herein is an Auger electron-emitting radionuclide. The radioisotope can be an a-emitting radionuclide, a P-emitting radionuclide, or a y-emitting radionuclide.

[0211] The present disclosure provides the radioimmunoconjugate comprising a DLL3 - binding region, a chelator-linker, and a radioisotope, wherein the radioisotope is an alpha emitter selected from the list consisting of 225-Ac, 223-Ra, 224-Ra, 227-Th, 212-Pb, 212-Bi, and 213- Bi. In certain embodiments, the radioisotope is 225-Ac. 225AC is an alpha emitter with a half-life (tl / 2) of 9.9 days. It decays via a cascade of 6 short-lived progeny to stable bismuth-209 (209Bi). The decay path of 225AC yields 4 alpha particles with energies ranging from 5.8 to 8.4 MeV with the alpha particles travelling between 47 to 85 pm in tissue. When targeted to cancer cells, the short range of alpha radiation in human tissue (corresponding to 2 to 3 cells) allows the selective killing of targeted cancer cells while sparing surrounding healthy tissue. The high energy of alpha radiation and its associated high linear energy transfer lead to highly effective cell killing via deoxynucleotide (DNA) double-strand and DNA cluster breaks, which are largely independent of cell cycle and oxygenation status. In certain embodiments, the radioisotope is 111-In. mln is a gamma emitting radionuclide with a tl / 2 of 2.8 days. It decays via electron capture to stable cadmium- 111. The decay yields 2 gamma-ray emissions with energies of 171 keV and 245 keV that allow for SPECT imaging of the patient.

[0212] It should be noted that the disclosure is not limited to the radioisotope of an alpha emitter. It may be a beta emitter selected from 177-Lu, 90-Y, 67-Cu, and 153-Sm, or a gamma emitter selected from 111-In, 89-Zn, 123-1, 99m-Tc, and 68-Ga.Administration of radioimmunoconjugates

[0213] In general, the radioimmunoconjugates can be administered to a subject in need thereof by any route suitable for the administration of antibody -containing pharmaceutical compositions, such as, for example, subcutaneous, intraperitoneal, intravenous, intramuscular, intratumoral, or intracerebral, etc. In certain embodiments, the radioimmunoconjugates are administered intravenously. The administration is on a suitable dosage schedule, for example, weekly, twice weekly, monthly, twice monthly, once every two weeks, once every three weeks, or once a month etc. In certain embodiments, the antibodies are administered once every three weeks.Pharmaceutical compositions

[0214] In certain embodiments, immunoconjugate is include in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, diluent, or carrier. The immunoconjugate may be formulated to deliver a particular amount of radioactivity per dose. In certain embodiments, the dose delivers at least about 0.02 mCi. In certain embodiments, the dose delivers at least about 0.04. In certain embodiments, the dose delivers at least about 0.08 mCi. In certain embodiments, the dose delivers at least about 0.12 mCi. In certain embodiments, the dose delivers at least about 0.16 mCi. In certain embodiments, the dose delivers at least about 0.17 mCi. In certain embodiments, the dose delivers about 0.02 mCi. In certain embodiments, the dose delivers about 0.043 mCi. In certain embodiments, the dose delivers about 0.086 mCi. In certain embodiments, the dose delivers about 0.129 mCi.Jn certain embodiments, the dose delivers about 0.172 mCi.

[0215] In certain embodiments, the antibodies of the current disclosure are administered suspended in a sterile solution. In certain embodiments, the solution comprises about 0.9% NaCl. In certain embodiments, the solution comprises about 5.0% dextrose. In certain embodiments, the solution further comprises one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate, ascorbate and hydroxymethylaminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyol / disaccharide / polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA, DTP A, or EGTA.

[0216] In certain embodiments, the antibodies of the current disclosure are shipped / stored lyophilized and reconstituted before administration. In certain embodiments, lyophilized antibody formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose,dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial comprised of glass or other suitable non-reactive material. The antibodies when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than 7.0. In certain embodiments, the pH canbe between 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[0217] In certain embodiments, the radioimmunoconjugates described herein must be stored with appropriate safety measures to minimize radiation exposure. Ready -to-use solution may be shipped frozen and must be stored frozen (-20°C) prior to thawing for patient administration. When stored at -20°C, the radioimmunoconjugates has a 168-hour shelf-life.

[0218] Also described herein are kits comprising one or more of the antibodies described herein in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier, and a device for administration.

[0219] In certain embodiments, described herein is a method of preparing a cancer treatment comprising admixing one or more pharmaceutically acceptable excipients, carriers, or diluents and an antibody of the current disclosure. In certain embodiments, described herein is a method of preparing a cancer treatment for storage or shipping comprising lyophilizing one or more antibodies of the current disclosure.EXAMPLES

[0220] The following illustrative examples are representative of embodiments of compositions and methods described herein and are not meant to be limiting in any way.Example 1. Antibody Production

[0221] VHH-Fc plasmids were generated by cloning the VHH sequence, with a hinge and Fc portion (human IgGl CH2-CH3) into a mammalian expression vector. In some instances, mutations were introduced into the Fc portion. To produce recombinant VHH-Fc and variants thereof, plasmid was transfected into HEK293.SUS cells (ATUM, or similar). After 3 -5 days of secretion, the antibody-containing supernatant was cleared of cells by centrifugation and sterile filtration. Antibodies were purified using Mab Select SuRe PCC column (GE, Cat#: 11003495) and buffer exchange into PBS, pH 7.0. Proteins were quantified u sing A280 orBCA. The purity of the antibodies were tested by SDS-PAGE, capillary electrophoresis, HPLC-SEC and LC-MS using standard protocols. Regarding VHH polypeptides, see, for example, McMahon et al., Nature Structural & Molecular Biology | VOL 25 | MARCH 2018 | 289-296 Yeast surface display platform for rapid discovery of conformationally selective nanobodies: Moutel et al., eLife 2016;5:el6228NaLi-Hl : A universal synthetic library of humanized nanobodies providinghighly functional antibodies and intrabodies . De Genst E, Saerens D, Muyldermans S, Conrath K. Antibody repertoire development in camelids. Dev Comp Immunol. 2006;30(l -2):187-98. doi: 10.1016 / j.dci.2005.06.010. PMID: 16051357. Vincke C, Gutierrez C, WerneryU, Devoogdt N, Hassanzadeh-Ghassabeh G, Muyldermans S. Generation of single domain antibody fragments derived from camelids and generation of manifold constructs. Methods Mol Biol. 2012;907:145-76. doi: 10.1007 / 978-l-61779-974-7_8. PMID: 22907350. Arbabi Ghahroudi M, Desmyter A, Wyns L, Hamers R, Muyldermans S. Selection and identification of single domain antibody fragments from camel heavy-chain antibodies. FEBS Lett. 1997 Sep 15 ;414(3 ): 521 -6. doi: 10.1016 / s0014-5793(97)01062-4. PMID: 9323027.

[0222] For VHH humanization, see, for example, Vincke C, Loris R, Saerens D, Martinez - Rodriguez S, Muyldermans S, Conrath K. General strategy to humanize a camelid single - domain antibody and identification of a universal humanized nanobody scaffold. J Biol Chem. 2009 Jan 30;284(5):3273-84. doi: 10.1074 / jbc.M806889200. Epub 2008 Nov 14. PMID: 19010777.

[0223] For VHH stability, see, for example, Kunz P, Flock T, Soler N, Zaiss M, Vincke C, Sterckx Y, Kastelic D, Muyldermans S, Hoheisel JD. Exploiting sequence and stability information for directing nanobody stability engineering. Biochim Biophys Acta Gen Subj . 2017 Sep;1861(9):2196-2205. doi: 10.1016 / j.bbagen.2017.06.014. Epub 2017 Jun 20. PMID: 28642127; PMCID: PMC5548252; Kunz P, Zinner K, MiickeN, BartoschikT, Muyldermans S, Hoheisel JD. The structural basis of nanobody unfolding reversibility and thermoresistance. Sci Rep. 2018 May 21;8(1):7934. doi: 10.1038 / s41598-018-26338-z. PMID: 29784954; PMCID: PMC5962586.Example 2. VHHFcl47 Binding Affinity to DLL3

[0224] The affinity of VHHFM47 (SEQ ID NO: 417; variable region SEQ ID NO: 403) for human DLL3 compared to mouse, rat and cynomolgus monkey orthologs were determined by surface plasmon resonance (SPR) to establish the appropriate nonclinical species for toxicity, biodistribution, and dosimetry studies. The Kinetic binding analysis was performed on a BiaCore 8K SPR instrument. Briefly, VHHFcl47 was immobilized using anti -human immunoglobulin (IgG) capture and the affinity of VHHFcl47 to the purified extracellular domain of human, cynomolgus monkey, rat, and mouse DLL3 protein was assessed.

[0225] VHHFcl47 binds human DLL3 with an affinity (Kd) of 2.8 nMand cross-reacts with cynomolgus monkey DLL3 within a 10 -fold affinity difference to human DLL3. VHHFcl47 shows weak binding to ratDLL3 and insignificant binding to mouse DLL3 (Table 2). The data for detection of binding affinity to DLL3 Orthologs indicates the high affinity of VHHFcl47 tohuman DLL3.Example 3. VHHFcl47 and ABDI 47 are internalized by DLL3 expressing cells

[0226] DLL3- mediated binding and internalization was assessed in the SHP-77 human SCLC cell line which shows low expression of DLL3 surface antigen, approximately 3000 receptors / cell, see, Giffin MJ, etal. AMG 757, a half-life extended, dll3-targeted bispecific t-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021 ; 27(5): 1526-1537. A pH-sensitivedye, pHAb was conjugated to control hlgG, VHHFcl47, or its conjugated form, ABD 147 and then incubated with cells at 37°C for 2 hours. An increase in fluorescence as pHAb-conjugated antibody internalizes into the acidic endosomal compartment of cells can be detected by flow cytometry.

[0227] The data for detection of antibody internalization at indicated time points are shown in FIG. 1. The detection of the antibody internalization indicates that VHHFcl47 specifically binds human DLL3 with high affinity and is internalized by DLL3 -expressing cancer cells. These results also demonstrate that ABD 147 and the unconjugated antibody VHHFcl47 exhibit similar cancer cell binding and internalization.Example 4. 225Ac-ABD147 Conjugate is effective in shrinking Xenografted SHP-77 Mouse Tumors

[0228] The efficacy of 225Ac-ABD147 was assessed in immunocompromised mice subcutaneously (SC) implanted with human SCLC cell line SHP-77. Briefly, female athymic nude mice were implanted with SC SHP-77 tumors. Mice (n=7 / group) were administered a single IV dose of cold (non-radiolab eled) ABD147 (control, 32 pg protein, 1.6 mg / kg) or 225Ac-ABD147 ata dose of 8 kBq (16 pgprotein, 0.8 mg / kg, low dose), 12 kBq(24 pgprotein,1 .2 mg / kg, medium dose) or 16 kBq (32 pg protein, 1 .6 mg / kg, high dose) at a specific activity of 0.5 kBq / pg. Body weight and tumor size were measured 3 times weekly until end of the study at 12 weeks post-injection. The tumor measurement frequency was reduced once tumors ceased to be measurable in the 225Ac-ABD147-treated groups. Mice were sacrificed due to tumor burden or when they reached the study endpoint on Day 84.

[0229] Treatment was well tolerated, and no AEs were observed throughout the study other than body weight loss (up to 13% in the 12 kBq group) within the first 2 weeks of 225 Ac - ABD147 dosing, with full recovery following diet supplementation (FIG. 2A). Mice treated with the 225Ac-ABD147 showed tumor regression in a dose-dependent manner with complete tumor ablation or sustained regression observed in 5 of 7 animals (71%) in the high -dose (16 kBq) cohort, whereas treatment with non-radiolabeled ABD 147 did not show tumor regression (FIG. 2B) The remaining 2 animals in the high dose cohort exhibited tumor regression over 30 days followed by tumor regrowth that was sustained for up to 50 days after treatment until euthanasia. The 5 of 7 high dose 225Ac-ABD147-treated mice exhibiting complete tumor ablation or sustained regression survived until the end of study on Day 84. Mice in the control cohort (non-labeled ABD147) exhibited a rapid tumor growth resulting in euthanasia due to tumor burden within 16 days post -treatment (median survival of 9 days) (FIG. 2C).Example 5. 225Ac-ABD147 Conjugate is effective in shrinking Xenografted NCL-H82 Mouse Tumors

[0230] The efficacy of 225Ac-ABD147 was assessed in immunocompromised mice implanted SC with the human SCLC cell line NCI-H82, which shows low expression of DLL3 surface antigen, approximately 1000 receptors / cell, see, Giffin MJ, et al. AMG 757, a half-life extended, dll3-targeted bispecific t-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021 ;27(5): 1526-1537. Female athymic nude mice were implanted SC with NCI-H82 tumors. In a similar manner as in Example 4, mice (n=8 / group) were administered a single IV dose of cold ABD147 or 225Ac-ABD147. Body weight and tumor size were measured 3 times weekly until end of the study at 12 weeks post-injection. The tumor measurement frequency was reduced once tumors ceased to be measurable in the 225Ac-ABD147 -treated groups. Mice were sacrificed due to tumor burden or when they reached the study endpoint on Day 84.

[0231] Treatment was well tolerated, and no adverse effects on body weight gains were observed throughout the study (FIG. 3A). Mice treated with the 22sAc-ABD147 showed tumor regression in a dose-dependent manner with complete responses or sustained regressionsobserved in 5 of 8 animals (63%) in the high-dose (16 kBq) cohort, whereas treatment with nonradiolabeled ABD 147 did not show tumor regression (FIG. 3B). The remaining 3 animals in the high dose cohort exhibited tumor regression over 30 days followed by tumor regrowth that was sustained for greater than 50 days after treatment, which required euthanasia for 2 animals with the other surviving until Day 78. The 4 of 8 high dose 22sAc-ABD147-treated mice with complete responses or sustained regressions survived until the end of study on Day 84, with 1 of 8 surviving to Day 84 but showing complete tumor regrowth. Conversely, mice in the control cohort (cold ABD 147) exhibited a rapid tumor growth resulting in euthanasia due to tumor burden within 22 days post-treatment (median survival of 9 days) (FIG. 3C).Example 6. VHHFcl47 binds specifically to DLL3

[0232] To confirm the specificity of VHHFcl47 to DLL3, Human Membrane Protein Array was performed to assess the binding of VHHFcl47 to the closest protein family members, DLL1 and DLL4. VHHFcl47 was captured using anti-human capture sensors and bound only to human DLL3, with no binding observed to either human DLL1 or DLL4 (data not shown). To further confirm specificity and selectivity, VHHFcl47 was tested in a membrane proteome array (Integral Molecular, Inc.) that tests specific binding to 6,000 human proteins in a cell expression assay, which includes DLL3, and close family members (e.g., DLL1, DLL4, Notch 1, Notch 2, Notch 3, JAG1, DLK1, DLK2) to identify any potential off -target interactions and evaluate potential interactions for biological relevance using additional in vitro assessments. VHHFcl47 was found to be specific and selective for its target DLL3.Example 7. Pharmacokinetics ofniIn-ABD147 in Naive hFcRn Transgenic Mice

[0233] The non- conjugated antibody component of ABD 147, VHHFc-147 incorporates a single c(Fc) point mutation (H435Q) to reduce human FcRn binding, thereby increasing antibody clearance from the blood. This feature is intended to reduce the systemic radiation exposure resulting from ABD147. VHHFcl47 also incorporates Fc mutations that ablate Fc effector functions mediated through binding to Fc -gamma-receptors or complement components.

[0234] To assess the pharmacokinetics (PK) of 11 Iln-ABD147 activity, a single dose of 11 Iln-ABD147 was administered in human FcRn transgenic (Tg32) mice which carry a knockout mutation of mouse FcRn gene (Fcgrt) and express the human FcRn transgene (FCGRT) under its own promoter. PK and clearance of human IgG in human FcRn transgenic Tg32 micestrongly correlates with the plasma clearance rates (coefficient of determination [r2] = 0.83) and elimination half-life (r2= 0.71) in humans (Avery, 2016; Nakamura, 2021). Briefly, ABD147 was radiolabeled with 11 Unto high radiochemical purity (>99 %). Fifteen naive female human FcRn transgenic (Tg32) received a single IV dose of approximately 3 MBq and 0.3 mg / kg protein at a specific activity of 0.5 MBq / pg. Mice were euthanized at 10 minutes and 24, 72, 168, and 336 hours (n = 3 mice / time point). Blood and plasma were collected for mln PK by gamma counting.

[0235] Following IV injection, mIn-ABD147 cleared rapidly from the blood of hFcRn transgenic mice with approximately 95% of the injected activity cleared from the blood by 24 hours (FIG. 4). Plasma Cmax was 85.4 %ID / mL at 10 minutes and AUClast of 830.2 %ID / mL.h (Table 3). Activity counts were also used to calculate approximate ABD 147 Cmax and AUC by mass (pg / mL) (Table 4). nIn-ABD147 had an elimination half-life in blood and plasma of 43 and 41 hours, respectively.Example 8. Toxicokinetics of ABD147 in Naive Cynomolgus Monkeys

[0236] Toxicokinetics were evaluated as part of the single dose GLP toxicity study of cold ABD147. Cynomolgus monkeys (3 to 5 animals / sex / group) were administered a single IV dose of vehicle or cold ABD147 at dose levels of 6 mg / kg or 30 mg / kg. Blood was collected for toxicokinetic analysis predose, 10 minutes, and 1 -, 4-, 24-, 48-, 72-, 140-, 240-, and 384-hours post-dose. ABD 147 plasma concentrations were measured using a validated ELISA method.

[0237] Following IV administration of 6 or 30 mg / kg ABD 147, the plasma concentration of ABD147 declined over time (FIG. 5A and FIG. 5B). Mean Cmax and AUC0-48h generally increased in a dose proportional manner between the 6 mg / kg and 30 mg / kg dose (Table 5). No sex differences were observed for ABD 147 Cmax or total exposures (AUC0-48hor AUC0-384h) at either dose level. The elimination half-life48h-384hat 30 mg / kg was approximately 43 hours and is comparable with the elimination half-life determined for mIn-ABD147 in human FcRn transgenic mice in Example 7 and mIn-ABD147 in cynomolgus monkeys in Example 9.

[0238] In addition, there were no abnormal detailed clinical observations or microscopic findings in key vital organs (data not shown). There were no ABD147-related effects on group mean respiration rates when compared to controls (data not shown). There were no ABD 147- related changes in ECG parameters and all the ECG waveforms evaluated in the study were qualitatively and quantitatively considered normal for the cynomolgus monkey (data not shown). Overall, a single IV administration of 6 and 30 mg / kg of ABD 147 resulted in no test article related effects on any of these parameters, and the NOEL of the study was 30 mg / kg.Example 9. Pharmacokinetic of Illln-ABD147 in Naive Cynomolgus Monkeys

[0239] To assess blood and plasma PK of 11 Iln-ABD147 in naive Cynomolgus Monkeys, a single dose of 11 Iln-ABD147 was administered. In brief, ABD147 was radiolabeled with 11 Un to high radiochemical purity (>98%) for each synthesis to treat 3 cohorts of animals at the 2 intended mass dose levels. Male and female naive cynomolgus monkeys were administered 11 Iln-ABD147 at a target mass dose of either 0.3 mg / kg or 3.0 mg / kg at a specific activity of 0.1 MBq / pg or 0.01 MBq / pg, respectively. This corresponded to an 11 Un activity of approximately 74 to 111 MBq (2 to 3 mCi) suitable for quantitative SPECT imaging. Monkeys received 11 Iln-ABD147 by IV injection (n = 3 / sex). To cover 5 effective elimination half-lives based on the human FcRn transgenic mouse study, blood was collected at defined timepoints up to 240 hours post-dose. The activities in blood and plasma were quantified by gamma counter.

[0240] In general, the PK of 11 Iln-ABD147 was comparable when injected IV at either mass dose (0.3 mg / kg (FIG. 6) or 3 mg / kg (FIG. 7). At each dose level, approximately 90% of the injected 11 Iln-ABD147 activity was cleared from the blood in the first 24 hours. The calculated elimination half-life of between 37 to 40 hours was also similar at each mass dose and was consistent between blood and plasma (Table 6). In conclusion, the PK of 111 In -ABD 147 was consistent between a mass dose of 0.3 and 3 mg / kg and no significant sex differences were observed.

[0241] There were no observed sex differences in any PK parameter in the 3 mg / kg cohort (see Table 7 for mean Cmax and AUC ratios). At 0.3 mg / kg, blood clearance (CL) was somewhat higher in female (17.05 ± 2.12 mL / h) versus male monkeys (11.76 ± 3.62 mL / h); however, the difference in AUClast was within 1.3 fold between sexes (see Table 7 for mean Cmax and AUC ratios) and did not reach statistical significance (p > 0.05, t test).

[0242] 11 Iln-ABD147 activity counts were also used to calculate approximate ABD 147 concentrations by mass (pg / mL) to assess dose proportionality (Table 8; Cmax and AUC only). The approximate 10-fold difference in Cmax and AUC between a dose of 0.3 mg / kg and 3mg / kg demonstrate that exposure increased in a dose proportional manner in both male and female monkeys. Further, the PK of 11 Iln-ABD147 in cynomolgus monkeys showed similar distribution and elimination kinetics to that observed in human FcRn transgenic mice in Example 7. Exposure (Cmax and AUC pg / mL conversion) was comparable between the 2 species at a mass dose of 0.3 mg / kg (human FcRn mice plasma Cmax 7.4 pg / mL and AUClast 72.5 pg / mL.h; cynomolgus monkey female plasma Cmax 7.3 pg / mL and AUClast 81.5pg / mL.h). These data demonstrating comparable Cmax and AUC between monkeys and human FcRn transgenic mice at the same mass dose indicate exposure of ABD147 scales by body weight between these species.Example 10. Bio distribution of Illln-ABD147 in Naive hFcRn Transgenic Mice

[0243] To evaluate the biodistribution of 11 Iln-ABD147 in human FcRn transgenic Tg32 mice, a single dose of 11 Iln-ABD147 was administered. 11 Iln-ABD147 was prepared and injected by IV in female human FcRn mice (n=l 5) in a similar manner as in Example 7. Tissues were collected at 5 defined timepoints (n = 3) up to 14 days post-dose and tissue activity concentrations quantified by gamma counting.

[0244] 11 Iln-ABD147 distributed rapidly to tissues following IV injection in Tg32 mice.Tissue activity concentrations of mIn-ABD147 were highest in liver and peaked at 24 and 72 h post-injection (30.5 ± 1.7 %ID / g at 72 h) indicating that the liver was the major organ for clearance of mIn-ABD147 from the blood. Activity concentrations in the lung (16.7 ±0.8 %ID / g), kidneys (11.9 ± 0.3 %ID / g), and bone marrow (13.3 ± 0.7 %ID / g) were highest at 10 minutes with subsequent clearance at later timepoints. A substantial proportion of activity at 10 minutes can be attributed to the blood pool in these tissues since >95% of the ID was stilldetected in the blood at this timepoint. Activity concentration in liver, lung, and bone marrow decreased to 8.6 ± 0.2, 0.3 ± 0, and 4.1 ± 0.3 %ID / g, respectively, at 336 h post-dose, indicating elimination of mln from the tissues over time (FIG. 8). The data for detection indicates that 11 Iln-ABD147 distributes rapidly to tissues following IV injection and the liver is the major organ for clearance of 11 Iln-ABD147 from the blood.Example 11. Bio distribution of Illln-ABD147 in Nai've Cynomolgus Monkeys

[0245] Tissue biodistribution in the monkey was considered to be the most appropriate nonclinical model to predicthuman organ radioactive exposures to 11 Iln-ABD147 and 225Ac- ABD147. To evaluate the biodistribution of 11 Iln-ABD147 in Naive Cynomolgus Monkeys, a single dose of 11 Iln-ABD147 was administered. 11 Iln-ABD147 was prepared and injected by IV in naive male and female cynomolgus monkeys (n=3 / sex / group) in a similar manner as in Example 9. The activity concentrations in tissues were determined by serial SPECT / CT out to 10 days post 11 Iln-ABD147 injection. Tissue distribution and activity concentrations were assessed by WB SPECT / CT imaging at 5 timepoints from 1 h to 240 h post-injection.

[0246] Activity concentrations were assessed at each timepoint in all major organs as defined by CT: bladder, bone, brain, heart, large intestine, kidney, liver, lungs, small intestine, and spleen. There were no additional tissues that could be defined with a nuclear medicine signal with the exception of cervical lymph nodes. Activity concentrations were then used to generate time integrated activity coefficients that served as inputs for normal organ dosimetry. Since the spatial resolution of SPECT / CT limits direct quantification of bone marrow, the blood radioactivity -time profile was used as the source organ for marrow dosimetry.

[0247] Radionuclide excretion from animals was assessed using SPECT-based determination ofWB I l lln-ABD147 activity (%ID remaining in WB region of interest analysis). The data in FIG. 9 shows whole-body cclearance of 11 Un from naive Cynomolgus Monkeys receiving 11 Iln-ABD147. The data for detection reflects isotope excretion from the body. Of note, animals were fasted overnight prior to anesthesia for each imaging timepoint. This coupled with potential voiding as a result of animal handling may have contributed to the absence of a clear nuclear medicine signal in the bladder or intestines.

[0248] SPET / CT quantification (FIG. 10; representative images from a single animal) was used to calculate the activity concentration of mIn-ABD147 in tissues. The overall distribution pattern was similar for each mass dose cohort (0.3 and 3 mg / kg) and between male and female monkeys. No nuclear medicine signal was observed in unanticipated locations, including in tissues where DLL3 has been reported to be cytoplasmically expressed in NHP and humantissues, such as the pancreas or the pituitary gland, see, Giffin MJ, et al. AMG 757, a half-life extended, dll3-targeted bispecific t-cell engager, shows high potency and sensitivity in preclinical models of small-cell lung cancer. Clin Cancer Res. 2021 ;27(5): 1526-1537.

[0249] The data in FIG. 11A and FIG. 11B show the activity concentrations in tissue of naive Male Cynomolgus Monkeys from 0.3 mg / kg and 3 mg / kg mass dose cohort, respectively . The data in FIG. 12A and FIG. 12B show the activity concentrations in tissue of naive female Cynomolgus Monkeys from 0.3 mg / kg and 3 mg / kg mass dose cohort, respectively.

[0250] Taken together, these results reveal that overall distribution pattern is similar for each mass dose cohort (0.3 and 3 mg / kg) and between male and female monkeys, with the highest activity concentrations observed in the liver, followed by the kidney.

[0251] The liver accounted for the largest fraction of injected mIn-ABD147 activity at each timepoint with a peak on Day 1 or 3 in individual animals ranging from 19.4 to 40.3 %ID and declining to 6.7 to 30.1 %ID on Day 10 (FIG. 13). Liver exposure tended to be higher in females versus males and at the low versus high mass dose. However, no significant differences were observed in liver AUClast between dose levels or sexes (p > 0.05, t test) as shown in Table 9.Example 12. Dosimetry Extrapolations to Project Human Radiation Absorbed Dose of 225AC- ABD147 From mIn-ABD147 Distribution in Cynomolgus Monkeys

[0252] The monkey tissue and blood activity concentrations for 111 In -ABD 147 were used to generate inputs for dosimetry analysis to assess the predicted radiation absorbed dose to critical organs for 111 In- ABD 147 and 225Ac-ABD147. The activity concentration (%ID / g) over time was used to compute the cynomolgus monkey time integrated activity coefficients in each organ. Cynomolgus monkey values were scaled to estimate %ID for human organ masses, and subsequently to compute human organ and WB dosimetry estimates for 1 11 In with extrapolation to 225 Ac using OLINDA / EXM 2.0, see Stabin MG, et al. OLINDA / EXM: The Second- Generation Personal Computer Software for Internal Dose Assessment in Nuclear Medicine.Journal of Nuclear Medicine 2005; 46: 1023-1027. The biodistribution of 11 Un and 225Ac was assumed to be equivalent based on the mouse PK and biodistribution study. Other than 213Bi, all daughter ions generated from 225Ac decay in solid organs were assumed to stay resident in that tissue since ABD 147 is known to internalize within cells through nonspecific endocytosis of the antibody and DLL3 -driven internalization to tumor cells. To account for potential redistribution of 213Bi released from the chelate after 225Ac decay in the blood compartment, it was assumed that 40 % of blood activity for 213Bi and all its daughter isotopes would translocate and decay in the kidneys, and 60 % would decay in the remainder of the WB.

[0253] Extrapolation to 225Ac ABD147 radiation absorbed dose to human tissues (mGy / MBq) using inputs from either male or female monkeys and from both mass dose cohorts are shown in FIG. 14A and FIG. 14B. Extrapolation to radiation absorbed doses for 111 In - ABD147 in humans was also conducted to support the use of the imaging agent in the clinic (FIG. 15A and FIG. 15B). The total body effective dose (mSv / MBq) incorporates the recommended nominal RBE factor of 5 for 225 Ac to account for a higher linear-energy-transfer- and biologic effect for the same absorbed doses for the alpha-emitter and an RBE of 1 for 11 Un, see Sgouros G, et al. MIRD Pamphlet No. 22 (Abridged) : Radiobiology and Dosimetry ofa- Particle Emitters for Targeted Radionuclide Therapy*. Journal of Nuclear Medicine. 2010; 51:311-328.

[0254] For 11 Iln-ABD147 the total body effective dose ranged from 0.16 to 0.22 mSv / MBq based on estimates from each NHP cohort. The planned administered 11 Iln-ABD147 activity of 185 MBq for SPECT / CT imaging in patients therefore corresponds to a WB dose of less than 50 mSV. The total body 11 Un dosimetry projections are similar to prior studies that have used 11 Un IgG- based antibodies administered at 185 MBq (5 mCi) for imaging patients, see Vallabhajosula S, etal. Pharmacokinetics and Biodistribution of 11 Un- and 177Lu-Labeled J591 Antibody Specific for Prostate-Specific Membrane Antigen: Prediction of 90Y-J591 Radiation Dosimetry Based on 1 Ilin or 177Lu? Journal of Nuclear Medicine 2005; 46:634 - 641; see Mardirossian G, etal. Radiation AbsorbedDose from Indium-11 l-CYT-356. Journal of Nuclear Medicine.

[0255] To calculate equivalent absorbed dose (mGy-Eq / MBq) for 225Ac-ABD147 in each organ an RBE factor of 5 was applied. The projected equivalent radiation absorbed dose to red marrow, kidney andliverwere generally comparable between extrapolations from the 0.3 and 3.0 mg / kg treated groups (Table 10), reflecting the similar tissue distribution of 111 In -ABD 147 at either mass dose tested. Dosimetry extrapolations from male and female cohorts gave similar projected radiation exposure to red marrow and kidney. There was a trend for higher radiation absorbed dose to liver from females, particularly in the 0.3 mg / kg dose cohort however this didnot reach statistical significance.

[0256] Established external-beam radiation (EBRT) tissue tolerance limits of 2 Gy, 30 Gy, and 23 Gy for red marrow, liver, and kidney, respectively (Wahl, 2021; Emami, 1991) were used to estimate administered activities of 225 Ac-ABD 147 to reach tolerance (ABD-2022- CR25DE). This indicated that red marrow and liver are the likely dose-limiting organs for 225Ac-ABD147. Activities for tolerance limits ranged from 6.5 - 7.7 MBq for red marrow and from 6.6 - 11.4 MBq for liver, depending on the dosimetry estimates from each cohort of animals (Table 10). Using the most sensitive cohort from the distribution study (0.3 mg / kg female monkeys), the administered activity for tissue tolerance for 225Ac-ABD147 was estimated to be 6.5 MBq, giving a projected equivalent absorbed dose of 2 Gy to red marrow. The calculated radiation absorbed dose to liver at the 6.5 MBq maximum administered activity ranged from 30 Gy -Eq, based on dosimetry from the 0.3 mg / kg female cohort, down to 17 Gy- Eq, based on dosimetry from the 3 mg / kg male cohort.Example 13. mIn-ABD147 possesses high tumor-specific targeting and accumulates in xenografted SHP-77 tumors.

[0257] Biodistribution to DLL3 expressing tumors was evaluated following single IV dose administration of 11 Iln-ABD147. Severe combined immunodeficiency beige (SCID-beige) mice were implanted with SHP-77 tumors and treated with a single IV dose of 11 Iln-ABD147 when tumors reached a mean tumor volume of 250 mm3(n = 4 mice, approximately 3 MBq and 0.35 mg / kg protein ata specific activity of 0.5 MBq / pg). The biodistribution was determined bygamma counting of blood and tissues 72 hours post-injection.

[0258] Following IV injection, 11 Iln-ABD147 demonstrated high tumor accumulation by 72 h (mean 32.3 ± 2.5 % ID / g) and was over double the activity concentration measured in the highest non-tumor tissues, the kidney (mean 14.9 ± 0.7 %ID / g) and liver (mean 14.5 ±1.5 %ID / g) (FIG. 16). Biodistribution to other tissues was comparable to that observed in nontumor-bearing wild-type mice at the same time point (data not shown). The data of detection indicates a high accumulation in tumor after IV injection of mIn-ABD147.Example 14. mIn-ABD147 possesses high tumor-specific targeting and accumulates in xenografted NCI-H82 tumors.

[0259] The NCI-H82 cell line has an even lower DLL3 receptor density of approximately 1000 epitopes / cell, compared with SHP-77 cell line. Biodistribution to NCI-H82 Tumors was evaluated following single IV dose administration of mIn-ABD147.

[0260] In the first study, athymic nude mice with xenografted NCI-H82 tumors were dosed with mIn-ABD147 when tumors reached a mean tumor volume of 250 mm3(n = 7 mice, approximately 3 MBq and 0.3 mg / kg protein [6 pg per mouse and average group weight of approximately 20 g] at a specific activity of 0.5 MBq / g). The biodistribution was determined by gamma counting of tissues resected 96 hours post -injection and analyzed to obtain %ID / g.

[0261] Preferential tumor accumulation of 11 Iln-ABD147 was observed following IV injection despite even lower DLL3 expression in the NCI-H82 versus SHP-77 cells. NCI-H82 tumor accumulation (mean 24.4 ±2.2 %ID / g) exceeded the liver (mean 12.4 ± 1.1 %ID / g) and kidney concentration (mean 9.8 ± 0.9 %ID / g) by at least 2-fold (FIG. 17).

[0262] In the second study using female athymic nude mice with xenografted NCI-H82 tumors, in vivo mIn-ABD147 biodistribution was evaluated at 24, 72, and 144 h post-treatment (mean tumor volume of240mm3atthe time of treatment). Mice were imaged using SPECT / CT and an imaging dose of mln tracer (approximately 10 MBq and 1 mg / kg mass dose; specific activity 0.5 MBq / pg). At the 144 h timepoint, blood and tissues were also collected (n = 3 mice) to confirm biodistribution by gamma counting.

[0263] SPECT / CT demonstrated that mIn-ABD147 was taken up 24 h post -injection then retained in tumor tissue out to 144 h (FIG. 18A, representative SPECT / CT image, FIG. 18B quantification of in vivo tissue biodistribution). However, in kidneys and liver, initial uptake was followed by tissue clearance from 24 to 144 hours. At the 144 -hour endpoint, tissues were excised (n = 3 mice) to determine tissue activity concentration by gamma counting. This analysis confirmed that tumor accumulation (mean of 20 ± 2 %ID / g) exceeded the liver (mean 10 ± 0 %ID / g) and kidney concentration (mean 7 ± 1 %ID / g) (FIG. 18C); results that wereconsistent with the 96-hour biodistribution data reported in the first NCI -H82 study above. Biodistribution to other tissues was comparable to non -tumor-bearing wild-type mice at the 168- hour time point (data not shown).

[0264] In the third study, the relationship between mass dose administered and biodistribution of mIn-ABD147 was assessed. Female athymic nude mice xenografted with SHP-77 tumors were IV injected with mIn-ABD147 at a mass dose of approximately 1 mg / kg (n = 12), 3 mg / kg (n = 4), or 10 mg / kg (n = 12). Activity was kept constant at approximately 3 MBq by varying the specific activity from 0.1 to 1 MBq / pg). The mean tumor volume at time of treatment was 318 mm3 across all groups. Four animals per time point per group were subsequently euthanized at 24-, 72-, and 168-hours post-injection for the 1 and 10 mg / kg groups, and at 1-day post-injection for the 3 mg / kg group, and blood and tissues were resected and activity counted by gamma counter.

[0265] At 24 hours post-dose, the 1 mg / kg and 3 mg / kg dose showed comparable biodistribution in all tissues examined (tumor, kidneys, liver, spleen, blood, and plasma). At 1 day post-injection, the 10 mg / kg group had lower tumor activity concentration (6.6 ± 0.5 %ID / g) compared to 1 and 3 mg / kg doses (12.7 ± 1.0 %ID / g and 11.7 ± 0.4 %ID / g, respectively). This suggests that at the 10 mg / kg dose, saturation of DLL3 binding on tumor cells occurred, resulting in lower overall tumor uptake. Saturation of tumor uptake at 10 mg / kg corresponded to a trend for longer blood residency time, higher liver uptake on Day 1, and greater kidney exposure at Day 3 and 6 (FIG. 19A and FIG. 19B).Example 15.225Ac-ABD147 shows high accumulation in xenografted NCI-H82 tumors

[0266] The distribution of225Ac-ABD 147 to tumors and normal tissues was evaluated in female athymic nude mice with xenografted NCI-H82 SCLC tumors. Mice were treated with225Ac-ABD147 when tumors reached a mean volume of 195 mm3 (n=5 mice, 12.5 kBq, 1.0 mg / kg protein, 0.5 kBq / pg specific activity). The activity concentrations of 225 Ac in tumor, blood and normal organs were quantified by gamma counting tissues resected 7 days postinjection. This method quantifies the gamma emissions associated with221Fr and213Bi in the 225 Ac decay scheme and was measured at least 24 hours after tissues were collected to allow for equilibration of 225AC daughter ion decay. Gamma counts therefore reflect the amount of225Ac that had accumulated in the tissues and not derived from daughter ions that may have translocated in vivo.

[0267] 225Ac-ABD147 showed high accumulation in resected tumors (24.4 ± 6.1 %ID / g) compared to the liver (14.9 ± 3.3 %ID / g) and kidney (6.7 ± 1.2 %ID / g) as the 2 normal tissueswith the highest activity levels (FIG. 20).Example 16. Pharmacokinetics and Dosimetry of111In-ABD147 in Human Patients

[0268] Pharmacokinetics and dosimetry ofi nIn-ABD147 was evaluated in three Human patients (Patient 1, Patient 2, and Patient 3). Demographics of Patients 1 -3 are presented in Table 11. Each patient tolerated infusion ofi nIn-ABD147 or225Ac-ABD147 without infusion related reaction (IRR). One of the three patients experienced no serious adverse events (SAEs). Two patients exhibited SAEs not determined to be related to study treatment.225Ac-ABD147 was administered in a single dose at 0.8 MBq (0.02 mCi) (10.7 kBq / Kg / pCi / Kg, for a ~75 Kg patient), andi nIn-ABD147 was administered in a single dose at and 185 MBq (5 mCi).U 1ln- ABD147 and225Ac-ABD147 were administered with a formulation comprising 20 mM sodium acetate, 65 mM sodium chloride (NaCl), 5% Sucrose, 0.02 % Polysorbate 80, 5 mMDiethylenetriaminepentaacetic acid (DTP A), 50 mM Sodium, and Ascorbate at pH 5.8.Study Schema

[0269] Patients 1-3 were evaluated for whole-blood gamma counter pharmacokinetics (PK) and were imaged via whole body planar scan and SPECT / CT scan across study timepoints, after infusion with a single dose ofl uIn-ABD147. Patients were infused withn iIn-ABD147 over the course of 60 minutes, followed by whole-blood gamma counter PK measurements and SPECT / CT scans at 15 minutes post end-of-irradiation (EOI), 30 minutes post EOI, 1 hour postEOI, 2 hours post EO I, 4 hours post EO I, 24 hours post EOI, 48 hours post EO I, and at 72 hours or 96 hours post EOI. Whole body planar scans were performed at 1 hour, 4 hours, 24 hours, 48 hours, and 96 hours post EOI.

[0270] Whole-blood gamma counter PK measurements for Patients 1 -3 are presented in Table 12. PK parameters measured included elimination half-life (h), clearance rate (L / h), CMax(%ID / mL), Vss (L), and AUC ast (%ID / mL.h). PK parameters were analyzed by noncompartmental analysis (NCA) and two-compartment model analysis using Phoenix WinNonlin™ software. %ID / mL was calculated using the equation: %ID / g x Plasma Density (1.025 g / mL - universal value) = %ID / mL. Table 13 shows CMax(%ID / mL) values, blood volume (mL), and injected dose (%) for each patient at 15 minutes post EOI. Injected dose (%) is a measure of the percentage of11Hn- ABD 147 radioactivity that is absorbed and retained in the blood. FIG. 21 A shows counts per minute per gram (cpm / g) at timepoints 15 minutes post EOI to 96 hours post EOI. FIG. 21B shows %ID / mL values at timepoints 15 minutes post EOI to 96 hours post EOI. FIGs. 22A-22C show two-compartment model curve fitting for observed and predicted cpm / g for Patient 1 (FIG. 22 A), Patient 2 (FIG. 22B), and Patient 3 (FIG. 22C). FIGs. 23A-23C show two-compartment model curve fitting for observed and predicted Cxiax for Patient 1 (FIG. 23A), Patient 2 (FIG. 23B), and Patient 3 (FIG. 23C). These data show comparable exposure and clearance with NCA and with two -compartment model analysis, with an elimination half-life of less than 1 day (24 hours).

[0271] Patients 1-3 were assessed for white blood cell (WBC) count (including neutrophils and lymphocytes, platelet (PLT) count, and red blood cell (RBC) count. FIGs. 28A-28C show WBC count, neutrophil count (NEUT), and lymphocyte count (LYM) for Patient 1 at baseline, 72 hours post-EOI withniIn-ABD147, atDay 1 of infusion with225Ac-ABD147, atDay 8 post- EOI with225Ac-ABD147, at Day 15 post-EOI with225Ac-ABD147, at Day 22 post-EOI with225Ac-ABD147, at Day 29 post EOI with225Ac-ABD147, and at Day 36 post-EOI with225Ac- ABD147 (FIG. 28A), forPatient2 atbaseline, 72 hours post-EOI with1HIn-ABD147, at Day 1 of infusion with225Ac-ABD147, at Day 8 post-EOI with225Ac-ABD147, and at Day 15 post- EOI with225Ac-ABD147 (FIG. 28B), and for Patient 3 at baseline, at a timepoint between the baseline measurement and 96 hours post-EOI withniIn-ABD147 (denoted as *), at Day 8 post- EOI with225Ac-ABD147, and atDay 15 post-EOI with225Ac-ABD147 (FIG. 28C). FIGs. 29A- 29C show platelet counts for Patient 1 (FIG. 29A), Patient 2 (FIG. 29B), and Patient 3 (FIG. 29C), at the timepoints discussed in FIGs. 28A-28C. FIGs. 30A-30C show platelet counts for Patient 1 (FIG. 30A), Patient 2 (FIG. 30B), and Patient 3 (FIG. 30C), at the timepoints discussed in FIGs. 28A-28C. These data show that blood cell counts for Patients 1 -3 remained stable post-EOI withniIn-ABD147 and with225Ac-ABD147.

[0272] FIG. 24 shows representative whole body planar images from Patient 2 at 1 hour post EOI, 4 hours post EOI, 24 hours post EOI, 48 hours post EOI, and 96 hours post EOI, in anterior and posterior views. FIG. 24 shows uptake in liver 2402 that clears overtime, with markedly less uptake in other tissues, such as the gastrointestinal tract. FIG. 25 shows SPECT / CT measurements of average absorbed dose (MBq / mL) in liver, spleen, pelvis, and kidney in Patients 1-3 at 15 minutes post EOI to 72 hours post EOI. Table 14 shows averaged total AUC (MBq h / mL) of absorbed dose ofniIn-ABD147 and extrapolated absorbed dose of225Ac-ABD147, and effective half-life (Teff (h)) of1HIn-ABD147 and extrapolated for225Ac- ABD147. Tables 15A-15B provide average estimated absorbed dose in various organs for Patients 1-3, as determined by OLINDA / EXM® software, as described by Stabin et al., (OLINDA / EXM: The Second-Generation Personal Computer Software for Internal Dose Assessment in Nuclear Medicine, Journal of Nuclear Medicine , 2005). These data show increased absorbed dose in liver, with minimal absorbed dose in radiosensitive tissues including kidney, spleen, and pelvic tissue. Further, these data show that estimated mean liver absorbed dose is less than 30 Gray (Gy) at a 4.8 MBq dose level, and that dosing at 6.4 MBq is not expected to reach intolerant Gy levels. These data suggest that the dosages determined from dosimetry studies in non -human primates, as described in Example 12, are safe within the three patients studied.

[0273] FIGs. 26A-26D show representative SPECT / CT scan images of a lung lesion in Patient 2, 48 hours post EOI. FIG. 26A shows a CT scan image of the lung lesion 2602 in the axial plane, measuring 1.7 cm. FIG. 26B shows a corresponding SPECT image of the CT scan (FIG. 26 A), exhibiting localization of1HIn-ABD147 to the lung lesion 2602. FIG. 26C shows a CT scan image of the lung lesion 2602 in the sagittal plane. FIG. 26D shows a corresponding SPECT image of the CT scan (FIG. 26C), exhibiting localization of1HIn-ABD147 to the lung lesion 2602.

[0274] Together, these data show that PK and image analysis of1HIn-ABD147 shows broad biodistribution and rapid clearance rates, as expected from preclinical studies described herein. Further, lesion uptake of11Bn -ABD 147 was visible and evaluable in two out of three patients.Example 17. Comparison of Human pharmacokinetic parameters correlates with preclinical pharmacokinetic parameters

[0275] PK analysis was performed in the three Human patients from Example 16, naive non-human primates (NHPs), and naive hFcRnmice, as described herein. FIGs. 27A-27C show comparisons of average %ID / mL (FIG. 27A), CMax(FIG. 27B), and %ID (FIG. 27C) in blood of Patients 1-3 dosed with 0.2 mg / kginIn-ABD147, NHPs dosed with 0.3 mg / kg or 3 mg / kg1HIn-ABD147, male hFcRn mice dosed with 1 mg / kginIn-ABD147, and female hFcRn mice dosed with 0.3 mg / kgniIn-ABD147. Table 16 shows average %ID cleared in the first 24 hours across species, as described herein. Table 17 shows absorbed dose ofinIn-ABD147(mGy / MBq) in Patients 1-3, as described in Example 16, and in male and female non-human primates, as described in Example 12 These data show that absorbed dose, PK and clearance rates ofniIn-ABD147 are comparable in Human patients to preclinical study estimates.

[0276] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0277] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.SEQUENCES DESCRIBED HEREINFcl ( SEQ ID NO : 1 )I253AAPELLGGPSVFLFPPKPKDTLMASRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGFc2 ( SEQ ID NO : 2 )S254AAPELLGGPSVFLFPPKPKDTLMIARTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGFc3 ( SEQ ID NO : 3 )H310AAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLAQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGFc4 ( SEQ ID NO : 4 )H435QAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNQYTQKSLSLSPGFc5 ( SEQ ID NO : 5 )Y436AAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHATQKSLSLSPGFc6 ( SEQ ID NO : 6 )H310A / H435QAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLAQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNQYTQKSLSLSPGFc7 (SEQ ID NO: 7)AEASSAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGFc8 (SEQ ID NO: 8)AEASS / H310AAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLAQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGFc9 (SEQ ID NO: 9)AEASS / H435QAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNQYTQKSLSLSPGFc wild type (SEQ ID NO: 10)APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG2RS15d (SEQ ID NO: 20)QVQLQESGGGSVQAGGSLKLTCAASGYIFNSCGMGWYRQSPGRERELVSRISGDGDTWHKESVK GRFTISQDNVKKTLYLQMNSLKPEDTAVYFCAVCYNLETY WGQGTQVTVSS2RS15d CDR1 GYIFNSCG (SEQ ID NO: 21)2RS15d CDR2 ISGDGDT (SEQ ID NO: 22)2RS15d CDR3 AVCYNLETY (SEQ ID NO: 23) hz!0D9v7.251 (SEQ ID NO: 30)EVQLVESGGGEVQPGGSLRLSCAASGS I FS INAMGWYRQAPGKQRELVAGFTGDTNTIYAESVKGRFTISRDNAKNTVYLQMSSLRAEDTAVYYCAADVQLFSRDYEFYWGQGT LVTVKP hzlOD9v7.251 CDR1 GSIFSINA (SEQ ID NO: 31) hzlOD9v7.251 CDR2 FTGDTNT (SEQ ID NO: 32) hzlOD9v7.251 CDR3 AADVQLFSRDYEFY (SEQ ID NO: 33)SEQ ID NO: 40 (Wild-type human IgGl-hinge)EPKSCDKTHTCPPCPSEQ ID NO: 41 (C220S IgGl-hinge)EPKSSDKTHTCPPCPSEQ ID NO: 42 (WT-Fc / C220S IgGl-hinge)EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSEQ ID NO: 43 ( 435Q / AEASS-Fc / C22 OS IgGl-hinge)EPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNQYTQKSLSLSPG-Ill-

Claims

CLAIMSWhat is claimed is:

1. A method of treating a tumor or cancer of an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a radioimmunoconjugate, wherein the radioimmunoconjugate comprises a DLL3 antigen binding region coupled to a radioisotope, wherein the DLL3 antigen binding region comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO: 315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO: 515, SEQ ID NO: 131 , SEQ ID NO: 231, SEQ ID NO: 431 , or SEQ ID NO: 531 , wherein the radioisotope comprises 225-Ac, and wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.02 mCi to about O.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

2. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers from about 0.04 mCi to about 0.172 mCi of radiation to the individual per administration, thereby treating the tumor or cancer of the individual.

3. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.02 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

4. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.043 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

5. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.086 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

6. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.129 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

7. The method according to claim 1, wherein the therapeutically effective amount of the radioimmunoconjugate delivers about 0.172 mCi to the individual per administration, thereby treating the tumor or cancer of the individual.

8. The method according to any one of claims 1 to 7, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% identical to that setforth in any one of SEQ ID NO: 101 to 106, 201 to 206, 301 to 306, 401 to 306, and 501 to 506.

9. The method according to any one of claims 1 to 8, wherein the DLL3 antigen binding region comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112; and c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO: 115, or SEQ ID NO: 131.

10. The method according to any one of claims 1 to 9, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 101 to SEQ ID NO: 106.

11. The method according to any one of claims 1 to 10, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence of any one of SEQ ID NO: 101 to SEQ ID NO: 106.

12. The method according to any one of claims 1 to 8, wherein the DLL3 antigen binding region comprises:a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 207 to SEQ ID NO: 209; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 210 to SEQ ID NO: 212; and c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 213 to SEQ ID NO: 215, or SEQ ID NO: 231.

13. The method according to any one of claims 1 to 8 or 12, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206.

14. The method according to any one of claims 1 to 8 or 12, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 201 to SEQ ID NO: 206.

15. The method according to any one of claims 1 to 8, wherein the DLL3 antigen binding region comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 307 to SEQ ID NO: 309; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 310 to SEQ ID NO: 312; and c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 313 to SEQ ID NO: 315.

16. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306.

17. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 301 to SEQ ID NO: 306.

18. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 303.

19. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 303.

20. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 304.

21. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 304.

22. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 305.

23. The method according to any one of claims 1 to 8 or 15, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 305.

24. The method according to any one of claims 1 to 8, wherein the DLL3 antigen binding region comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 407 to SEQ ID NO: 409; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 410 to SEQ ID NO: 412; and c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 413 to SEQ ID NO: 415, or SEQ ID NO: 431.

25. The method according to any one of claims 1 to 8 or 24, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable regioncomprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406.

26. The method according to any one of claims 1 to 8 or 24, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 403.

27. The method according to any one of claims 1 to 8 or 24, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 403.

28. The method according to any one of claims 1 to 8 or 24, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 401 to SEQ ID NO: 406.

29. The method according to any one of claims 1 to 8, wherein the DLL3 antigen binding region comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 507 to SEQ ID NO: 509; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 510 to SEQ ID NO: 512; and c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 513 to SEQ ID NO: 515, or SEQ ID NO: 531.

30. The method according to any one of claims 1 to 8 or 29, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.

31. The method according to any one of claims 1 to 8 or 29, wherein the DLL3 antigen binding region comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.

32. The method accordingto any one of claims 1 to 31, wherein the DLL3 antigen binding region is humanized.

33. The method accordingto any one of claims 1 to 32, wherein the DLL3 antigen binding region does not comprise an immunoglobulin light chain.

34. The method according to any one of claims 1 to 33, wherein the DLL3 antigen binding region comprises or consists of a VHH.

35. The method of any one of claims 1 to 34, wherein the radioimmunoconjugate comprises an immunoglobulin heavy chain constant region.

36. The method of claim 35, wherein the immunoglobulin heavy chain constant region comprises a CH2 domain of an immunoglobulin, CH3 domain of an immunoglobulin, or a CH2 domain and a CH3 domain of an immunoglobulin.

37. The method of claim 35 or 36, wherein the immunoglobulin heavy chain constant region comprises a CH2 domain and a CH3 domain of an immunoglobulin.

38. The method of any one of claims 35 to 37, wherein the immunoglobulin heavy chain constant region is an IgA, IgGl, IgG2, IgG3, or IgG4 isotype.

39. The method of any one of claims 35 to 37, wherein the immunoglobulin heavy chain constant region is an IgGl isotype.

40. The method of any one of claims 35 to 37, wherein the immunoglobulin heavy chain constant region is an IgG4 isotype.

41. The method of any one of claims 35 to 40, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region or alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn).

42. The method of any one of claims 35 to 40, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region and alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn).

43. The method of any one of claims 35 to 40, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that reduces an effector function of the immunoglobulin heavy chain constant region.

44. The method of any one of claims 35 to 40, wherein the immunoglobulin heavy chain constant region comprises an alteration to one or more amino acid residues that alters binding of the radioimmunoconjugate to a neonatal Fc receptor (FcRn).

45. The method of any one of claim 41 to 44, wherein the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is an alteration that reduces complement dependent cytotoxicity (CDC), antibody-dependent cell-cytotoxicity (ADCC), antibody-dependent cell-phagocytosis ADCP, or a combination thereof.

46. The method of any one of claims 41 to 45, wherein the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region is selected from the list consisting of: (a) 297A, 297Q, 297G, or 297D, (b) 279F, 279K, or 279L, (c) 228P, (d) 235 A, 235E, 235 G, 235Q, 235R, or 235 S, (e) 237 A, 237E, 237K, 237N, or237R, (f) 234A, 234V, or234F, (g) 233P, (h) 328A, (i) 327Q or 327T, (j) 329A, 329G, 329Y, or 329R (k) 33 I S, (1) 236F or 236R, (m) 238A, 238E, 238G, 238H, 2381, 238V, 238W, or 238 Y, (n) 248 A, (o) 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, or 254V, (p) 255N, (q) 256H, 256K, 256R, or 256V, (r) 264S, (s) 265H, 265K, 265S, 265Y, or 265A, (t) 267G, 267H, 2671, or 267K, (u) 268K, (v) 269N or 269Q, (w) 270 A, 270G, 270M, or 270N, (x) 271T, (y) 272N, (z) 292E, 292F, 292G, or 2921, (aa) 293S, (bb) 301W, (cc) 304E, (dd) 311E, 311G, or 311 S, (ee) 316F, (ff) 328V, (gg) 330R, (hh) 339E or 339L, (ii) 3431 or 343V, (jj) 373A, 373G, or 373 S, (kk) 376E, 376W, or 376Y, (11) 380D, (mm) 382D or 382P, (nn) 385P, (oo) 424H, 424M, or 424V, (pp) 434I, (qq) 438G, (rr) 439E, 439H, or 439Q, (ss) 440A, 440D, 440E, 440F, 440M, 440T, or 440V, (tt) K322A, (uu) L235E, (vv) L234A and L235A, (ww) L234A, L235A, and G237A, (xx) L234A, L235A, andP329G, (yy) L234F, L235E, and P331 S, (zz) L234A, L235E, and G237A, (aaa), L234A, L235E, G237A, and P331 S (bbb) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S, (ccc) L234A, L235A, and P329A, (ddd) G236R and L328R, (eee) G237A, (fff) F241A, (ggg) V264A, (hhh) D265A, (iii) D265A and N297A, (jjj) D265A and N297G, (kkk) D270A, (111) A330L, (mmm) P331A or P33 I S, (nnn) E233P, (ooo) L234A, L235E, G237A, A33 OS, P33 I S, and (ppp) any combination of (a) - (ppp), per EU numbering.

47. The method of any one of claims 41 to 46, wherein the alteration to the one or more amino acid residues that reduces the effector function of the immunoglobulin heavy chain constant region comprises L234A, L235E, G237A, A330S, and P33 I S per EU numbering.

48. The method of any one of claims 41 to 47, wherein the amino acid alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) reduces the serum half-life of the radioimmunuconjugate.

49. The method of any one of claims 41 to 48, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 251, 252, 253, 254, 255, 288, 309, 310, 312, 385, 386, 388, 400, 415, 433, 435, 436, 439, 447, and combinations thereof per EU numbering.

50. The method of any one of claims 41 to 49, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor(FcRn) is to an amino acid residue selected from the list consisting of: 253, 254, 310, 435, 436 and combinations thereof per EU numbering.51 . The method of any one of claims 41 to 50, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 1253 A, I253D, I253P, S254A, H310A, H310D, H310E, H310Q, H435A, H435Q, Y436A, and combinations thereof per EU numbering.

52. The method of any one of claims 41 to 51, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 1253 A, S254A, H310A, H435Q, Y436A and combinations thereof per EU numbering.

53. The method of any one of claims 41 to 52, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) is to an amino acid residue selected from the list consisting of: 1253 A, H310A, H435Q, and combinations thereof per EU numbering.

54. The method of any one of claims 41 to 53, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises 1253 A per EU numbering.

55. The method of any one of claims 41 to 53, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises H310A per EU numbering.

56. The method of any one of claims 41 to 53, wherein the alteration to the one or more amino acid residues that alters binding of the radioimmunoconjugate to the neonatal Fc receptor (FcRn) comprises H435Q per EU numbering.

57. The method of any one of claims 1 to 56, wherein the DLL3 antigen binding region further comprises a linker amino acid sequence or a human IgG hinge region.

58. The method of claim 57, wherein the human IgG hinge region comprises an amino acid sequence set forth in SEQ ID NO: 41 .

59. The method of any one of claims 35 to 58, wherein the DLL3 antigen binding region is coupled to the immunoglobulin heavy chain constant region by a human IgG hinge region.

60. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120, SEQ ID NO: 216 to SEQ ID NO: 220, SEQ ID NO: 316 to SEQ ID NO: 320, SEQ ID NO: 416 to SEQ ID NO: 420, and SEQ ID NO: 516 to SEQ ID NO: 520.61 . The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120, SEQ ID NO: 216 to SEQ ID NO: 220, SEQ ID NO: 316 to SEQ ID NO: 320, SEQ ID NO: 416 to SEQ ID NO: 420, and SEQ ID NO: 516 to SEQ ID NO: 520.

62. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120.

63. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 116 to SEQ ID NO: 120.

64. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 216 to SEQ ID NO: 220.

65. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 216 to SEQ ID NO: 220.

66. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 316 to SEQ ID NO: 320.

67. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 317.

68. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 317.

69. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 318.

70. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 318.71 . The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 319.

72. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 319.

73. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 316 to SEQ ID NO: 320.

74. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO: 416 to SEQ ID NO: 420.

75. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical toSEQ ID NO: 417.

76. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence set forth in SEQ ID NO: 417.

77. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 416 to SEQ ID NO: 420.

78. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 516 to SEQ ID NO: 520.

79. The method of any one of claims 1 to 59, wherein the radioimmunoconjugate comprises an amino acid sequence identical to any one of SEQ ID NO: 516 to SEQ ID NO: 520.

80. The method of any one of claims 1 to 79, wherein the radioimmunoconjugate binds DLL3 at a KD of 10 nanomolar or less.

81. The method of any one of claims 1 to 79, wherein the radioimmunoconjugate binds DLL3 at a KDof 5 nanomolar or less.

82. The method of any one of claims 1 to 79, wherein the radioimmunoconjugate binds DLL3 at a KDof 2 nanomolar or less.

83. The method of any one of claims 1 to 79, wherein the radioimmunoconjugate binds DLL3 at a KDof 1 nanomolar or less.

84. The method of any one of claims 1 to 83 wherein the radioimmunoconjugate further comprises a chelating agent.

85. The method of claim 84, wherein the molecular weight of the radioimmunoconjugate is between 60 and 110 kDa.

86. The method of any one of claims 1 to 85, wherein the radioimmunoconjugate has a serum half-life of less than 15 days.

87. The method of any one of claims 1 to 85, wherein the radioimmunoconjugate has a serum half-life of less than 10 days.

88. The method of any one of claims 1 to 85, wherein the radioimmunoconjugate has a serum half-life of less than 120 hours.

89. The method of any one of claims 1 to 85, wherein the radioimmunoconjugate has a serum half-life of less than 72 hours.

90. The method of any one of claims 84 to 89, wherein the chelating agent is a radioisotope chelating agent.

91. The method of any one of claims 84 to 89, wherein the chelating agent is an alpha emitter chelating agent.

92. The method of any one of claims 84 to 89, wherein the chelating agent is a beta-emitter or gamma-emitter chelating agent.

93. The method of any one of claims 84 to 92, wherein the chelating agent is selected from the list consisting of: DOTA, D03A, DOTAGA, DOTAGA anhydride, Py4Pa, Py4Pa-NCS, Crown, Macropa, Macropa-NCS, HEHA, CHXoctapa, Bispa, Noneunpa, and combinations thereof.

94. The method of any one of claims 84 to 92, wherein the chelating agent is selected from the list consisting of: DOTMA, DOTPA, DO3 AM-acetic acid, DOTP, DOTMP, DOTA-4AMP, CB-TE2A, NOTA, NOTP, TETPA, TETA, PEPA, H4Octapa, H2Dedpa, DO2P, EDTA, DTPA- BMA, 3,2,3-LI(HOPO), 3,2-HOPO, Neunpa, Neunpa-NCS, Octapa, PyPa, Porphyrin, Deferoxamine, DFO*, and combinations thereof.

95. The method of any one of claims 84 to 92, wherein the chelating agent is DOTA.

96. The method of any one of claims 84 to 92, wherein the chelating agent is DOTAGA.

97. The method of any one of claims 84 to 92, wherein the chelating agent is Py4Pa.

98. The method of any one of claims 84 to 97, wherein the chelating agent is directly coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region.

99. The method of any one of claims 84 to 97, wherein the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region by a linker.

100. The method of claim 99, wherein the linker is selected from: 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p- aminobenzyl oxy carbonyl ( PAB), and those resulting from conjugation with linker reagents: N - Succinimidyl 4-(2 -pyridylthio) pentanoate forming linker moiety 4 -mercaptopentanoic acid (SPP), Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l -carboxylate (SMCC), N- Succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB), polyethylene glycol (PEG), a polyethylene glycol polymer (PEGn), and S-2-(4-Isothiocyanatobenzyl) (SCN).

101. The method of claim 99, wherein the linker is selected from: polyethylene glycol (PEG), a polyethylene glycol polymer (PEGn), and 4-benzyl.

102. The method of any one of claims 84 tolOl, wherein the chelating agent comprises a linker-chelator resulting from conjugation with:DOTAGA),103. The method of any one of claims 84 to 102, wherein the chelating agent comprises a linker-chelator resulting from conjugation with:DOTAGA).

104. The method of any one of claims 84 to 103, wherein the chelating agent comprises a linker-chelator resulting from conjugation with:

105. The method of any one of claims 84 to 104, wherein the chelating agent comprises a linker-chelator resulting from conjugation with:

106. The method of any one of claims 84 to 105, wherein the chelating agent comprises a linker-chelator selected from:

107. The method of any one of claims 84 to 106, wherein the chelating agent comprises a linker-chelator that is:

108. The method of any one of claims 84 to 107, wherein the chelating agent comprises a linker-chelator that is:

109. The method of any one of claims 84 to 108, wherein the chelating agent comprises a linker-chelator that is:

110. The method of any one of claims 84 to 109, wherein the chelating agent comprises a linker-chelator that is:

111. The method of any one of claims 84 to 110, wherein the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 1 :1 to 8:1.

112. The method of any one of claims 84 to 110, wherein the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 1 :1 to 6:1.

113. The method of any one of claims 84 to 110, wherein the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 2:1 to 6:1.

114. The method of any one of claims 84 to 110, wherein the chelating agent is coupled to the DLL3 antigen binding region and / or the immunoglobulin heavy chain constant region at a ratio of 4:1.

115. The method of any one of claims 1 to 114, wherein the radioisotope is an alpha emitter.

116. The method of any one of claims 1 to 114, wherein the radioisotope is an alpha emitter selected from the list consisting of 225-Ac, 223-Ra, 224-Ra, 227-Th, 212-Pb, 212-Bi, and 213- Bi.

117. The method of any one of claims 1 to 114, wherein the radioisotope is 225-Ac.

118. The method of any one of claims 1 to 114, wherein the radioisotope is a beta emitter.

119. The method of any one of claims 1 to 114, wherein the radioisotope is a beta emitter selected from 177-Lu, 90-Y, 67-Cu, and 153-Sm.

120. The method of any one of claims 1 to 114, wherein the radioisotope is a gamma emitter.

121. The method of any one of claims 1 to 114, wherein the radioisotope is a gamma emitter selected from 111-In, 89-Zn, 123-1, 99m-Tc, and 68-Ga.

122. The method of any one of claims 84 to 121, wherein the molecular weight of the radioimmunoconjugate is between 60 and 100 kDa.

123. The method of any one of claims 84 to 121, wherein the molecular weight of the radioimmunoconjugate is between 60 and 90 kDa.

124. The method of any one of claims 84 to 121, wherein the molecular weight of the radioimmunoconjugate is between 65 and 90 kDa.

125. The method of any one of claims 84 to 121, wherein the molecular weight of the radioimmunoconjugate is between 70 and 90 kDa.

126. The method of any one of claims 84 to 125, wherein the radioimmunoconjugate forms a dimer with another radioimmunoconjugate.

127. The method of any one of claims 1 to 126, wherein the radioimmunoconjugate is included in a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and the radioimmunoconjugate.

128. The method of any one of claims 1 to 127, wherein the radioimmunoconjugate is administered intravenously.

129. The method of any one of claims 1 to 128, wherein the tumor or cancer comprises a solid tissue tumor or cancer.

130. The method of any one of claims 1 to 128, wherein the tumor or cancer expresses DLL3.

131. The method of any one of claims 1 to 130, wherein the tumor or cancer comprises lung cancer cell, breast cancer, ovarian cancer, or neuroendocrine cancer.

132. The method of claim 131, wherein the neuroendocrine cancer comprises a carcinoma.

133. The method of claim 131, wherein the lung cancer comprises a non-small cell lung cancer (NSCLC).

134. The method of claim 131, wherein the lung cancer comprises small cell lung cancer (SCLC).

135. The method of claim 131, wherein the lung cancer comprises a large-cell neuroendocrine carcinoma (LCNEC) or a pulmonary LCNEC.

136. The method of any one of claims 1 to 135, wherein the individual has previously received a platinum based chemotherapeutic.

137. The method of claim 136, wherein the platinum based chemotherapeutic is selected from the list consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, and combinations thereof.

138. The method of any one of claims 1 to 137, wherein the tumor or cancer is refractory to treatment with at least one previous anti-neoplastic agent.

139. The method of any one of claims 1 to 138, wherein the individual has adequate renal function or adequate hepatic function.

140. The method of claim 139, wherein the individual has adequate renal function.

141. The method of claim 139, wherein the individual has adequate hepatic function.

142. The method of any one of claims 1 to 141, wherein the tumor or cancer is a locally advanced cancer.

143. The method of any one of claims 1 to 141, wherein the tumor or cancer is a metastatic cancer.

144. The method of any one of claims 1 to 141, wherein the tumor or cancer is an extensive stage cancer.

145. The method of any one of claims 1 to 144, wherein the method is associated with a lower incidence of gastrointestinal side-effects.

146. The method of claim 145, wherein the gastrointestinal side-effects comprise one or more of diarrhea, nausea, vomiting, loss of appetite, stomach ulcers, cramps, abdominal pain, indigestion, bloating, or gas.

147. The method of any one of claims 1 to 146, the method further comprising selecting the individual based on a positive result from an assay of a prior administration of a DLL3 -binding reagent coupled or complexed to a gamma-emitting radionuclide, wherein the positive result from the assay indicates binding of the DLL3 -binding reagent to a tumor or cancer of the individual.

148. The method of claim 147, wherein the gamma-emitting radionuclide comprises 111-In.

149. The method of claim 147 or 148, wherein the gamma-emitting radionuclide is administered at a dose of about 5 mCi.

150. The method of any one of claims 147 to 149, wherein the assay comprises Single-Photon Emission Computed Tomography combined with Computed Tomography (SPECT / CT).

151. The method of any one of claims 147 to 150, wherein the DLL3 -binding reagent comprises: a. a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in any one of SEQ ID NO: 107 to SEQ ID NO: 109, SEQ ID NO: 207 to SEQ ID NO: 209, SEQ ID NO: 307 to SEQ ID NO: 309, SEQ ID NO: 407 to SEQ ID NO: 409, or SEQ ID NO: 507 to SEQ ID NO: 509; b. a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in any one of SEQ ID NO: 110 to SEQ ID NO: 112, SEQ ID NO: 210 to SEQ ID NO: 212, SEQ ID NO: 310 to SEQ ID NO: 312, SEQ ID NO: 410 to SEQ ID NO: 412, or SEQ ID NO: 510 to SEQ ID NO: 512; and / or c. a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in any one of SEQ ID NO: 113 to SEQ ID NO:115, SEQ ID NO: 213 to SEQ ID NO: 215, SEQ ID NO: 313 to SEQ ID NO:315, SEQ ID NO: 413 to SEQ ID NO: 415, SEQ ID NO: 513 to SEQ ID NO:515, SEQ ID NO: 131 , SEQ ID NO: 231, SEQ ID NO: 431 , or SEQ ID NO: 531 .

152. The method of claim 151, wherein the DLL3 -binding reagent comprises a heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NO: 501 to SEQ ID NO: 506.

153. The method of any one of claims 147 to 152, wherein the gamma-emitting radionuclide is complexed to the DLL3 -binding reagent by a linker-chelator.

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