Subcutaneous administration of Anti-DLL3 agent for treatment of cancer

Abstract

Provided herein is a method for treating DLL3-expressing cancers using an anti-DLL3 antigen-binding protein administered subcutaneously. The anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22, and may be administered to a subject once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

Description

Amgen Ref. No. 10990-W001-SECSUBCUTANEOUS ADMINISTRATION OF ANTI-DLL3 AGENT FOR TREATMENT OF CANCERFIELD

[0001] The disclosure relates to a method of subcutaneously administering an anti- DLL3 antigen-binding protein to treat DLL3-expressing cancers.INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY

[0002] Incorporated by reference in its entirety herein is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: one 47.5 kilobyte (kb) XML file entitled “10990-W001 -SEC SQL. xml,” created on September 8, 2025.BACKGROUND

[0003] Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a poor prognosis and limited therapeutic options, representing about 13% of all newly diagnosed lung cancers, with more than 235,000 adults receiving a diagnosis of SCLC in the U.S. in 2021 . Survival rates have remained low for several decades, with only 7% of SCLC patients surviving five years, in a large part due to the lack of new therapies to combat this form of lung cancer. Approximately one third of patients present with limited stage disease, defined by the presence of tumors that fit in a single radiation field. The remaining patients present with extensive-stage disease, defined by presence of tumors outside a single radiation field, often with disseminated metastatic disease.

[0004] Patients typically respond well to the current first-line standard of care, which includes chemotherapy (combined with thoracic radiation therapy (TRT) for limited stage disease or anti-PD-L1 for extensive stage disease), but often quickly relapse with chemoresistant disease, for which few therapeutic options are currently available (Gong, J. and Salgia, R. J Oncol Pract., 14(6): 359-36 (2018)). To reduce the harsh side effects of chemotherapy and improve therapeutic outcomes, immunotherapeutics have beenAmgen Ref. No. 10990-W001-SEC developed as an alternative to the current standard of care. Most recently, IMDELLTRA® (tarlatamab-dlle) is the firstT cell engager (TCE) therapy approved by the U.S. Food and Drug Association (FDA) for the treatment of adults with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy.

[0005] While immunotherapeutics like IMDELLTRA® have improved safety and efficiency profiles, they typically are administered via intravenous infusion, often requiring extended periods of hospitalization for patients. Thus, there remains a need for more convenient administration routes for cancer immunotherapeutics requiring minimal or no hospital stays.SUMMARY

[0006] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

[0007] E1 . The disclosure provides a method of treating a DLL3-expressing cancer. The method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22.

[0008] E2. In a method of treating a DLL3-expressing cancer described herein, such as the method of E1 , the method further comprises administering 10 mg to 60 mg of the anti- DLL3 antigen-binding protein to the subject once every two weeks (Q2W).

[0009] E3. The disclosure also provides a method of treating a DLL3-expressing cancer which comprises subcutaneously administering an anti-DLL3 antigen-binding protein (such as an anti-DLL3-antigen binding protein comprisingthe amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22) to a subject in need thereof according to the following regimen: (1 ) a first administration of 0.5 mg to 5 mg, such as 0.5 mg to 3 mg, on day 1 ; (2) a second administration of 5 mg to 60 mg, such as 10 mg to 30 mgAmgen Ref. No. 10990-W001-SEC on day 8; and (3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter (Q2W), wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.

[0010] E4. In a method of treating a DLL3-expressing cancer described herein, such as the method of E3, the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22.

[0011] E5. In a method of treating a DLL3-expressing cancer described herein, such as the method of E3 or E4, the first, second, and subsequent administrations of the anti-DLL3 antigen-binding protein are administered over the course of multiple 28-day cycles.

[0012] E6. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E5, the second and subsequent administrations of the anti- DLL3 antigen-binding protein achieve a Ctrough, that, on average, corresponds to the Ctrough achieved by an intravenous (IV) administration of 10 mg of the anti-DLL3 antigen-binding protein.

[0013] E7. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E6, each of the second and subsequent administrations are 2- fold, 5-fold, 10-fold, 15-fold, 20-fold, 30-fold, or 40-fold greater than the first administration.

[0014] E8. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E7, the first administration comprises about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, or 3.5 mg of the anti-DLL3 antigen-binding protein.

[0015] E9. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E8, each of the second and subsequent administrations comprises 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg of the anti-DLL3 antigen-binding protein.Amgen Ref. No. 10990-W001-SEC

[0016] E10. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E9, the first administration comprises 1 mg, the second administration comprises 10 mg, and each of the one or more subsequent administrations comprises 10 mg of the anti-DLL3 antigen-binding protein.

[0017] E11. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E3-E9, the first administration comprises about 1 mg, the second administration comprises 15 mg, and each of the one or more subsequent administrations comprises 15 mg of the anti-DLL3 antigen-binding protein.

[0018] E12. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1-E11 , the DLL3-expressing cancer is a neuroendocrine cancer.

[0019] E13. In a method of treating a DLL3-expressing cancer described herein, such as the method of E12, the DLL3-expressing cancer is a pulmonary neuroendocrine cancer.

[0020] E14. In a method of treating a DLL3-expressing cancer described herein, such as the method of E13, the DLL3-expressing cancer is small cell lung cancer (SCLC).

[0021] E15. In a method of treating a DLL3-expressing cancer described herein, such as the method of E13 or E1 , the DLL3-expressing cancer is limited stage small cell lung cancer (LS-SCLC).

[0022] E16. In a method of treating a DLL3-expressing cancer described herein, such as the method of E13 or E14, the DLL3-expressing cancer is extensive stage small cell lung cancer (ES-SCLC).

[0023] E17. In a method of treating a DLL3-expressing cancer described herein, such as the method of E16, the neuroendocrine cancer is refractory SCLC or relapsed SCLC.

[0024] E18. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1 -E17, the cancer has progressed or relapsed following at least one previous cancer treatment.Amgen Ref. No. 10990-W001-SEC

[0025] E19. In a method of treating a DLL3-expressing cancer described herein, such as the method of E18, the at least one previous cancer treatment comprises platinumbased chemotherapy.

[0026] E20. In a method of treating a DLL3-expressing cancer described herein, such as the method of E19, the platinum-based chemotherapy comprises carboplatin or cisplatin.

[0027] E21 . In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1 -E17, the subject has not received any prior line of cancer treatment.

[0028] E22. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1 -E12, the DLL3-expressing cancer is an extrapulmonary neuroendocrine cancer.

[0029] E23. In a method of treating a DLL3-expressing cancer described herein, such as the method of E22, the DLL3-expressing cancer is neuroendocrine prostate cancer (NEPC).

[0030] E24. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1 -E23, the method further comprises administering at least one additional therapeutic agentto the subject.

[0031] E25. In a method of treating a DLL3-expressing cancer described herein, such as the method of E24, the at least one additional therapeutic agent comprises a corticosteroid, saline, or an anti-IL6 antibody.

[0032] E26. In a method of treating a DLL3-expressing cancer described herein, such as the method of E25, the corticosteroid comprises dexamethasone.

[0033] E27. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E24-E26, dexamethasone is administered on day 1 and day 8 of a first 28-day cycle.Amgen Ref. No. 10990-W001-SEC

[0034] E28. In a method of treating a DLL3-expressing cancer described herein, such as the method of E24, the at least one additional therapeutic comprises an anti-PD1 antibody or anti-PD-L1 antibody.

[0035] E29. In a method of treating a DLL3-expressing cancer described herein, such as the method of E28, the anti-PD-L1 antibody is durvalumab.

[0036] E30. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E1-E29, the anti-DLL3 antigen-binding protein is tarlatamab.

[0037] E31 . A method of treating a DLL3-expressing cancer is described herein. The method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 10 mg on day 8; (3) a subsequent administration of 10 mg on day 15, and (4) one or more further subsequent administrations of 10 mg once every two weeks (Q2W) thereafter.

[0038] E32. A method of treating a DLL3-expressing cancer is described herein. The method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 15 mg on day 8; (3) a subsequent administration of 15 mg on day 15, and (4) one or more further subsequent administrations of 15 mg once every two weeks (Q2W) thereafter.

[0039] E33. A composition comprising an anti-DLL3 antigen-binding protein for the treatment of a DLL3-expressing cancer is described herein. The anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22, and the treatment comprises subcutaneously administering the anti-DLL3 antigen-binding protein to the subject according to the following regimen: (1 ) a first administration of 0.5 mgto 5 mg, such as 0.5 mgto 3 mg, on day 1 ; (2) a second administration of 5 mg to 60 mg, such as 10 mg to 30 mg, on day 8; and (3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter, wherein each of the second and subsequent administrations comprise the same amountAmgen Ref. No. 10990-W001-SEC of anti-DLL3 antigen-binding protein, which amount is greaterthan the amount of a nti- DLL3 antigen-binding protein in the first administration.

[0040] E34. In a composition comprising an anti-DLL3 antigen binding protein described herein, such as the composition of E33, the anti-DLL3 antigen-binding protein is tarlatamab.

[0041] E35. In a composition comprising an anti-DLL3 antigen binding protein described herein, such as the composition of E33 or E34, the treatment comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg administered on day 1 ; (2) a second administration of 10 mg or 15 mg on day 8; (3) a subsequent administration of 10 mg or 15 mg on day 15, and (4) one or more further subsequent administrations of 10 mg or 15 mg once every two weeks thereafter.

[0042] E36. In a composition comprising an anti-DLL3 antigen binding protein described herein, such as the composition of any one of E33-E35, the DLL3-expressing cancer is small cell lung cancer (SCLC).

[0043] E37. In a composition comprising an anti-DLL3 antigen binding protein described herein, such as the composition of E36, the DLL3-expressing cancer is extensive stage small cell lung cancer (ES-SCLC).

[0044] E38. Use of an anti-DLL3 antigen-binding protein in the manufacture of a medicament for the treatment of a DLL3-expressing cancer in a subject is described herein. In a use of an anti-DLL3 antigen-binding protein described herein, the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22, and the treatment comprises subcutaneously administeringthe anti-DLL3 antigen-binding protein to the subject accordingto the following regimen: (1 ) a first administration of 0.5 mg to 5 mg on day 1 ; (2) a second administration of 5 mgto 60 mg on day 8; and (3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter, wherein each of the second and subsequent administrations comprise the same amount of anti-DLL3 antigen-bindingAmgen Ref. No. 10990-W001-SEC protein, which amount is greaterthan the amount of anti-DLL3 antigen-binding protein in the first administration.

[0045] E39. In a use of an anti-DLL3 antigen-binding protein described herein, such as the use of E38, the anti-DLL3 antigen-binding protein is tarlatamab.

[0046] E40. In a use of an anti-DLL3 antigen-binding protein described herein, such as the use of E38 or E39, the treatment comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 10 mg or 15 mg on day 8; (3) a subsequent administration of 10 mg or 15 mg on day 15, and (4) one or more further subsequent administrations of 10 mg or 15 mg once every two weeks thereafter.

[0047] E41 . In a use of an anti-DLL3 antigen-binding protein described herein, such as the use of any one of E38-E40, the DLL3-expressing cancer is small cell lung cancer (SCLC).

[0048] E42. In a use of an anti-DLL3 antigen-binding protein described herein, such as the use of E41 , the DLL3-expressing cancer is extensive stage small cell lung cancer (ES- SCLC).

[0049] E43. A method of treating a DLL3-expressing cancer is provided herein. The method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof according to the following regimen: (1 ) a first administration of 0.5 mg to 5 mg, such as 0.5 mg to 3 mg, on day 1 ; (2) a second administration of 5 mg to 60 mg, such as 15 mg to 35 mg, on day 8; and (3) one or more subsequent administrations of 5 mg to 60 mg, such as 15 mg to 35 mg, beginning on day 22 and once every three weeks thereafter (Q3W), wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.

[0050] E44. A method of treating a DLL3-expressing cancer is provided herein. The method comprises subcutaneously administering an anti-DLL3 antigen-binding protein toAmgen Ref. No. 10990-W001-SEC a subject in need thereof according to the following regimen: (1 ) a first administration of 0.5 mg to 5 mg on day 1 ; (2) a second administration of 5 mg to 60 mg, such as 30 mg to 50 mg, on day 8; and (3) one or more subsequent administrations of 5 mg to 60 mg, such as 30 mg to 50 mg, beginning on day 29 and once every four weeks thereafter (Q4W), wherein each of the second and subsequent administrations comprises the same amount of anti- DLL3 antigen-binding protein, which amount is greaterthan the amount of anti-DLL3 antigen-binding protein in the first administration.

[0051] E45. In a method of treating a DLL3-expressing cancer described herein, such as the method of E43 or E44, the first administration comprises 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, or 3.5 mg of the anti-DLL3 antigen-binding protein.

[0052] E46. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E43-E45, each of the second and subsequent administrations comprises 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 45 mg of the anti- DLL3 antigen-binding protein.

[0053] E47. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E43-E46, the first administration comprises 1 mg, the second administration comprises 10 mg, 15 mg, 22.5 mg, 30 mg, 35 mg, 40 mg, or 45 mg and each of the one or more subsequent administrations comprises 10 mg, 15 mg, 22.5 mg, 30 mg, 35 mg, 40 mg, or 45 mg of the anti-DLL3 antigen-binding protein.

[0054] E48. In a method of treating a DLL3-expressing cancer described herein, such as the method of any one of E43-E47, the anti-DLL3 antigen-binding protein is tarlatamab.

[0055] E49. A method of treating a small cell lung cancer (SCLC) is provided herein.The method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22.Amgen Ref. No. 10990-W001-SEC

[0056] E50. In a method of treating a small cell lung cancer described herein, such as the method of E49, the method comprises administering 10 mg or 15 mg of the anti-DLL3 antigen-binding protein to the subject once every two weeks (Q2W).

[0057] E51 . In a method of treating a small cell lung cancer described herein, such as the method of E49, the method comprises administering 15 mg to 35 mg of the anti-DLL3 antigen-binding protein to the subject once every three weeks (Q3W).

[0058] E52. In a method of treating a small cell lung cancer described herein, such as the method of E49, the method comprises administering 30 mg to 50 mg of the anti-DLL3 antigen-binding protein to the subject once every four weeks (Q4W).

[0059] E53. In a method of treating a small cell lung cancer described herein, such as the method of any one of E49-E52, the anti-DLL3 antigen-binding protein comprises SEQ ID NO: 24 or SEQ ID NO: 47.BRIEF DESCRIPTION OF THE DRAWING(S)

[0060] FIG. 1 is a flow diagram showing the protocol for Parts 1 and 2 of the clinical study described in Example 1. 0 = cycle; D= day; N = Number of subjects; SC= subcutaneous; Q2W = every 2 weeks.

[0061] FIG. 2 is a flow diagram showing the protocol for the clinical study described in Example 1 including part 3 (alternative dosing). C = cycle; D= day; N = Number of subjects; SC= subcutaneous; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks.DETAILED DESCRIPTION

[0062] Provided herein is a method of treating a cancer that expresses delta-like ligand 3 (DLL3) via subcutaneous administration of an anti-DLL3 antigen-binding protein to a subject. DLL3 is a non-canonical Notch ligand expressed primarily during embryonic development that functions during somitogenesis (Kusumi et al., Meeh Dev 2001 ;100:141 - 4; Geffers et al. J Cell Biol 2007;178:465-76; Chapman et al., Hum Mol Genet 2011 ;20:905- 16; and Morimoto et al., Development 2012; 139:4365-73). Together with achaete-scuteAmgen Ref. No. 10990-W001-SEC complex homolog 1 , a transcription factor that regulates DLL3 expression, DLL3 is required for neuroendocrine differentiation and SCLC tumorigenesis (Saunders et al., Sci Transl Med 2015;7:302ra136; Sabari et al., Nat Rev Clin Oncol 2017;14:549-61 ; and Owen et al., J Hematol Oncol 2019; 12:61 .).

[0063] Subcutaneous (SC) administration of an anti-DLL3 antigen binding protein advantageously reduces or eliminates the need for hospitalization and improves patient convenience. Subcutaneous administration may also reduce adverse events associated with some intravenously (IV)-administered immunotherapeutics, including cytokine release syndrome (CRS) and neurotoxicity, by delaying and lowering maximum serum concentration (Cmax) of the anti-DLL3 antigen-binding protein (Ball et al. Mabs, 2023; 14(1 )). On the other hand, compared to IV administration, SC administration may carry a greater risk of immunogenicity (e.g., production of anti-drug antibodies) of an anti-DLL3 antigen binding protein such as those disclosed herein, which could negatively impact the efficacy of the protein (Ball et al., Mabs, 2023; 14(1)).Anti-DLL3 Antigen-Binding Proteins

[0064] In some aspects, the disclosed method comprises administering an anti-DLL3 antigen-binding protein to a subject in need thereof. The term “antigen-binding protein,” as used herein, refers to a proteinaceous molecule that specifically binds to an antigen. For example, an antigen-binding protein may comprise an antibody or an antigen-binding fragment thereof, (such as a monoclonal antibody, for example an IgG 1 or lgG2 monoclonal antibody), an antibody protein product, a bispecific T cell engager (BiTE®) molecule, a bispecific antibody, a trispecific antibody, or an Fc fusion protein.

[0065] An antigen-binding protein typically comprises the heavy chain variable region (VH) and / or the light chain variable region (VL) of an antibody, or comprises domains derived therefrom. In some embodiments, an antigen-binding protein comprises the structural requirements of an antibody which are sufficient for immunospecific target binding. This structural requirement may be defined by, for example, the presence of atAmgen Ref. No. 10990-W001-SEC least three light chain complementarity determining regions (CDRs) (i.e., CDR1 , CDR2, and CDR3 of the VL region) and / or three heavy chain CDRs (i.e., CDR1 , CDR2, and CDR3 of the VH region), or of all six CDRs.

[0066] As used herein, the term “antibody” refers to an immunoglobulin of any isotype with specific bindingto the target antigen; an antibody may be a polyclonal or monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, etc. In a native antibody, a heavy chain comprises a variable region, VH, and three constant regions, CH1 , CH2, and CH3. The VH domain is at the amino-terminus of the heavy chain, and the CH3 domain is atthe carboxy-terminus. In a native antibody, a light chain comprises a variable region, VL, and a constant region, CL. The variable region of the light chain is at the aminoterminus of the light chain. In a native antibody, the variable regions of each light / heavy chain pair typically form the antigen-binding site. The constant regions are typically responsible for effector function. A native antibody is a tetramer of two full-length heavy chains and two full-length light chains.

[0067] In a human antibody, CH1 means a region havingthe amino acid sequence at positions 118 to 215 of the EU index or EU numbering system, which is based on the sequential numbering of the first human IgG 1 sequenced (i.e., the “EU antibody”) (Edelman et al., Proc Natl Acad Sci USA, 63(1): 78-85 (1969)). A highly flexible amino acid region called a “hinge region” exists between CH1 and CH2. CH2 represents a region having the amino acid sequence at positions 231 to 340 of the EU index, and CH3 represents a region having the amino acid sequence at positions 341 to 446 of the EU index.

[0068] “CL” represents a constant region of a light chain. In the case of a kappa (K) chain of a human antibody, CL represents a region havingthe amino acid sequence at positions 108 to 214 of the EU index. In a lambda (A) chain, CL represents a region having the amino acid sequence at positions 108 to 215.

[0069] In a native antibody, the variable regions typically exhibit the same general structure in which relatively conserved framework regions (FRs) are joined by threeAmgen Ref. No. 10990-W001-SEC hypervariable CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From N-terminus to C- terminus, both light and heavy chain variable regions typically comprise the domains FR1 , CDR1 , FR2, CDR2, FR3, CDR3 and FR4. Typically, CDR3 is the greatest source of molecular diversity within the antigen binding site. The assignment of amino acids to each domain is typically in accordance with the definitions of Kabat et al. (1991 ) Sequences of Proteins of Immunological Interest (National Institutes of Health, Publication No. 91-3242, vols. 1-3, Bethesda, Nd.); or Chothia, C., and Lesk, A. M. (1987) J. Mol. Biol., 196: 901 -917. In some embodiments, the CDRs of an antigen-binding protein are defined accordingto the definition of Kabat or Chothia. In the present application, the term “CDR” refers to a CDR from either the light or heavy chain, unless otherwise specified.

[0070] The human DLL3 protein has an extracellular region comprising several domains: a signal peptide, an N-terminus domain, a Delta / Serrate / LAG-2 (DSL) domain, six epidermal growth factor (EGF)-like repeats (i.e., EGF-1 , EGF-2, EGF-3, EGF-4, EGF-5, and EGF-6), and a membrane proximal domain. The DLL3 C-terminus comprises the transmembrane domain. Alternative splicing of the gene encoding DLL3 produces two isoforms of the protein, which differ at the C-terminus but are identical in the extracellular region. The canonical DLL3 isoform is a 619 amino acid protein, the sequence of which is provided herein as SEQ ID NO: 1 and is disclosed in UniProt Q9NYJ7 and NCBI Reference Sequence: NP_058637.1 . The amino acid sequence of the human DLL3 extracellular region comprises SEQ ID NO: 2, and the specific domains of the extracellular region may be defined by the amino acid positions shown in Table 1 .Amgen Ref. No. 10990-W001-SECTable 1

[0071] An exemplary anti-DLL3 antigen-binding protein is a BiTE® (bispecific T cell engager) molecule. BiTE® molecules are recombinant protein constructs made from two flexibly linked binding domains, each domain derived from antibodies. Antigen-binding domains retain the ability to specifically bind to an antigen (preferably with substantially the same binding affinity). Examples of an antigen-binding domains include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab’)2fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; and (v) a dAb fragment (Ward et al., Nature 341 :544-546 (1989)), which consists of a VH domain. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linkerthat enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. ScienceAmgen Ref. No. 10990-W001-SEC242:423-426 (1988) and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988). One binding domain of BiTE® molecule is specific for a tumor-associated surface antigen (such as DLL3); the second binding domain is specific for CD3, a subunit of the T cell receptor complex on T cells. By their design, BiTE® molecules are uniquely suited to transiently connect T cells with target cells and, at the same time, potently activate the inherent cytolytic potential of T cells against target cells. See e.g., International Patent Publication Nos. WO 99 / 54440, WO 2005 / 040220, and WO 2008 / 119567, each of which is incorporated by reference in its entirety.

[0072] In some aspects of the method, the anti-DLL3 antigen-binding protein comprises a first binding domain that binds to human DLL3 on the surface of a target cell and a second binding domain that binds to human CD3 on the surface of a T cell. The anti- DLL3 antigen binding-protein described herein may bind to any domain of the extracellular region defined herein. In some aspects, the first domain of the anti-DLL3 antigen-binding protein binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 2. In other aspects, the first domain of the anti-DLL3 antigen-binding protein binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 3. For example, the first domain of the anti-DLL3 antigen-binding protein binds to an epitope of DLL3 comprised within the amino acid sequence of SEQ ID NO: 4.

[0073] The term “epitope” refers to any polypeptide determinant capable of specifically bindingto an immunoglobulin, a T cell or B cell receptor, or any interacting protein, such as a surface protein. In certain embodiments, an epitope is a region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope may have specific three-dimensional structural characteristics (e.g., a “conformational” epitope) and / or specific charge characteristics. Conversely, the term “paratope,” as used herein, refers to the region of an antibody that recognizes and binds to an epitope of an antigen.Amgen Ref. No. 10990-W001-SECParatopes primarily, but not exclusively, are located in the CDRs (Kunik et al., PLoS Comput Biol 8(2): e1002388 (2012). doi.org / 10.1371 / journal.pcbi.1002388).

[0074] The CDRs of exemplary DLL3-binding domains and CD3-binding domains are provided in Table 7. The CDRs can be defined according to Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any method of CDR determination well known in the art. See, e.g., Kabat et al., 1991 , Sequences of Proteins of Immunological Interest, 5thed. (hypervariable regions); Chothia et aL, 1989, Nature 342:877-883 (structural loop structures). AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular’s AbM antibody modeling software (Accelrys®). The identity of the amino acid residues in a particular antibody that make up a CDR can be determined using methods well known in the art.

[0075] In certain embodiments, the DLL3-binding domain of the anti-DLL3 antigenbinding protein comprises (a) a heavy chain variable region (VH) that comprises (i) a VH complementarity determining region one (CDR-H1 ) comprising the amino acid sequence of SEQ ID NO: 5, (ii) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 6, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 7; and (b) a light chain variable region (VL) that comprises (i) a VL complementarity determining region one (CDR- L1) comprising the amino acid sequence of SEQ ID NO: 8, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.

[0076] In certain embodiments, the DLL3-binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO: 11 , and a VL that comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the VH and VL are joined by a linker to form a single chain Fv (scFv). Linkers are known in the art and further described in, e.g., WO2017 / 021349, hereby incorporated by reference in its entirety. In certain embodiments, the DLL3 binding domain comprises the amino acid sequence of SEQ ID NO: 13Amgen Ref. No. 10990-W001-SEC

[0077] In various aspects, the CD3-binding domain of the anti-DLL3 antigen-binding protein comprises (a) a VH that comprises (i) a CDR-H1 comprisingthe amino acid sequence of SEQ ID NO: 14, (ii) a CDR-H2 comprisingthe amino acid sequence of SEQ ID NO: 15, and (iii) a CDR-H3 comprisingthe amino acid sequence of SEQ ID NO: 16; and a VL that comprises (i) a CDR-L1 comprisingthe amino acid sequence of SEQ ID NO: 17, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (iii) a CDR-L3 comprisingthe amino acid sequence of SEQ ID NO: 19.

[0078] In certain embodiments, the CD3-binding domain comprises a VH that comprises the amino acid sequence of SEQ ID NO: 20, and a VL that comprises the amino acid sequence of SEQ ID NO: 21 . In some embodiments, the VH and VL are joined by a linkerto form a single chain Fv (scFv). In some embodiments, the linker is a peptide linker. In certain embodiments, the CD3-binding domain comprises the amino acid sequence of SEQ ID NO: 22. In some aspects, the anti-DLL3 antigen-binding protein described herein comprises the amino acid sequence of SEQ ID NO: 23.

[0079] In certain aspects, in addition to the DLL3-binding domain and the CD3-binding domain, the anti-DLL3 antigen-binding protein described herein comprises a third domain which comprises an Fc domain (or 2 Fc domains). Preferably, the Fc domain amino acid sequence(s) are positioned C-terminal of the first and second binding domains, through other arrangements (for example, Fc domain(s) sequences that are not C-terminal to the first binding domain and second binding domain) are also contemplated. For example, in certain embodiments, the third domain comprises two polypeptide monomers, each comprising a hinge, a CH2 domain, and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker. Preferably, the third domain comprises in an N- to C-terminal order: hinge-CH2-CH3-linker-hinge-CH2-CH3. It is appreciated that common C-terminal variants such as C-terminal lysine clipping may be present in constructs comprising Fc domains.

[0080] In various aspects, the anti-DLL3 antigen-binding protein is tarlatamab. As discussed herein, tarlatamab has been approved by the U.S. FDA underthe brand nameAmgen Ref. No. 10990-W001-SECIMDELLTRA®. The activity of tarlatamab requires the simultaneous binding to both target cells (DLL3+ cells) and T cells. The pharmacological effect of tarlatamab is mediated by specific redirection of previously primed cytotoxic CD8+ or CD4+ T lymphocytes to kill DLL3+ cells. Clinical evaluations of tarlatamab in earlier lines of SCLC (monotherapy and combination therapy) and neuroendocrine prostate cancer are ongoing (see, e.g., ClinicalTrials.gov Identifiers NCT03319940 and NCT04702737 and Owonikoko et al., Journal of Clinical Oncology 39:15_suppl, 8510-8510 (2021 )). Tarlatamab is described in detail in, for example, WO 2017 / 021349 and WO 2021 / 092134. Tarlatamab comprises the amino acid sequence of SEQ ID NO: 24. In some aspects, the anti-DLL3 antigen-binding protein may be a C-terminal lysine-clipped version of tarlatamab, an example of which comprises the amino acid sequence of SEQ ID NO: 47.

[0081] In other aspects of the disclosure, the anti-DLL3 antigen-binding protein is a single chain polypeptide comprising one or more scFvs fused to one or more single domain monoclonal antibodies (sdmAb). Optionally, the scFv-sdmAb format may comprise a domain that serves to extend the half-life of the protein. In this regard, the anti-DLL3 antigen-binding protein may comprise, from N to C terminus, an scFv that binds CD3, a linker peptide, a sdmAb that binds serum albumin, a peptide linker, and a sdmAb that binds DLL3. The disclosure contemplates an anti-DLL3 antigen-binding protein comprising the amino acid sequence of SEQ ID NO: 25. An alternate format comprises, from N- to C- terminus, a sdmAb that binds DLL3, a peptide linker, a sdmAb that binds serum albumin, a peptide linker, and an scFv that binds CD3. An example of such an anti-DLL3 antigenbinding protein comprises the amino acid sequence of SEQ ID NO: 26. Anti-DLL3 antigenbinding proteins comprising these formats are further described in, e.g., International Patent Publication No. WO 2020 / 069028, incorporated by reference in its entirety and particularly with respect to disclosure relatingto anti-DLL3 antigen-binding proteins and associated amino acid sequences.

[0082] The anti-DLL3 antigen-binding protein of the method also may take the form of a traditional bispecific IgG-like antibody, wherein one arm binds DLL3 and the second armAmgen Ref. No. 10990-W001-SEC binds CD3. In various aspects, the antibody construct comprises two arms comprising, from N- to C- terminus, a VL domain, a CL domain, a peptide linker, a VH domain, a CH1 domain, a peptide linker, and an Fc domain (scFab-Fc). In various aspects, the a nti- DLL3 antigen-binding protein disclosed herein comprises a first domain that binds to DLL3 (preferably human DLL3) and comprises (a) a heavy chain variable region (VH) that comprises (i) a VH complementarity determining region one (CDR-H1 ) comprising the amino acid sequence of SEQ ID NO: 27, (ii) a CDR-H2 comprisingthe amino acid sequence of SEQ ID NO: 28, and (iii) a CDR-H3 comprisingthe amino acid sequence of SEQ ID NO: 29; and (b) a light chain variable region (VL) that comprises (i) a VL complementarity determining region one (CDR-L1 ) comprisingthe amino acid sequence of SEQ ID NO: 30, (ii) a CDR-L2 comprisingthe amino acid sequence of SEQ ID NO: 31 , and (iii) a CDR-L3 comprisingthe amino acid sequence of SEQ ID NO: 32. Optionally, the first domain binds DLL3 and comprises a VH region comprisingthe amino acid sequence of SEQ ID NO: 33 and a VL region comprisingthe amino acid sequence of SEQ ID NO: 34. In various aspects, the DLL3 binding region of the antigen-binding protein comprises SEQ ID NO: 35. The second domain binds to CD3 (preferably human CD3), and comprises (a) a VH that comprises (i) a CDR-H1 comprisingthe amino acid sequence of SEQ ID NO: 37, (ii) a CDR- H2 comprisingthe amino acid sequence of SEQ ID NO: 38, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 39; and (b) a VL that comprises (i) a CDR-L1 comprisingthe amino acid sequence of SEQ ID NO: 40, (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41 , and (iii) a CDR-L3 comprisingthe amino acid sequence of SEQ ID NO: 42. Optionally, the second domain binds CD3 and comprises a VH region comprisingthe amino acid sequence of SEQ ID NO: 43 and a VL region comprisingthe amino acid sequence of SEQ ID NO: 44. In various aspects, the CD3 binding region of the antigen-binding protein comprises SEQ ID NO: 45. The anti-DLL3 antigen-binding protein optionally comprises the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46. Anti-DLL3 antigen-binding proteins are further described in, e.g., International Patent Publication No. WO 2019 / 234220, incorporated by reference inAmgen Ref. No. 10990-W001-SEC its entirety and particularly with respect to disclosure relatingto anti-DLL3 antigen-binding proteins and associated amino acid sequences.

[0083] Thus, in some aspects, the disclosure provides a method of treating a DLL3- expressing cancer comprising subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof, wherein the anti-DLL3 antigen-binding protein comprises a first domain that binds to DLL3 and comprises (a) a heavy chain variable region (VH) that comprises (i) a CDR-H1 comprisingthe amino acid sequence of SEQ ID NO: 27, (ii) a CDR-H2 comprisingthe amino acid sequence of SEQ ID NO: 28, and (iii) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 29; and (b) a light chain variable region (VL) that comprises (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 30, (ii) a CDR-L2 comprisingthe amino acid sequence of SEQ ID NO: 31 , and (iii) a CDR-L3 comprisingthe amino acid sequence of SEQ ID NO: 32, and a second domain that binds to CD3 and comprises (a) a VH that comprises (i) a CDR-H1 comprisingthe amino acid sequence of SEQ ID NO: 37, (ii) a CDR-H2 comprisingthe amino acid sequence of SEQ ID NO: 38, and (iii) a CDR-H3 comprisingthe amino acid sequence of SEQ ID NO: 39; and (b) a VLthat comprises (i) a CDR-L1 comprisingthe amino acid sequence of SEQ ID NO: 40, (ii) a CDR-L2 comprisingthe amino acid sequence of SEQ ID NO: 41 , and (iii) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some aspects, the method may comprise administering the anti-DLL3 antigen-binding protein accordingto a regimen comprising (1 ) a first administration of about 0.5 mg to about 5 mg (e.g., 1 mg) on day 1 ; (2) a second administration of about 5 mgto about 60 mg on day 8 (e.g., 10 mg or 15 mg); and (3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter (Q2W). In various aspects, the method may comprise administering the anti-DLL3 antigen-binding protein accordingto a regimen comprising (1 ) a first administration of about 0.5 mgto about 5 mg (e.g., 1 mg) on day 1 ; (2) a second administration of about 5 mgto about 60 mg (e.g., 22.5 mg or 30 mg) on day 8; and (3) one or more subsequent administrations beginning on day 22 and once every three weeks thereafter (Q3W). In other aspects, the method may comprise administering the anti-DLL3 antigen-binding protein according to a regimen comprising (1 ) a first administration ofAmgen Ref. No. 10990-W001-SEC about 0.5 mg to about 5 mg (e.g., 1 mg) on day 1 ; (2) a second administration of about 5 mg to about 60 mg (e.g., 45 mg) on day 8; and (3) one or more subsequent administrations beginning on day 29 and once every four weeks thereafter (Q4W). In certain aspects, the anti-DLL3 antigen-binding protein may comprise the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46. In exemplary aspects, each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigenbinding protein in the first administration.Method of Treating Cancer

[0084] Provided herein is a method of treating a DLL3-expressing cancer, which comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof. For example, in some aspects, the method provided herein comprises administering an anti-DLL3 antigen-binding protein comprising the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22. In other aspects of the method, the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 23. In various aspects, the anti-DLL3 antigen-binding protein is tarlatamab, which comprises the amino acid sequence of SEQ ID NO: 24.

[0085] The term “subcutaneous (SC) administration,” as used herein, refers a method of delivering a therapeutic agent directly into the subcutaneous tissue, which is the layer of fat and connective tissue located below the dermis and epidermis layers of skin. Unlike muscle, subcutaneous tissue does not have a rich blood supply, and absorption of drugs delivered subcutaneously is therefore slower than via the intramuscular route (Dougherty and Lister, The Royal Marsden Manual of Clinical Nursing Procedures. Oxford: Wiley- Blackwell (2015)). Subcutaneous administration routes are more convenient for patients, as treatment sessions can occur completely or partially outside of a hospital. Moreover, as discussed above, subcutaneous administration may also reduce adverse events like cytokine release syndrome (CRS) and neurotoxicity. Subcutaneous administration isAmgen Ref. No. 10990-W001-SEC typically performed using a syringe and needle, an auto-injector, or infusion pump. In other embodiments, subcutaneous administration may be achieved using an implant. Subcutaneous implants are small, often pellet-like devices that are implanted under the skin and release a drug slowly over a long period, such as months or years. A variety of drugs, including numerous biological drugs, have been approved for subcutaneous administration, including but not limited to, hormones, opioid addiction treatments, and immunosuppressants, in various indications including inflammation and oncology, in particular.

[0086] In some aspects, the DLL3-expressing cancer is a neuroendocrine cancer (i.e., neuroendocrine neoplasm). In this regard, the DLL3-expressing cancer may be a pulmonary neuroendocrine cancer or an extrapulmonary neuroendocrine cancer. In various aspects of the disclosure, the subject is suffering from a pulmonary neuroendocrine cancer, such as small cell lung cancer (SCLC), examples of which include relapsed / refractory SCLC (RR SCLC), extensive stage SCLC (ES SCLC) (which may be relapsed or refractory), and limited-stage SCLC (LS-SCLC) (which may be relapsed or refractory). LS-SCLC often refers to SCLC cancers found only on one side of the chest (e.g., only in one lung), enabling treatment with a single radiation field. In various aspects of the disclosure, LS-SCLC has not progressed in the subject following concurrent chemoradiation therapy. ES SCLC includes cancers that have spread more widely throughout the lung and / or to the other lung, and often to other locations within the body. Relapsed SCLC include cancers which, e.g., reemerge within three months of a first line of treatment (e.g., chemotherapy and / or radiation).

[0087] In other aspects, the DLL3-expressing cancer is an extrapulmonary neuroendocrine cancer, such as glioma, glioblastoma, melanoma, prostate cancer such as neuroendocrine prostate cancer, neuroendocrine pancreatic cancer, hepatoblastoma, large cell pulmonary neuroendocrine cancer, pancreatic neuroendocrine cancer, bladder neuroendocrine cancer, gastric neuroendocrine cancer, adrenal exocrine tumors, Merkel cell carcinoma, neuroblastoma, head and neck carcinoid or neuroendocrine cancer, headAmgen Ref. No. 10990-W001-SEC and neck paraganglioma, or cervical small cell neuroendocrine cancer. In certain aspects, the extrapulmonary neuroendocrine cancer is neuroendocrine pancreatic cancer (NEPC).

[0088] In various aspects, the subject suffers from a DLL3-expressing cancer (e.g., SCLC) and has not received any prior line of cancer treatment. By “prior line of treatment” is meant a previous treatment with another anticancer therapeutic, e.g., a first- or second- line cancer therapy or standard of care therapy, before administration of the anti-DLL3 antigen-binding protein. For example, in some aspects, the disclosed method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject as a first- line therapy for cancer (e.g., SCLC). In other aspects, the subject suffers from a DLL3- expressing cancer (e.g., SCLC) which has not progressed or relapsed after one or more prior lines of treatment. In some aspects, for example, the subject has received a first-line cancer therapy, after which the subject’s disease has not progressed (defined as ongoing response or stable disease per Response Evaluation Criteria in Solid Tumors Version 1 .1 (RECIST 1 .1 )). In other aspects, the subject suffers from a DLL3-expressing cancer (e.g., SCLC) which has recurred after one or more prior lines of treatment in the subject, such as a SCLC recurrence aftertwo or more prior lines of treatment in the subject. For example, the subject has, in various aspects, received at least one, two, three, four, five, or six prior lines of treatment for the SCLC (or other DLL3-expressing cancer). In various aspects, at least one of the prior lines of treatment is a platinum-based chemotherapeutic.Alternatively or in addition, at least one of the prior lines of treatment is anti-PD1 antibody or anti-PD-L1 antibody therapy. For instance, the subject may have undergone a combination of therapies including platinum-based chemotherapy and anti-PD1 antibody or anti-PD-L1 antibody therapy. Where the subject has undergone prior lines of treatment, administration of the anti-DLL3 antigen-binding protein may occur at any timepoint following completion of the prior lines of treatment. For instance, the anti-DLL3 antigenbinding protein may be administered at least 28 days (e.g., at least 60 days or at least 90 days) after the completion of any prior lines of treatment for SCLC (or other DLL3-positive cancer).Amgen Ref. No. 10990-W001-SEC

[0089] Provided herein are methods of treating a DLL3-expressing cancer in a human subject comprising subcutaneously administering about 0.5 mg to about 60 mg of an anti- DLL3 antigen binding protein (e.g., tarlatamab) once every two weeks (also referred to as “Q2W”). In some aspects, the method comprises subcutaneously administeringthe anti- DLL3 antigen-binding protein in an amount ranging from about 0.5 mg to about 60 mg, about 0.5 mg to about 50 mg, 0.5 mg to about 40 mg, about 0.5 mg to about 30 mg, about 0.5 mgto about 20 mg, about 0.5 mgto about 10 mg, about 0.5 mg to about 5 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 60 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 25 mg, about 15 mgto about 20 mg, about 20 mg to about 60 mg, about 20 mg to about 50 mg, about 20 mg to about 40 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 40 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 45 mg, about 50 mg to about 60 mg, or about 50 mg to about 55 mg.

[0090] In certain aspects of the method provided herein, the anti-DLL3 antigen-binding protein (e.g., tarlatamab) is administered subcutaneously to the subject according to the following regimen: (1 ) a first administration of about 0.5 mg to about 5 mg (e.g., about 0.5 mg to about 3 mg) on day 1 , such as about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, or 4 mg; (2) a second administration of about 5 mgto about 60 mg on day 8, such as about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg; and (3) one or more subsequent administrations of about 5 mg to about 60 mg, such as about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg, beginning on day 15 and once every two weeks (Q2W) thereafter, wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.Amgen Ref. No. 10990-W001-SEC

[0091] In other aspects, the anti-DLL3 antigen binding protein (e.g., tarlatamab) is administered subcutaneously to the subject accordingto the following regimen: (1) a first administration of about 0.5 mgto about 5 mg (e.g., about 0.5 mg to about 3 mg) on day 1 , such as about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, or 4 mg; (2) a second administration of about 5 mgto about 60 mg (e.g., about 10 mgto about 40 mg) on day 8, such as about 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg; and (3) one or more subsequent administrations of about 5 mgto about 60 mg, such as about 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg, beginning on day 22 and once every three weeks (Q3W) thereafter, wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigenbinding protein in the first administration.

[0092] In some aspects, the anti-DLL3 antigen binding protein (e.g., tarlatamab) is administered subcutaneously to the subject accordingto the following regimen: (1) a first administration of about 0.5 mgto about 5 mg (e.g., about 0.5 mg to about 3 mg) on day 1 , such as about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, or 4 mg; (2) a second administration of about 5 mgto about 60 mg (e.g., about 10 mgto about 50 mg) on day 8, such as about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg; and (3) one or more subsequent administrations of about 5 mg to about 60 mg, such as about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg, beginning on day 29 and once every four weeks (Q4W) thereafter, wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greaterthan the amount of anti-DLL3 antigen-binding protein in the first administration.

[0093] As used herein, the terms “first administration,” “second administration,” and “subsequent administration(s)” define the individual amount of the anti-DLL3 antigenbinding protein that is administered at a given point in time.Amgen Ref. No. 10990-W001-SEC

[0094] The anti-DLL3 antigen-binding protein (e.g., tarlatamab) may be administered to the subject in accordance with a treatment regimen that involves cycles of periodic administration of the anti-DLL3 antigen-binding protein to the subject. A cycle may comprise any appropriate period of time, and multiple cycles may be employed which entail different frequency of administration and / or different quantities administered. In some aspects, one cycle in the course of treatment comprises administeringthe anti-DLL3 antigen-binding protein once every two weeks (or “Q2W”); however, other cycles with different dosing regimens may be part of the overall course of treatment. In one example, repeated administrations of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) are administered over the course of one or multiple 21 -day or 28-day cycles. For example, in some aspects, the first, second, and subsequent administrations of the anti-DLL3 antigenbinding protein are administered over the course of multiple 21 -day or 28-day cycles.

[0095] A first cycle may be employed to offer a “step dose” of the antigen-binding protein, which refers to an initial quantity of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) that is lower than the ultimate target quantity of the anti-DLL3 antigen-binding protein. A “step-up” dosing regimen may include one or more quantities of the anti-DLL3 antigen-binding protein that increase to reach a target quantity, It is believed that incrementally increasing the dose of T cell engager molecules administered to a patient before reaching the target dose level allows for priming of a subject’s immune system in a more gradual manner, thereby modulating the balance between T cell activation and expansion, and cytokine-mediated efficacy and toxicity.

[0096] In some aspects, the method provided herein comprises a first administration or step dose of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) of about 0.5 mg to about 5 mg, such as about 0.5 mg to about 3 mg, on day 1 of a 21 -day or 28-day cycle. For example, the first administration may comprise about 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, or 3.5 mg of the anti-DLL3 antigen-binding protein. In some aspects, the first administration comprises about 1 mg of the anti-DLL3 antigen-binding protein on day 1 of a 21 -day or 28- day cycle. In certain aspects, the method further comprises second and subsequentAmgen Ref. No. 10990-W001-SEC administrations of the anti-DLL3 antigen-binding protein that contain a target quantity of the anti-DLL3 antigen-binding protein. A “target” quantity, dose, or administration of an anti-DLL3 antigen-binding protein refers to a quantity that achieves a desired effect (e.g., ameliorating or reducing the severity of SCLC or other DLL3-expressing cancer, or shortening the length of the SCLC or other DLL3-expressing cancer). In certain aspects, each of the second and subsequent administrations of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration. For example, each of the second and subsequent administrations of the anti-DLL3 antigen binding protein are the same and at least 1 .5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 25- fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 55-fold, at least 60-fold, at least 65-fold, at least 70-fold, at least 75-fold, at least 80-fold, at least 85-fold, at least 90-fold, at least 95-fold, at least 10O-fold, or at least 120-fold, at least 150-fold, or at least 200-fold higher than the first administration. In certain aspects, the second and subsequent administrations of the anti-DLL3 antigen-binding protein may be 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 30-fold, or 40-fold greater than the first administration.

[0097] In various aspects, a quantity of anti-DLL3 antigen-binding protein (e.g., tarlatamab) is chosen for the second and subsequent administrations that achieves exposures similar to the pharmacokinetics (PK) parameters of the anti-DLL3 antigenbinding protein following intravenous (IV) administration. Exemplary PK parameters for the anti-DLL3 antigen-binding protein following intravenous administration include, but are not limited to, concentration in the bloodstream immediately prior to administration of the next dose (which may be referred to “Ctrough” or “Cmin”), and area under the concentrationtime curve (AUC) over a dosing interval. In some aspects, the second and subsequent administrations achieve a Ctraugh, that, on average, corresponds to the Ctrough achieved by an intravenous (IV) administration of the anti-DLL3 antigen-binding protein. In certain aspects, the second and subsequent administrations achieve a Ctrough, that, on average,Amgen Ref. No. 10990-W001-SEC corresponds to the CtrOugh achieved by an IV administration of 10 mg of the anti-DLL3 antigen-binding protein, such as tarlatamab. Exemplary PK parameters for the recommended IV dosage of IMDELLTRA® (tarlatamab-dlle) are shown in Table 2. In certain aspects where the anti-DLL3 antigen-binding protein is tarlatamab, the second and subsequent administrations of tarlatamab desirably achieve a Ctrough, that, on average, corresponds to the Ctrough achieved by the steady state IV administration of 10 mg tarlatamab every two weeks shown in Table 2.Table 2. Pharmacokinetic Parameters of Tarlatamab-dlle Following IV administration

[0098] In certain aspects of the method, each of the second and subsequent administrations of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) may comprise about 5 mgto about 60 mg of the anti-DLL3 antigen-binding protein. Thus, in some aspects, each of the second and subsequent administrations comprises the anti-DLL3 antigen-binding protein in an amount ranging from about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mgto about 40 mg, about 5 mgto about 30 mg, about 5 mgto about 20 mg, about 5 mgto about 10 mg, about 10 mgto about 60 mg, about 10 mgto about 55 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mgto about 25 mg, about 10 mg to about 15 mg, about 20 mg to about 60 mg, about 20 mg to about 55 mg, about 20 mg to about 50 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 30 mg to about 60 mg, about 30 mg to about 50 mg, about 30 mg toAmgen Ref. No. 10990-W001-SEC about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, or about 50 mg to about 55 mg. For example, each of the second and subsequent administrations may comprise about 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of the anti-DLL3 antigen-binding protein. In certain aspects, the second administration comprises about 10 mg, about 15 mg, about 20 mg, about 22.5 mg, about 30 mg, about 40 mg, or about 45 mg of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) and is administered to the subject on day 8 of a 21 -day or 28 day cycle. In additional aspects, the method comprises one or more subsequent subcutaneous administrations beginning on day 15 and once every two weeks thereafter (Q2W), each comprising about 10 mg or 15 mg of the anti-DLL3 antigen-binding protein. In other aspects, the method comprises one or more subsequent subcutaneous administrations beginning on day 22 and once every three weeks thereafter (Q3W), each comprising about from about 15 mg to about 35 mg (e.g., 22.5 mg or 30 mg) of the anti-DLL3 antigen-binding protein. In some aspects, the method comprises one or more subsequent subcutaneous administrations beginning on day 29 and once every four weeks thereafter (Q4W), each comprising from about 30 mg to about 50 mg (e.g., 30 mg or 45 mg) of the anti-DLL3 antigen-binding protein.

[0099] As merely an example, the method comprises subcutaneously administering an anti-DLL3 antigen-binding protein (e.g., tarlatamab) to the subject according to the following regimen: a first administration comprising about 1 mg on day 1 , a second administration comprising about 10 mg or 15 mg on day 8, a subsequent administration comprising about 10 mg or 15 mg of the anti-DLL3 antigen-binding protein on day 15 of a first 28-day cycle, after which 10 mg or 15 mg of the anti-DLL3 antigen-binding is administered once every two weeks (Q2W) in one or more additional 28-day cycles. As a further example, the disclosure provides a method of treating a DLL3-expressing cancer, which method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 10 mg on day 8; (3) a subsequent administration of 10 mg on day 15, and (4) one or more further subsequent administrationsAmgen Ref. No. 10990-W001-SEC of 10 mg once every two weeks thereafter (Q2W). Alternatively, in another example, the disclosure provides a method of treating a DLL3-expressing cancer, which method comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 15 mg on day 8; (3) a subsequent administration of 15 mg on day 15, and (4) one or more further subsequent administrations of 15 mg once every two weeks thereafter (Q2W).

[0100] In another exemplary embodiment, the method comprises subcutaneously administering an anti-DLL3 antigen-binding protein (e.g., tarlatamab) to the subject according to the following regimen: a first administration comprising about 0.5 mg to about 3 mg on day 1 , a second administration comprising about 15 mg to about 35 mg on day 8 of a first 21-day cycle, a subsequent administration comprising about 15 mgto about 35 mg of the anti-DLL3 antigen-binding protein on day 22 of a second 21 -day cycle, after which about 15 mgto about 35 mg of the anti-DLL3 antigen-binding is administered once every three weeks (Q3W) in one or more additional 21 -day cycles. Alternatively, in another example, the disclosure provides a method of treating a DLL3-expressing cancer, which method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 30 mg on day 8 of a first 21-day cycle; (3) a subsequent administration of 30 mg on day 22 of a second 21-day cycle, and (4) one or more further subsequent administrations of 30 mg once every three weeks thereafter (Q3W). In yet a further example, in some aspects, the disclosure provides a method of treating a DLL3- expressing cancer, which method comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 22.5 mg on day 8 of a first 21-day cycle; (3) a subsequent administration of 22.5 mg on day 22 of a second 21 -day cycle, and (4) one or more further subsequent administrations of 22.5 mg once every three weeks thereafter (Q3W).Amgen Ref. No. 10990-W001-SEC

[0101] In another exemplary embodiment, the method comprises subcutaneously administering an anti-DLL3 antigen-binding protein (e.g., tarlatamab) to the subject according to the following regimen: a first administration comprising about 0.5 mg to about 3 mg on day 1 , a second administration comprising about 30 mg to about 50 mg on day 8 of a first 28-day cycle, a subsequent administration comprising about 30 mgto about 50 mg of the anti-DLL3 antigen-binding protein on day 29 of a second 28-day cycle, after which about 30 mg to about 50 mg of the anti-DLL3 antigen-binding is administered once every four weeks (Q4W) in one or more additional 28-day cycles. As a further example, the disclosure provides a method of treating a DLL3-expressing cancer, which method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 45 mg on day 8 of a first 28-day cycle; (3) a subsequent administration of 45 mg on day 29 of a second 28-day cycle, and (4) one or more further subsequent administrations of 45 mg once every four weeks thereafter (Q4W). In yet a further example, in some aspects, the disclosure provides a method of treating a DLL3- expressing cancer, which method comprises administering tarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 30 mg on day 8 of a first 28- day cycle; (3) a subsequent administration of 30 mg on day 29 of a second 28-day cycle, and (4) one or more further subsequent administrations of 30 mg once every four weeks thereafter (Q4W).

[0102] In certain aspects where the anti-DLL3-antigen-binding protein comprising the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46, the method provided herein comprises subcutaneously administering the anti-DLL3-antigen- binding protein to a subject (e.g., human) with a DLL3-expressing cancer once weekly (QW) or once every three weeks (Q3W), optionally with a step-dose in the first cycle where the anti-DLL3 antigen-binding protein is administered. In certain embodiments, the method comprises subcutaneously administering at least about 90 mg / kg (e.g., 100 mg / kg, 120 mg / kg, 150 mg / kg, or 200 mg / kg) of the anti-DLL3-antigen-binding protein (e.g., a moleculeAmgen Ref. No. 10990-W001-SEC comprisingthe amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46) QW or Q3W to the subject. In certain embodiments, the method comprises subcutaneously administering the anti-DLL3 antigen-binding protein (e.g., a molecule comprisingthe amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46) QW in an amount that achieves a Ctrough corresponding to, on average, the Ctrough achieved by the steady state IV administration of about 90 mg / kg once every week. In certain embodiments, the method comprises subcutaneously administeringthe anti- DLL3-antigen-binding protein (e.g., a molecule comprisingthe amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46) Q3W in an amountthat achieves a Ctrough corresponding to, on average, the Ctrough achieved by the steady state IV administration of about 90 mg / kg once every three weeks. In various exemplary embodiments where the anti-DLL3 antigen-binding protein comprising the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46, the DLL3- expressing cancer is SCLC, large cell neuroendocrine carcinoma of the lung (LCNEC), or extrapulmonary neuroendocrine carcinomas.

[0103] Due to the risk of CRS and neurotoxicity, in various embodiments, the method comprises hospitalizing and monitoringthe subject for up to about 48 hours (e.g., about 24 hours, 22 hours, 12 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour) after the administration of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) on day 1 and day 8 of cycle 1 (i.e., C1 D1 and C1 D8). In other aspects, subjects may not be monitored following administration of the anti-DLL3 antigen-binding protein. In certain embodiments, the method may comprise measuring the level of one or more cytokines in the subject’s blood or serum, such as IL-6, IL-8, IL-10, TNF-a, and IFN-g, after the administration of the anti-DLL3 antigen-binding protein (e.g., tarlatamab) in cycle 1 and hospitalizing and monitoring the subject for up to about 48 hours (e.g., about 24 hours, 12 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour) if any of the level of any of the cytokines is above a normal reference level. In other aspects, subjects may be monitored for up to 10 hours following all subcutaneous administrations of theAmgen Ref. No. 10990-W001-SEC a nti-DLL3-a ntige n-bin di ng protein in cycle 2. The cytokines can be measured or tested using methods known in the art.

[0104] In various exemplary embodiments, the method comprises hospitalizing and continuously monitoring the subject after the administration of the anti-DLL3 antigenbinding protein (e.g., a molecule comprising the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 46), in particular in the first cycle when the binding protein is administered. For example, wearable devices may be provided to the subject after the administration for monitoring CRS and / or neurotoxicity events.Additional Therapeutic Agents

[0105] In some embodiments, the method provided herein further comprises the administration of one or more additional therapeutic agents to the subject. For example, in certain aspects, the method may comprise administration of the anti-DLL3 antigen-binding protein and at least one additional therapeutic agent to achieve a desired biological effect in a subject (i.e., as part of a “combination therapy”). In other aspects, one or more additional therapeutic agents may be administered to prevent, reduce, or mitigate the risk of adverse effects associated with the administration of the anti-DLL3 antigen-binding protein.

[0106] In some aspects, the at least one additional therapeutic agent may be a chemotherapeutic agent. Exemplary classes of chemotherapeutic agents include alkylating agents, antimetabolites, topoisomerase inhibitors, anti-tumor antibiotics, mitotic inhibitors, and protein kinase inhibitors. In certain embodiments, the chemotherapeutic agent is an alkylating agent. Alkylating agents include subgroups such as oxazaphosphorines, nitrogen mustards, imidazotetrazines, nitrosoureas, alkyl sulfonate, hydrazines, and platinum-based agents. In exemplary embodiments, the alkylating agent may be a platinum-based agent such as cisplatin, carboplatin, or oxaliplatin.Amgen Ref. No. 10990-W001-SEC

[0107] In some aspects of the disclosed method, the anti-DLL3 antigen-binding protein is administered in combination with an antagonist of the PD-1 / PD-L1 signaling pathway. Programmed Cell Death protein 1 (PD-1), also known as CD279, SLEB2, and hSLE1 , is a transmembrane protein expressed on activated T, natural killer (NK) and B lymphocytes, macrophages, dendritic cells (DCs) and monocytes. Notably, PD-1 is highly expressed on tumor-specific T cells (Han et al., Am J Cancer Res 10(3): 727-742 (2020)). PD-1 binds to B7 protein family members, PD-1 Ligand 1 (PD-L1 ; also referred to as CD279 and B7-H1) and PD-1 Ligand 2 (also known as PD-L2, CD273, and B7-DC). PD-L1 is constitutively expressed on T and B cells, macrophages and dendritic cells, whereas PD-L2 expression is typically restricted to activated DC and macrophages (Xing et al., Oncoimmunology 7(3): e1356144 (2017) (doi: 10.1080 / 2162402X.2017.1356144)). PD-1 inhibits both adaptive and innate immune responses. The PD-1 / PD-L1 axis is involved in the suppression of T cell immune responses in cancer. Antagonists of this pathway have been clinically validated across a number of solid tumor indications. PD-1 inhibitors, e.g., nivolumab, pembrolizumab, and cemiplimab, and PD-L1 inhibitors, e.g., atezolizumab, avelumab, and durvalumab, target the PD-1 / PD-L1 pathway, and each has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of various cancers. In various embodiments, agents targeting PD-L1 (e.g., PD-L1 blocking agent) can be used in methods disclosed herein to treat DLL3-expressing cancers. Exemplary agents targeting PD-L1 include anti-PD-L1 antibodies such as atezolizumab, avelumab, and durvalumab. In various aspects of the disclosure, the method comprises administering to the subject durvalumab. While any order of administration of the anti-DLL3 antigen-binding protein and the anti-PD1 antibody (or other PD1 antagonist) or anti-PD-L1 antibody (or other PD-L1 antagonist) is contemplated (prior to, concurrently, or after the administration), the anti- PD1 or anti-PD-L1 is administered before the anti-DLL3 antigen-binding protein in various aspects of the method. In certain aspects, the anti-DLL3 antigen-binding protein may be administered in combination with an antagonist of the PD-1 / PD-L1 signaling pathway and a platinum-based agent. In exemplary embodiments, the anti-DLL3 antigen-binding protein is administered in combination with an anti-PD-L1 antibody (e.g., atezolizumab orAmgen Ref. No. 10990-W001-SEC durvalumab) and optionally a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin).

[0108] A major adverse effect associated with the use of the anti-DLL3 antigen-binding protein is cytokine release syndrome (CRS). Therapeutic agents useful for preventing, reducing, or mitigatingthe risk of CRS include, but are not limited to, corticosteroids (e.g., dexamethasone), fluid (e.g., saline), etanercept (e.g., ENBREL™), and an a nti-l L6 antibody (e.g., tocilizumab or siltuximab). In some aspects of the method, dexamethasone is administered (oral or IV) priorto administration of the anti-DLL3 antigen-binding protein on day 1 and day 8 of the first cycle. An exemplary dose of dexamethasone comprises about 8 mg / administration (maximum of 24 mg / day). An a nti-l L6 antibody (e.g., tocilizumab or siltuximab) may be administered as needed. An exemplary dose of tocilizumab comprises about 4-8 mg / kg, which can be repeated for an additional three administrations with an at least 8-hour interval between doses. Symptoms of CRS include fever, nausea, fatigue, headache, myalgias, malaise, and therapeutic agents useful for treating such these symptoms (e.g., paracetamol / acetaminophen for fever) may also be used.

[0109] The anti-DLL3 antigen-binding protein may also be part of a therapeutic regimen that comprises administration of a chemotherapeutic agent to the subject. Examples of chemotherapeutic agents include, but are not limited to, amrubicin, altretamine, amsacrine, L-asparaginase, colaspase, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytophosphane, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fluorouracil, fludarabine, fotemustine, ganciclovir, gemcitabine, hydroxyurea, idarubicin, ifosfamaide, irinotecan, lomustine, lurbinectedin, melphalan, mercaptopurine, methotrexate, mitoxantrone, mitomycin C, nimustine, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raltitrexed, temozolomide, teniposide, tioguanine, thiotepa, topotecan, vinblastine, vincristine, vindesine, and vinorelbine.Amgen Ref. No. 10990-W001-SECDLL3 Expression

[0110] For any of the methods of treating a DLL3-expressing cancer (e.g., SCLC, NEPC) described herein, the cancer cells desirably express DLL3 on the cell surface. In other embodiments, the cancer cells express DLL3 on the cell surface and in the cytoplasm. In some aspects, cell surface expression and intercellular expression of DLL3 protein may be determined by immunohistochemistry (IHC) or positron emission tomography (PET). Any suitable IHC assay for determining DLL3 protein expression may be used in connection with the present disclosure. Desirably, the IHC assay is approved by a regulatory agency, such as the U.S. Food and Drug Association (FDA) or an agency that has CE-IVD registration authority. DLL3-specific IHC assays, and components thereof, are known in the art and commercially available from a variety of sources. For example, DLL3 expression in cancer or tumor cells may be detected using the VENTANA® DLL3 (SP347) Assay (Roche Diagnostics, GmbH, Mannheim, Germany). Other anti-DLL3 antibodies that may be used to detect DLL3 expression in an IHC assay include, but are not limited to, NBP2-24669 (Novus Biological, Littleton, CO); PA5-26336 (Thermo Fisher Scientific, Waltham, MA); and ab229902 (Abeam, Cambridge, MA).

[0111] In other embodiments, DLL3 gene expression in cancer cells may be determined. Methods for detecting and quantifying gene expression (e.g., mRNA levels) are known in the art and can be used in the context of the present disclosure. Such methods include, for example, flow cytometry-based methods polymerase chain reaction (PCR) analysis, sequencing analysis (e.g., RNA sequencing), electrophoretic analysis, restriction fragment length polymorphism (RFLP) analysis, Northern blot analysis, quantitative PCR, reverse-transcriptase-PCR analysis (RT-PCR), and the like.

[0112] In some embodiments, at least 5% (e.g., 5%, 10%, or 20%) of the cells of a cancer may be positive for DLL3 as determined by IHC. The amount of DLL3-positive cancer cells in a sample obtained from a subject may be expressed in terms of the tumor proportion score (TPS). The “tumor proportion score” is the percentage of viable cancer or tumor cells showing partial or complete membrane and cytoplasmic stainingfor DLL3. InAmgen Ref. No. 10990-W001-SEC some embodiments, at least 25% (e.g., 30%, 35%, 40%, or 45%) of the cancer cells in a subject, or in a cancer sample obtained from a subject, express DLL3 (25% TPS). In certain embodiments, at least 50% (e.g., 55%, 60%, 65%, 70%, 80%, 90%, 99%, or 100%) of the cancer cells in a subject, or in an cancer sample obtained from a subject, express DLL3 (50% TPS). For example, at least 75% (e.g., 85%, 95%, or 100%) of the SCLC cells in a subject, or in an SCLC sample obtained from a subject, expresses DLL3 (75% TPS). Viable cancer or tumor cells refer to cancer or tumor cells with normal morphology and the intact nuclei (e.g., absence of nuclear blebbing) and are a qualitative assessment routinely performed by a person of ordinary skill in the art, e.g., a pathologist. In certain embodiments, a viable cancer or tumor cell is determined by a pathologist.

[0113] The level of DLL3 expression by IHC may also be determined by giving a tumor sample an IHC score based on DLL3-positive signal intensity. In some embodiments, tumor scoring is based on the methodology described in Huang et al, Arch Pathol Lab Med, 143(11 ): 1373-137 (2019). For example, to evaluate DLL3 staining, combined membrane and cytoplasmic H-scores may be collected at any magnification. H-score may be calculated using the following formula: 1 x (percentage of cells staining at 1 + intensity) + 2 x (percentage of cells staining at 2+ intensity) + 3 x (percentage of cells staining at 3+ intensity) and is typically in the range of 0-300. Surprisingly, inclusion of cytoplasmic DLL3 staining with membrane DLL3 staining does not diminish the predictive / correlative value of DLL3 expression with respect to therapeutic outcomes, and in fact results in a more efficient analysis. Negative or weak staining may be confirmed at a minimum of 20x magnification. DLL3 positivity may be defined as > 1% stained tumor cells. Hematoxylin and Eosin (H&E) staining may be performed using routine methods, and H&E-stained slides may be used to evaluate for tumor content and assessment of tissue quality. In some embodiments, a minimum of 100 viable tumor cells (e.g., 120, 130, 140, 150, 200, 300, 400, 500 or more viable tumor cells) are used for DLL3 evaluation. Tumor tissues may be scored for specific percentage tumor cell staining, as discussed above. Tumor tissues may also be scored for overall intensity of tumor cell DLL3 staining on a scale of 0 to 3 in increments of 1. For example, strong cytoplasmic and / or membranous DLL3 staining ofAmgen Ref. No. 10990-W001-SEC tumor cells may be scored as “3” or “3+,” moderate staining may be scored as “2” or “2+,” and weak staining may be scored as “1 ” or “1 +.” The absence of any DLL3-positive staining may be given a score of “0.” In some embodiments, an IHC intensity score of 2, 2+, 3, or 3+ (e.g., 2+. 3+, or 2+ and 3+) indicates a high level of DLL3 expression or DLL3 overexpression. In other embodiments, 3+ staining of tumor cells by IHC indicates a high level of DLL3 expression or DLL3 overexpression. In some embodiments, an IHC intensity score (e.g., 1 +, 2+, or 3+) is determined by a pathologist.

[0114] Thus, in some aspects, at least 25% (e.g., 30%, 35%, 40%, 45%) of the cancer cells in a subject treated by the disclosed methods express DLL3 as determined by, e.g., an IHC assay. In certain embodiments, at least 50% (e.g., 55%, 60%, 65%, 70%, 80%, 90%, 99%, or 100%) of the cancer cells express DLL3. For example, at least 75% (e.g., 85%, 95%, or 100%) of the cancer cells expresses DLL3. In certain embodiments, at least 25% (e.g., 30%, 40%, 50%, 60%, 70% or more) of the cancer cells express DLL3 at an intensity equal to or greater than 2+ (e.g., 2+, 3+, or 2+ and 3+) as determined by an IHC assay. For example, in some embodiments, a cancer (e.g., SCLC) has a DLL3 expression level in which at least 75% (e.g., 80%, 85%, 90%, 95%, 99%, or 100%) of the cancer cells express DLL3 at an intensity equal to or greater than 2+ (e.g., 2+, 3+, or 2+ and 3+) as determined by an IHC assay.

[0115] In accordance with the inventive method, the intensity of the IHC signal(s) detected in a sample may be compared to a predetermined reference value, such as a predetermined threshold value. The term “predetermined reference value” refers to an assay value, or defined amount of analyte, that is used to assess an assay result. For example, a predetermined reference value may be a DLL3-positive signal corresponding to a known quantity of DLL3 protein. The terms “predetermined threshold value” and “predetermined cut-off value” are used interchangeably herein to refer to an assay value, or defined amount of an analyte, that is used to assess DLL3 expression in a tumor sample from a subject by comparing the assay results against the predetermined threshold or cutoff value. While the present disclosure may provide exemplary predetermined thresholdAmgen Ref. No. 10990-W001-SEC levels, it is well-known that cut-off values may vary depending on the nature of the assay (e.g., antibodies employed, etc.). It further is well within the ordinary skill in the art to adapt the disclosure herein for other samples to obtain assay-specific reference or cutoff values for such assays based on this disclosure. Without being limited by theory, the use of paired, nested cut-offs (such as 25% TPS or 75% TPS) for identifying DLL3-expressing cancers ensures that moderate and high expressing tumor cells are included while also allowing analysis of strong DLL3 expression.Therapeutic Response

[0116] The efficacy of the disclosed methods for treating cancer (such as SCLC) may be assessed by a variety of clinical outcomes, endpoints, and / or measures. In this regard, clinical outcomes that may be assessed include, but are not limited to, Progression Free Survival (PFS), Overall Survival (OS), Objective Response (ORR), Disease Control Rate (DOR), Duration of Response (DOR). The term “progression free survival (PFS),” as used herein, refers to the time from randomization until first evidence of disease progression or death. The term “overall survival (OS),” as used herein, refers to the time from randomization to death. The term “objective response rate (ORR),” as used herein, is a measure of how a specific treatment impacts tumor burden in a patient with a history of solid tumors and refers to the proportion of patients that respond either partially or fully to therapy. The term “duration of response (DoR),” as used herein, refers to the time from randomization to disease progression or death in patients who achieve complete or partial response. The term “disease control rate (DCR),” as used herein, describes the percentage of patients with advanced cancer whose therapeutic intervention has led to a complete response, partial response, or stable disease. In some aspects, the disclosed methods desirably increase one or more of Progression Free Survival (PFS), Overall Survival (OS), Objective Response Rate (ORR), and / or Disease Control Rate (DCR) and Duration of Response (DOR) as compared to another therapeutic agent. Clinical endpoints withAmgen Ref. No. 10990-W001-SEC respect to cancer therapies are further described in, e.g., Delgado A. and Guddati, A.K., et al., Am J Cancer Res 2021 ;11 (4):1121 -1131.Kits

[0117] The disclosure further provides a kit comprising (a) a container comprising an anti-DLL3 antigen-binding protein as described herein (e.g., tarlatamab) and (b) a package insert containing instructions for treating a DLL3-expressing cancer in a subject by subcutaneously administering the anti-DLL3 antigen-binding protein according to the methods described herein. Such a kit may comprise an injection device, e.g., a syringe, injection needles, vessels comprising liquids for reconstitution of freeze-dried active agents and / or additives, or ready-prepared formulations in individual dosage units. In certain aspects, the kit comprises an injection device that is pre-filled with an aqueous formulation containing an amount of the anti-DLL3 antigen-binding protein appropriate for a single Q2W, Q3W, or Q4W administration as described herein (e.g., about 5 mg to about 60 mg such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg of the anti-DLL3 antigen-binding protein). Formulations suitable for subcutaneous administration of therapeutic proteins may include, for example, liquid formulations containing stabilizers (e.g., sugars, amino acids, surfactants, or buffers) to maintain protein integrity during storage and injection. In cases where long-term stability is required, lyophilized formulations are often employed, with the therapeutic protein freeze-dried in the presence of excipients to preserve structure and activity. Prior to administration, such lyophilized products are reconstituted with sterile diluents (e.g., water for injection or buffered solutions) to achieve the target protein concentration suitable for subcutaneous delivery.

[0118] Injection devices suitable for such kits include, but are not limited to, the AUTOTOUCH™ reusable autoinjector and the SURECLICK® autoinjector. Individual dosage units may be color-coded to select the appropriate dose to be administered at a givenAmgen Ref. No. 10990-W001-SEC time-point of the described treatment method. The package instructions may be provided in the kit as hard copies or in digital form.

[0119] The following examples further illustrate the invention but, of course, should not be construed as in anyway limiting its scope.EXAMPLE 1

[0120] This example describes a phase 1 b study evaluatingthe safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of subcutaneous tarlatamab in subjects with extensive stage small cell lung cancer.Study Rationale

[0121] In the first-in-human phase 1 DeLLphi-300 clinical trial in previously treated SCLC, tarlatamab administered intravenously (IV) demonstrated manageable toxicities and encouraging response durability (Paz-Ares et al, 2023). In the subsequent phase 2 DeLLphi-301 clinical trial of tarlatamab in third-line or later extensive stage SCLC (ES- SCLC), dose comparison between 10 mg and 100 mg resulted in selection of the 10 mg target dose administered IV every 2 weeks (Q2W) with 1 mg step dose on treatment initiation (Ahn et al, 2023) as the dosing regimen to be further evaluated in clinical studies. As reported in Ahn et al, 2023, among subjects treated with tarlatamab 10 mg IV Q2W (N= 100), objective response rate (ORR) was 40% with median progression-free survival (mPFS) of 4.9 months and 9-month overall survival (OS) estimate of 68%. The most common adverse event was cytokine release syndrome (CRS) in 51 % of patients treated with tarlatamab 10 mg IV Q2W. Most CRS events were grade 1 or 2 in severity with only 1 % of subjects with grade 3 CRS. The phase 2 study also reported 8% of subjects treated with tarlatamab 10 mg IV Q2W experienced immune effector cell-associated neurotoxicity syndrome (ICANS) and associated neurologic events.

[0122] Subcutaneous (SC) administration of T cell engager molecules (TCEs), such as tarlatamab, has the potential to not only improve convenience, but also provide delayed and lower maximum serum concentration (Cmax), which may improve Cmax-driven adverseAmgen Ref. No. 10990-W001-SEC events such as CRS and neurotoxicity (Ball et al, 2023). A concern with SC administration of TCEs against non-B-cell targets is immunogenicity. IV tarlatamab trials have reported a low incidence of immunogenicity (Ahn et al, 2023).

[0123] This phase 1 b study will evaluate the safety, tolerability, pharmacokinetics (PK), preliminary anti-tumor activity, and immunogenicity of SC tarlatamab in subjects with previously treated ES-SCLC that has progressed or recurred following at least one platinum-based anti-cancer treatment, identifying and studying a tarlatamab SC dose that would achieve similar exposures (serum concentration prior to dosing [Ctrough]), on average, relative to the previously optimized safe and effective dose of 10 mg IV Q2W (Ahn et al, 2023).Overall Design

[0124] The study includes a 21 -day screening period, treatment period, one safety follow-up (SFU) visit, and a long-term follow-up (LTFU) period. The study design is shown schematically in FIGS. 1 and 2, and the objectives and endpoints of the study are summarized in Table 3.Table 3Amgen Ref. No. 10990-W001-SEC

[0125] The study will consist of 3 parts: dose exploration (Part 1 ), dose expansion (Part 2), and alternative dosing (Part 3).Part 1 : Dose Exploration

[0126] The objective of Part 1 is to study the safety and tolerability of SC tarlatamab and identify a SC dose that would achieve exposures (Ctr0Uh), on average, similar to the previously optimized safe and effective dose of 10 mg IV Q2W. Multiple dose levels of SC tarlatamab may be explored in Part 1 to achieve this objective. The exposure range to be evaluated in this study will be within the range of exposures that have been deemed safe and tolerable in prior IV tarlatamab studies. Tarlatamab dosing schedule will be identicalAmgen Ref. No. 10990-W001-SEC to the previously evaluated IV regimen; specifically, tarlatamab will be administered SC starting with a step dose on cycle 1 day 1 (C1 D1 ) followed by the target dose on cycle 1 day 8 (C1 D8), cycle 1 day 15 (C1 D15), and then Q2W thereafter. In Part 1 , SC injections will be limited to the abdomen (right versus left, upper versus lower quadrants). Subjects will be assessed for dose-limiting toxicities (DLTs) for 21 days starting with C1 D1 . Dose escalation / de-escalation recommendations will be guided by a modified toxicity probability interval-2 (mTPI-2) model (Guo et al, 2017) with a target toxicity probability of 30%, equivalence toxicity interval of (25%, 35%) and probability of overdosing of 95%. Beta (1 , 1 ) will be used as a prior distribution. Subjects will be assessed for dose-limiting toxicities (DLTs) for 21 days starting with C1 D1 . A subject is DLT-evaluable when one of the following is met: (1 ) a subject experience a DLT during DLT period or (2) a subject completes 21 days of treatment and receives at least 2 of the planned tarlatamab administrations in cycle 1 .

[0127] In cohort 1 -1 , the step dose will be 1 mg and the target dose will be 10 mg, matching that of the selected IV recommended phase 2 dose (RP2D) from the DeLLphi-301 Study (NCT05060016). This RP2D via IV administration was selected based on data from the first-in-human Study 20160323, which explored a target dose range of 0.003 to 100 mg IV using a Q2W regimen in previously treated SCLC patients, as well as findings from the ongoing phase 2 Study 20200491 , which evaluated active dose levels of 10 and 100 mg IV on a Q2W schedule using a 1 mg step dose. Prior data has shown that 10 mg IV Q2W exhibited near maximal efficacy and favorable benefit-risk profile in the SCLC patient population (Ahn et al, 2023; Paz-Ares et al, 2023).

[0128] Following a dose level review meeting (DLRM) that will be held when 3-4 subjects are DLT-evaluable, up to a total of 20 subjects (including backfill enrollment) may be enrolled to better characterize the safety, tolerability, PK, and anti-tumor activity. After PK data is available for at least 7 evaluable subjects in cohort 1 -1 , PK analysis will be conducted for cohort 1-1 using historical PK data available following IV administration to estimate SC bioavailability. Subsequently, cohort 1 -2 SC step and target doses will beAmgen Ref. No. 10990-W001-SEC selected based on this analysis such that the exposures (Ctrouh) are predicted to be, on average, similar to the 10 mg IV Q2W dose. The dose level review team (DLRT) will reconvene to review PK data and proposed cohort 1-2 dose based on PK analysis, which will be considered with emerging safety and tolerability data to support the selected cohort 1 -2 dose.

[0129] Cohort 1-2 will enroll by the principles outlined for cohort 1 -1 , with a DLRM held when 3-4 subjects are DLT-evaluable, after which up to a total of 20 subjects (including backfill enrollment) may be enrolled to better characterize the safety, tolerability, PK, and anti-tumor activity. After PK data is available for at least 7 evaluable subjects in cohort 1 -2, PK analysis will be conducted to confirm the SC dose provides similar exposures (CtrOugh), on average, relative to the 10 mg IV Q2W dose. The DLRT will reconvene to review this PK data. If cohort 1 -2 exposures are similar, on average, to the 10 mg IV Q2W dose and if supported by emerging safety and tolerability data, dose expansion may open (see Part 2 below). Alternatively, cohort 1-3 may open with an updated dose using the same schedule, or an alternative dosing regimen estimated to provide similar exposures, on average, relative to the 10 mg IV Q2W dose based on updated PK analysis.

[0130] The exposure range to be evaluated in this study will be within the range of exposures that have been deemed safe and tolerable in prior IV tarlatamab studies. In some aspects, the highest planned SC target dose will not exceed is intended to be 30 mg, although adjustments may be implemented as deemed appropriate in view of emerging clinical data. Based on emerging such data, the sponsor may electto add additional arms via a future protocol amendment to study different doses or dosing schedules.Part 2: Dose Expansion

[0131] Followingthe selection of a SC dosing regimen in Part 1 , up to 40 subjects will be enrolled in Part 2. The step and target dose to be studied in Part 2 will be selected based on review of all available data based on the doses deemed safe and tolerable in Part 1.Amgen Ref. No. 10990-W001-SECSubcutaneous injections in Part 2 will be administered in eitherthe abdomen (right versus left, upper versus lower quadrants) or thigh (right versus left).Alternative Dosing (Part 3):

[0132] Followingthe selection of a Q2W SC dosing regimen from Part 1 that will be used in Part 2 dose expansion, Part 3 may open to test alternative dosing of SC tarlatamab. In Part 3, SC injections will be limited to the abdomen (right versus left, upper versus lower quadrants).

[0133] Cohorts 3-1 and 3-2 (if opened) will have 21 -day cycles comprising a step dose on C1 D1 , followed by the target dose administered on C1 D8, C2D1 , and then every 3 weeks (Q3W) thereafter. Step and target doses will be calculated based on the Q2W SC dosing regimen selected for Part 2 in order to achieve average exposures similar to the 10 mg IV Q2W dose.

[0134] Cohorts 3-3 and 3-4 (if opened) will have 28-day cycles with dosing consisting of a step dose on C1 D1 , followed by the target dose administered on C1 D8, C2D1 , and then every 4 weeks (Q4W). Step and target doses will be calculated based on the Q2W SC dosing regimen selected for Part 2 in order to achieve average exposures similar to the 10 mg IV Q2W dose.

[0135] Any cohort opened in Part 3 will have a DLRM held when at least 3 participants in the Part 3 safety run-in are DLT-evaluable. Followingthis DLRM, up to approximately 30 participants per cohort in Part 3 may be enrolled. In the safety run-in period in Part 3, participants will be assessed for DLTs for 21 days starting with C1 D1 .Number of Subjects

[0136] Up to a total of 220 subjects will be enrolled in Parts 1 , 2, and 3 (up to 60 subjects in Part 1 ,up to 40 subjects in Part 2, and up to approximately 120 subjects in Part 3).Amgen Ref. No. 10990-W001-SECSummary of Subject Eligibility Criteria

[0137] Key Inclusion Criteria:• Subjects > 18 years of age (or > legal adult age within country if it is older than 18 years) at time of signing informed consent.• Subjects with histologically or cytologically confirmed ES-SCLC that progressed or recurred following at least one line of platinum-based regimen.• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 .• Subjects must have adequate organ function (cardiac, pulmonary, kidney, and liver).• Subjects must be able to have SC injections administered in the abdomen (and / or thigh for Part 2).• Subjects without measurable disease or tumor tissue (fresh biopsy or archival) available may be permitted after discussion with and approval by Medical Monitor.

[0138] Key Exclusion Criteria:• Subjects that have received prior DLL3 targeted therapy.• Subjects with untreated or symptomatic brain metastases or those requiring therapy with steroids.• Note: Subjects with asymptomatic brain metastatic lesions are allowed following definitive treatment (Amgen Medical Monitor may approve untreated, asymptomatic brain metastasis if local therapy is not required per investigator judgment).• Subjects with leptomeningeal disease.• Subjects with baseline oxygen requirement.Treatments

[0139] Tarlatamab will be supplied as a sterile, single-use, preservative-free lyophilized drug product containing 25 mg, 10 mg, or 1 mg of tarlatamab per vial. Tarlatamab is intended for reconstitution with sterile water for injection. The drug productAmgen Ref. No. 10990-W001-SEC is formulated with L-glutamic acid, sucrose, polysorbate 80, pH 4.2. Tarlatamab will be administered as a SC injection (per institutional guidelines, with each injection < 30 seconds) with a step dose on C1 D1 followed by the target dose on C1 D8, C1 D15, and then Q2W thereafter in 28-day cycles in Parts 1 and 2 (cohorts 1-1 , 1 -2, 1 -3, and 2). In Part 3 cohorts 3-1 and 3-2, tarlatamab will be administered as SC injection(s) with a step dose on C1 D1 followed by the target dose on C1 D8, C2D1 , and then Q3W thereafter in 21-day cycles. In Part 3 cohorts 3-3 and 3-4, tarlatamab will be administered as SC injection(s) with a step dose on C1 D1 followed by the target dose on C1 D8, C2D1 , and then Q4W thereafter in 28-day cycles. The dosing by cohort is shown in Table 4.Table 4

[0140] All subjects must be hospitalized for a minimum of 24 hours post-tarlatamab injection on C1 D1 and C1 D8. At subsequent visits, additional hospitalization / monitoring may be required post-injection.

[0141] Dexamethasone: 8 mg oral or IV (or corticosteroid equivalent) will be administered within 1 hour prior to tarlatamab injection on C1 D1 and C1 D8.Amgen Ref. No. 10990-W001-SECSafety Assessments

[0142] Safety assessments that will be evaluated at certain time points during the study include, but are not limited to, vital signs, electrocardiograms, clinical laboratory tests, echocardiograms, multigated acquisition (MUGA) scan, cytokine release syndrome (CRS), and immune effector cell-associated Neurotoxicity Syndrome (ICANS). CRS is defined as a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T-cells and / or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction. For this trial, CRS will be defined according to the criteria referenced in the publication by Lee et al, 2019. For this trial, ICANS will be defined according to the criteria also referenced in the publication by Lee et al, 2019. While the grading system has been developed in large part from chimeric antigen receptor T-cells (CAR-T) therapies, symptoms of ICANS may be shared among immune effector cell-associated therapies such as BiTE® molecules.EXAMPLE 2

[0143] This example describes results from the ongoing phase 1 b study evaluating subcutaneous administration of tarlatamab described in Example 1 .

[0144] Thirty-seven participants have been treated according to the protocol of Example 1 , including 20 participants in Part 1 , cohort 1 -1 treated with a tarlatamab target dose of 10 mg administered subcutaneously (SC) every 2 weeks (Q2W) and 17 participants in Part 1 , cohort 1 -2 treated with a tarlatamab target dose of 15 mg administered SC Q2W. Participants in both cohorts 1 -1 and 1 -2 received a 1 mg step dose SC on day 1 .

[0145] Tarlatamab serum concentration was measured at C2D1 and C2D15 in 8-12 of treated participants in cohort 1 -1 . The preliminary PK parameter summaries for subcutaneous tarlatamab at C2D1 and C2D15 compared to intravenous (IV) administration are shown in Table 5 and Table 6.Amgen Ref. No. 10990-W001-SECTable 5. PK Parameters at Cycle 2 Day 1 (C2D1)Table 6. PK Parameters at Cycle 2 Day 15 (C2D15)

[0146] Based on the above results, SC bioavailability following the 10 mg Q2W regimen was estimated to be about 71 % to 75% based on AUCtau. Preliminary data from this study suggested that a 15 mg Q2W SC regimen achieves exposures comparable to the regimen of 10 mg Q2W IV.

[0147] Among the 37 treated participants of Part 1 , cohorts 1 -1 and 1 -2, 10 participants (27.0%) experienced any grade CRS, including 3 participants (8.1 %) with worst grade 2 CRS and 7 participants (18.9%) with grade 1 worst grade CRS. No grade 3 or higher CRS events were documented. No CRS events led to dose interruption, dose reduction, orAmgen Ref. No. 10990-W001-SEC discontinuation of tarlatamab. This preliminary CRS data compares favorably with the rate of CRS observed with a similar dose of IV tarlatamab (Ahn et al, NEJM 2025).

[0148] It should be understood that when describing a range of values, the characteristic being described could be an individual value found within the range. For example, “a dose from about 3 mgto about 100 mg,” could be, but is not limited to, 5 mg, 10 mg, 25 mg, 50 mg, etc. and any value in between such values. In any of the ranges described herein, the endpoints of the range are included in the range. However, the description also contemplates the same ranges in which the lower and / orthe higher endpoint is excluded.

[0149] “About” or “approximately,” when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or ±10% of the indicated value, whichever is greater.

[0150] Additional features and variations of the disclosure will be apparent to those skilled in the art from the entirety of this application, including the drawings, detailed description, and appended claims, and all such features are intended as aspects of the disclosure. Likewise, features of the disclosure described herein can be re-combined into additional embodiments that also are intended as aspects of the disclosure, irrespective of whether the combination of features is specifically mentioned above as an aspect or embodiment of the disclosure. The disclosure also includes all aspects narrower in scope in any way than the variations specifically mentioned. Also, only such limitations which are described herein as criticalto the invention should be viewed as such.Amgen Ref. No. 10990-W001-SECReferences

[0151] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.1 . Ahn MJ, Cho BC, Felip E, et aL "Tarlatamab for Patients with Previously Treated Small- Cell Lung Cancer." New England Journal of Medicine, vol. 389, no. 22, 2023, pp. 2063- 2075, doi:10.1056 / NEJMoa2307980.2. Ball K, Dovedi SJ, Vajjah P, Phipps A. "Strategies for clinical dose optimization of T cellengaging therapies in oncology." MAbs, vol. 15, no. 1 , 2023, d oi : 10.1080 / 19420862.2023.2181016.3. Bartlett NL, Giri P, Budde E, et al. "Subcutaneous (SC) Administration of Mosunetuzumab With Cycle 1 Step-Up Dosing Is Tolerable and Active in Patients With Relapsed / Refractory B-Cell Non-Hodgkin Lymphomas (R / R B-NHL): Initial Results From a Phase l / ll Study." Blood, vol. 138, Supplement 1 , 2021 , doi:10.1182 / blood-2021 -147937.4. Bristol Myers Squibb. "Bristol Myers Squibb Statement on Opdivo (nivolumab) Small Cell Lung Cancer U.S. Indication." 2020, [URL].5. Byers LA, Rudin CM. "Small cell lung cancer: where do we go from here?" Cancer, vol. 121 , 2015, pp. 664-672, doi:10.1002 / cncr.29098.6. Eisenhauer EA, Therasse P, Bogaerts J, et al. "New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1 .1 )." European Journal of Cancer, vol. 45, no. 2, 2009, pp. 228-247, doi:10.1016 / j.ejca.2008.10.026.7. Emerson A. Lim et al. "Safety and preliminary clinical activity of JNJ-63898081 (JNJ-081 ), a PSMA and CD3 bispecific antibody, for the treatment of metastatic castrate-resistantAmgen Ref. No. 10990-W001-SEC prostate cancer (mCRPC)." Journal of Clinical Oncology, vol. 40, 2022, pp. 279-279, d o i : 10.1200 / JC0.2022.40.6_suppl.279.8. Gustafsson Bl, Kidd M, Chan A, Malfertheiner MV, Modlin IM. "Bronchopulmonary neuroendocrine tumors." Cancer, vol. 113, 2008, pp. 5-21 , doi:10.1002 / cncr.23542.9. Gonzalez-Rodriguez E, Rodrfguez-Abreu D; Spanish Group for Cancer Immuno Biotherapy (GETICA). "Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events." Oncologist, vol. 21 , no. 7, 2016, pp. 804-816, doi:10.1634 / theoncologist.2015-0509.10. Horn L, Mansfield AS, Szczesna A, et al. "First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer." New England Journal of Medicine, vol. 2, [date not provided].11. Koinis F, Kotsakis A, Georgoulias V. "Small cell lung cancer (SCLC): no treatment advances in recent years." Translational Lung Cancer Research, vol. 5, 2016, pp. 39-50, doi: 10.3978 / j.issn.2218-6751 .2016.01 .03.12. Lee DW, Santomasso BD, Locke FL, et al. "ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells." Biology of Blood and MarrowTransplantation, vol. 25, 2019, pp. 625-638, doi:10.1016 / j.bbmt.2018.12.758.13. Neelapu SS, Turn mala S, Kebriaei P, et al. "Chimeric antigen receptor T-cell therapy - assessment and management of toxicities." Nature Reviews Clinical Oncology, vol. 15, no. 1 , 2018, pp. 47-62, doi:10.1038 / nrclinonc.2017.148.14. Owen DH, Giffin MJ, Bailis J, et al. "DLL3: an emerging target in small cell lung cancer." Journal of Hematology & Oncology, vol. 12, no. 1 , 2019, pp. 61 , doi: 10.1186 / s13045-019-Amgen Ref. No. 10990-W001-SEC15. Paz-Ares L, Dvorkin M, Chen Y, et aL "Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomized controlled, open-label, phase 3 trial." Lancet, vol. 394, no. 10212, 2019, pp. 1929-1939, doi:10.1016 / S0140-6736(19)32222-6.16. Paz-Ares L, Champiat S, Lai WV, et al. "Tarlatamab, a First-In-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small Cell Lung Cancer: An Open-Label, Phase I Study." Journal of Clinical Oncology, vol. 41 , no. 16, 2023, pp. 2893-2903, doi:10.1200 / JCO.22.02823.17. Rudin CM, Ismaila N, Hann CL, et al. "Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guideline." Journal of Clinical Oncology, vol. 33, 2015, pp. 4106-4111 , doi:10.1200 / JOP.2015.008201 .18. Saunders LR, Bankovich AJ, Anderson WC, et aL "A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo." Science Translational Medicine, vol. 7, 2015, pp. 302ra136, d oi : 10.1126 / scitranslmed.aac9459.19. Trigo J, Subbiah V, Besse B, et al. "Lurbinectedin as second-line treatment for patients with small-cell lung cancer: results from a single-arm, open-label, phase 2 basket trial." Lancet Oncology, vol. 21 , no. 5, 2020, pp. 645-654, doi:10.1016 / S1470-2045(20)30068-1 .Amgen Ref. No. 10990-W001-SECTable 7. Amino Acid SequencesAmgen Ref. No. 10990-W001-SECAmgen Ref. No. 10990-W001-SECAmgen Ref. No. 10990-W001-SECAmgen Ref. No. 10990-W001-SEC

Claims

Amgen Ref. No. 10990-W001-SECCLAIM(S):1 . A method of treating a DLL3-expressing cancer, which method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22.

2. The method of claim 1 , which comprises administering 10 mg to 60 mg of the anti-DLL3 antigen-binding protein to the subject once every two weeks (Q2W).

3. A method of treating a DLL3-expressing cancer, which method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof according to the following regimen: (1 ) a first administration of 0.5 mg to 5 mg on day 1 ; (2) a second administration of 5 mg to 60 mg on day 8; and (3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter (Q2W), wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greaterthan the amount of anti-DLL3 antigen-binding protein in the first administration.

4. The method of claim 3, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO:

225. The method of claim 3 or claim 4, wherein the first, second, and subsequent administrations of the anti-DLL3 antigen-binding protein are administered over the course of multiple 28-day cycles.

6. The method of any one of claims 3-5, wherein each of the second and subsequent administrations are 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 30-fold, or 40-fold greaterthan the first administration.Amgen Ref. No. 10990-W001-SEC7. The method of any one of claims 3-6, wherein the first administration comprises 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, or 3.5 mg of the anti-DLL3 antigen-binding protein.

8. The method of any one of claims 3-7, wherein each of the second and subsequent administrations comprises 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg of the anti-DLL3 antigen-binding protein.

9. The method of any one of claims 3-8, wherein the first administration comprises 1 mg, the second administration comprises 10 mg, and each of the one or more subsequent administrations comprises 10 mg of the anti-DLL3 antigen-binding protein.

10. The method of any one of claims 3-8, wherein the first administration comprises 1 mg, the second administration comprises 15 mg, and each of the one or more subsequent administrations comprises 15 mg of the anti-DLL3 antigen-binding protein.11 . The method of any one of claims 1 -10, wherein the DLL3-expressing cancer is a neuroendocrine cancer.

12. The method of claim 11 , wherein the DLL3-expressing cancer is a pulmonary neuroendocrine cancer.

13. The method of claim 12, wherein the DLL3-expressing cancer is small cell lung cancer (SCLC).

14. The method of claim 12 or claim 13, wherein the DLL3-expressing cancer is limited stage small cell lung cancer (LS-SCLC)15. The method of claim 12 or claim 13, wherein the DLL3-expressing cancer is extensive stage small cell lung cancer (ES-SCLC).

16. The method of claim 15, wherein the neuroendocrine cancer is refractory SCLC or relapsed SCLC.Amgen Ref. No. 10990-W001-SEC17. The method of any one of claims 1 -16, wherein the cancer has progressed or relapsed following at least one previous cancer treatment.

18. The method of claim 17, wherein the at least one previous cancer treatment comprises platinum-based chemotherapy.

19. The method of claim 18, wherein the platinum-based chemotherapy comprises carboplatin or cisplatin.

20. The method of any one of claims 1 -16, wherein the subject has not received any prior line of cancer treatment.21 . The method of claim 11 , wherein the DLL3-expressing cancer is an extrapulmonary neuroendocrine cancer.

22. The method of claim 21 , wherein the DLL3-expressing cancer is neuroendocrine prostate cancer (NEPC).

23. The method of any one of claims 1-22, which further comprises administering at least one additional therapeutic agent to the subject.

24. The method of claim 23, wherein the at least one additional therapeutic agent comprises a corticosteroid, saline, or an a nti-l L6 antibody.

25. The method of claim 24, wherein the corticosteroid comprises dexamethasone.

26. The method of any one of claims 23-25, wherein dexamethasone is administered on day 1 and day 8 of a first 28-day cycle.

27. The method of claim 23, wherein the at least one additional therapeutic comprises an anti-PD1 antibody or anti-PD-L1 antibody.

28. The method of claim 27, wherein the anti-PD-L1 antibody is durvalumab.Amgen Ref. No. 10990-W001-SEC29. The method of any one of claims 1 -28, wherein the anti-DLL3 antigen-binding protein is tarlatamab.

30. A method of treating a DLL3-expressing cancer, which method comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 10 mg on day 8; (3) a subsequent administration of 10 mg on day 15, and (4) one or more further subsequent administrations of 10 mg once every two weeks thereafter (Q2W).31 . A method of treating a DLL3-expressing cancer, which method comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen: (1 ) a first administration of 1 mg on day 1 ; (2) a second administration of 15 mg on day 8; (3) a subsequent administration of 15 mg on day 15, and (4) one or more further subsequent administrations of 15 mg once every two weeks thereafter (Q2W).

32. A composition comprising an anti-DLL3 antigen-binding protein forthe treatment of a DLL3-expressing cancer, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22, and wherein the treatment comprises subcutaneously administeringthe anti-DLL3 antigen-binding protein to the subject according to the following regimen:(1) a first administration of 0.5 mgto 5 mg on day 1 ;(2) a second administration of 5 mg to 60 mg on day 8; and(3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter (Q2W); wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.Amgen Ref. No. 10990-W001-SEC33. The composition of claim 32, wherein the anti-DLL3 antigen-binding protein is tarlatamab.

34. The composition of claim 32 or claim 33, wherein the treatment comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen:(1) a first administration of 1 mg administered on day 1 ;(2) a second administration of 10 mg or 15 mg on day 8;(3) a subsequent administration of 10 mg or 15 mg on day 15; and(4) one or more further subsequent administrations of 10 mg or 15 mg once every two weeks thereafter (Q2W).

35. The composition of any one of claims 32-34, wherein the DLL3-expressing cancer is small cell lung cancer (SCLC).

36. The composition of claim 35, wherein the DLL3-expressing cancer is extensive stage small cell lung cancer (ES-SCLC).

37. Use of an anti-DLL3 antigen-binding protein in the manufacture of a medicament for the treatment of a DLL3-expressing cancer in a subject, wherein the anti- DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22, and wherein the treatment comprises subcutaneously administering the anti-DLL3 antigen-binding protein to the subject according to the following regimen:(1) a first administration of 0.5 mgto 5 mg on day 1 ;(2) a second administration of 5 mg to 60 mg on day 8; and(3) one or more subsequent administrations beginning on day 15 and once every two weeks thereafter (Q2W);Amgen Ref. No. 10990-W001-SEC wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.

38. The use of claim 38, wherein the anti-DLL3 antigen-binding protein is tarlatamab.

39. The use of claim 37 or claim 38, wherein the treatment comprises administeringtarlatamab via subcutaneous injection to a subject in need thereof according to the following regimen:(1) a first administration of 1 mg on day 1 ;(2) a second administration of 10 mg or 15 mg on day 8;(3) a subsequent administration of 10 mg or 15 mg on day 15; and(4) one or more further subsequent administrations of 10 mg or 15 mg once every two weeks thereafter (Q2W).

40. The use of any one of claims 37-39, wherein the DLL3-expressing cancer is small cell lung cancer (SCLC).41 . The use of claim 40, wherein the DLL3-expressing cancer is extensive stage small cell lung cancer (ES-SCLC).

42. A method of treating a DLL3-expressing cancer, which method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof according to the following regimen:(1) a first administration of 0.5 mgto 5 mg on day 1 ;(2) a second administration of 5 mg to 60 mg on day 8; and(3) one or more subsequent administrations of 5 mgto 60 mg beginning on day 22 and once every three weeks thereafter (Q3W);Amgen Ref. No. 10990-W001-SEC wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.

43. A method of treating a DLL3-expressing cancer, which method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof according to the following regimen:(1) a first administration of 0.5 mgto 5 mg on day 1 ;(2) a second administration of 5 mg to 60 mg on day 8; and(3) one or more subsequent administrations of 5 mgto 60 mg beginning on day 29 and once every four weeks thereafter (Q4W); wherein each of the second and subsequent administrations comprises the same amount of anti-DLL3 antigen-binding protein, which amount is greater than the amount of anti-DLL3 antigen-binding protein in the first administration.

44. The method of any one of claim 42 or 43, wherein the first administration comprises 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, or 3.5 mg of the anti-DLL3 antigen-binding protein.

45. The method of any one of claims 42-44, wherein each of the second and subsequent administrations comprises 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 45 mg of the anti-DLL3 antigen-binding protein.

46. The method of any one of claims 42-45, wherein the first administration comprises about 1 mg, the second administration comprises 10 mg, 15 mg, 22.5 mg, 30 mg, or 45 mg, and each of the one or more subsequent administrations comprises 10 mg, 15 mg, 22.5 mg, 30 mg, or 45 mg of the anti-DLL3 antigen-binding protein.

47. The method of any one of claims 42-46, wherein the anti-DLL3 antigen-binding protein is tarlatamab.Amgen Ref. No. 10990-W001-SEC48. A method of treating a small cell lung cancer (SCLC), which method comprises subcutaneously administering an anti-DLL3 antigen-binding protein to a subject in need thereof, wherein the anti-DLL3 antigen-binding protein comprises the amino acid sequence of SEQ ID NO: 13 and the amino acid sequence of SEQ ID NO: 22.

49. The method of claim 48, which comprises administering 10 mg or 15 mg of the anti-DLL3 antigen-binding protein to the subject once every two weeks (Q2W).

50. The method of claim 48, which comprises administering 15 mg to 35 mg of the anti-DLL3 antigen-binding protein to the subject once every three weeks (Q3W).51 . The method of claim 48, which comprises administering 30 mg to 50 mg of the anti-DLL3 antigen-binding protein to the subject once every four weeks (Q4W).

52. The method of any one of claims 48-51 , wherein the anti-DLL3 antigen-binding protein comprises SEQ ID NO: 24 or SEQ ID NO: 47.

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