Combinations for the treatment of cancer

Abstract

In one aspect, provided herein are methods of treating cancer with a combination therapy comprising an anti-human B7-H3 antibody-drug conjugate and a DLL3 targeting trispecific protein.

Description

Attorney Docket Number: 14463-358-228COMBINATIONS FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 742,386, filed January 6, 2025 and of U.S. Provisional Patent Application No. 63 / 679,529, filed August 5, 2024, the disclosure of each of which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Cancer is a significant cause of morbidity and mortality worldwide. While the standards of care for many different cancer types have greatly improved over the years, current standards of care still fail to meet the need for effective therapies to improve treatment of cancer. Accordingly, there is a need in the art for new therapies, including, for example, combination therapies for the treatment of cancers. Provided herein are solutions to these and other problems in the art.SEQUENCE LISTING

[0003] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “ l4463-358-228_SEQ_LISTING.xmr, was created on July 28, 2025, and is 39,730 bytes in size.SUMMARY

[0004] In one aspect, provided is a method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;1NAI-5001911280(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.2NAI-5001911280

[0005] In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0006] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate, wherein the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II3NAI-5001911280Formula II wherein A represents a connecting position to the anti-human B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

[0007] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0008] In some embodiments of the method described herein, the method further comprises administering a therapeutically effective amount of a PD-1 or a PD-L1 inhibitor such a pembrolizumab or atezolizumab, further optionally comprises administering a therapeutically effective amount of carboplatin.

[0009] Compositions (e.g., pharmaceutical compositions) for use, uses and kits according to the present therapies are also provided herein.

[0010] In some embodiments of the methods, pharmaceutical compositions and uses provided herein, the cancer is a cancer associated with DLL3. In some embodiments, the cancer is a small cell lung cancer. In some embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive- stage small cell lung cancer. In some embodiments, the extensive-stage small cell lung cancer is relapsed or4NAI-5001911280refractory. In other embodiments, the cancer is a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is melanoma, small cell bladder cancer, or prostate cancer (e.g., metastatic castration resistant prostate cancer).BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic diagram of an exemplary design of a clinical study conducted to evaluate administration of the DLL3 targeting trispecific protein and ifinatamab deruxtecan in combination with a PD-1 or PD-L1 inhibitor as a first line therapy to newly diagnosed extensive-stage small cell lung cancer patients. As represented in FIG. 1, MK- 6070=anti-DLL3 trispecific binding protein; DLL3=delta-like canonical notch ligand 3; I- DXd=ifinatamab deruxtecan; N=number; MTD = maximum tolerated dose; MK-2400= ifinatamab deruxtecan, and Atezo=atezolizumab.

[0012] FIG. 2 is a schematic diagram showing an exemplary design of a clinical study for the combination of ifinatamab deruxtecan and the DLL3 targeting trispecific protein (MK-6070). As represented in FIG. 2, BOIN=Bayesian Optimal Interval; MK-6070=anti- DLL3 trispecific binding protein; DLL3=delta-like canonical notch ligand 3; I- DXd=ifinatamab deruxtecan; N=number; q2w=every 2 weeks; q3w=every 3 weeks; MAD=maximum administered dose; MTD = maximum tolerated dose; SCLC=small cell lung cancer; “a” denotes the Phase 1 study evaluating MK-6070 in combination with I-DXd in participants with SCLC as described in Example 2. “b” denotes that Arm 1, 2, and 3b commences after MTD (or MAD) of MK-6070 q2w and I-DXd q3w has been determined in Phase 1 study of Example 2. Arm 1 also commences after the projected MK 6070 q3w dose has been declared tolerable in Phase 1 study of Example 2. “c” denotes that for Arms 1 and 3b, q3w / q3w and q2w / q2w doses are projected as in Table 2. As denoted in “d” depending on the totality of emerging safety, pharmacokinetic, and efficacy data, the initial Safety Run-In is initiated in 10 participants or the dose expansion is initiated 15 additional participants. When multiple arms of dose expansion are open to enrollment, participants are randomized. “e” denotes that if Safety Run-In doses are not tolerated, the I-DXd dose is reduced one dose level per BOIN.

[0013] FIG. 3 is a schematic diagram showing an exemplary design of a clinical study evaluating different combination-based regimens with the DLL3 trispecific binding protein (MK-6070) and ifinatamab deruxtecan (MK-2400) in first-line extensive stage small cell lung cancer. As represented in FIG. 3, MK-6070=anti-DLL3 trispecific binding protein; DLL3=delta-like canonical notch ligand 3; I-DXd=ifmatamab deruxtecan; ADA=antidrug5NAI-5001911280antibodies; Atezo= atezolizumab; AUC=area under curve; BICR= blinded independent central review; carbo=carboplatin; DC= disease control; DL0=dose level 0; DL-l=dose level -1; DOR=duration of response; ECOG=Eastem Cooperative Oncology Group; ES- SCLC=extensive-stage small cell lung cancer; I-DXd=ifinatamab deruxtecan;ILD=interstitial lung disease; LDH=lactate dehydrogenase; N=number; OR=objective response; PD=progressive disease; PD-1 / Ll=programmed cell death 1 / ligand 1 protein;PF S=progressi on-free survival; PK=pharmacokinetic(s); q3w=every 3 weeks; SOC=standard of care; ULN=Upper limit of normal; “a” denotes that the dosing level in Part B will depend on the tolerated dosing level available from prior studies and Part A, with more than 1 dose level tested.DETAILED DESCRIPTION1. Definitions

[0014] Unless otherwise defined, terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art.

[0015] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0016] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.

[0017] The term “about” or “approximately” indicates and encompasses the designated value ± 10%.

[0018] In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first composition” and “second composition” are used to distinguish two compositions.

[0019] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments6NAI-5001911280are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0020] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry,” 2ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and “March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0021] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0022] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0023] “Antigen” refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) that is capable of mediating an immune response. Exemplary immune responses include antibody production and activation of immune cells, such as T cells, B cells or NK cells.

[0024] “Antigen binding fragment” or “antigen binding domain” refers to a portion of a protein that binds the antigen. Antigen binding fragments may be synthetic, enzymatically7NAI-5001911280obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as a VH, a VL, the VH and the VL, Fab, Fab’, F(ab’)2, Fd and Fv fragments, single-domain antibodies (sdAb) consisting of one VH domain or one VL domain, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as the VH and the VL) may be linked together via a synthetic linker to form various types of single antibody designs in which the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and the VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0025] “Single-domain antibodies” or “sdAb(s)” are antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single-domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single-domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, bovine. For example, in some embodiments, the single-domain antibodies of the disclosure are obtained: (1) by isolating the VHH domain of a naturally occurring heavy chain antibody; (2) by expression of a nucleotide sequence encoding a naturally occurring VHH domain; (3) by “humanization” of a naturally occurring VHH domain or by expression of a nucleic acid encoding such a humanized VHH domain; (4) by “camelization” of a naturally occurring VH domain from any animal species, and in particular from a species of mammal, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) by “camelization” of a “domain antibody” or “Dab,” or by expression of a nucleic acid encoding such a camelized VH domain; (6) by using synthetic or semi-synthetic techniques for preparing proteins, polypeptides or other amino acid sequences; (7) by preparing a nucleic acid encoding a single-domain antibody using techniques for nucleic acid synthesis known in the field, followed by expression of the nucleic acid thus obtained; and / or (8) by any combination of one or more of the foregoing. The term single-8NAI-5001911280domain antibody as used herein in its broadest sense is not limited to a specific biological source or to a specific method of preparation.

[0026] “Antibody” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. A full length antibody is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains. An antibody provided herein may include post-translational modifications thereof, e.g., C-terminal lysine clipping in the heavy chain or conversion of glutamine or glutamic acid to pyroglutamate or pyroglutamic acid, which may occur when recombinantly expressed in host cells (e.g., CHO cells), or during purifi cati on / storage .

[0027] “Trispecific” refers to a molecule (such as an antibody) that specifically binds three distinct antigens or three distinct epitopes within the same antigen. The trispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) o Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0028] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody9NAI-5001911280are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. A “human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, a “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, a “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et aL, (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-396, and in International Publication No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody.”

[0029] “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework region is derived from human immunoglobulin sequences. A humanized antibody may include substitutions in the framework regions so that the framework regions may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0030] The term “Fc region” means the C-terminal region of an immunoglobulin heavy chain that, in naturally occurring antibodies, interacts with Fc receptors and certain proteins of the complement system. The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art.

[0031] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three10NAI-5001911280CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et cd.. Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD.

[0032] A “Complementary Determining Region (CDR)” refers to one of three hypervariable regions (Hl, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH [3-sheet framework, or one of three hypervariable regions (LI, L2 or L3) within the non-framework region of the antibody VL [3-sheet framework. CDRs are variable region sequences interspersed within the framework region sequences. CDRs are well recognized in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable (V) domains. See Kabat et al., J Biol Chem, 1977, 252:6609-6616 and Kabat, Adv Protein Chem, 1978, 32: 1-75.CDRs have also been defined structurally by Chothia as those residues that are not part of the conserved [3-sheet framework, and thus are able to adapt different conformations. See Chothia and Lesk, J Mol Biol, 1987, 196:901-917. Both the Kabat and Chothia nomenclatures are well known in the art. AbM, Contact and IMGT also define CDRs. CDR positions within a canonical antibody variable domain have been determined by comparison of numerous structures. See Morea et al., Methods, 2000, 20:267-279 and Al-Lazikani et al., J Mol Biol, 1997, 273:927-48. Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable domain numbering scheme. Such terminology is well known to those skilled in the art.

[0033] A number of hypervariable region delineations are in use and are included herein.The Kabat CDRs are based on sequence variability and are the most commonly used. See Kabat et al. (1992) Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719. Chothia refers instead to the location of the structural loops (Chothia and Lesk, supra). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software. The Contact hypervariable regions are based on an analysis of the available complex crystal structures.

[0034] More recently, a universal numbering system ImMunoGeneTics (IMGT) Information System™ has been developed and widely adopted. See Lefranc et al., Dev Comp11NAI-5001911280Immunol, 2003, 27:55-77. IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. The IMGT CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. Correspondence between the Kabat, Chothia and IMGT numbering is also well known in the art (Lefranc el al., supra). An exemplary system, shown herein, combines Kabat and Chothia CDR definitions.

[0035] The light chain from any vertebrate species can be assigned to one of two types, called kappa (K) and lambda (X), based on the sequence of its constant domain.

[0036] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, a, y, and p, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0037] The terms “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CHI, CH2 and CH3 domains of the heavy chain and the CL domain of the light chain.

[0038] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-12NAI-5001911280terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific or trispecific.

[0039] “Multispecific” refers to a molecule that binds two or more distinct antigens or two or more distinct epitopes within the same antigen. Multispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) o Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0040] “Polynucleotide” refers to a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide.

[0041] “Protein” or “polypeptide” are used interchangeably herein and refer to a molecule that comprises one or more polypeptides each comprised of at least two amino acid residues linked by a peptide bond. Protein may be a monomer, or may be a protein complex of two or more subunits, the subunits being identical or distinct. Small polypeptides of less than 50 amino acids may be referred to as “peptides.” Protein may be a heterologous fusion protein, a glycoprotein, or a protein modified by post-translational modifications such as phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, pegylation or biotinylation.

[0042] “Recombinant” refers to polynucleotides, polypeptides, vectors, viruses and other macromolecules that are prepared, expressed, created or isolated by recombinant means.

[0043] “Single chain Fv” or “scFv” refers to a single chain protein comprising a VH, a VL and a linker between the VH and the VL. The scFv may have the VL and VH variable regions in either orientation, e.g., with respect to the N- to C-terminal order of the VH and the VL. The scFv may thus be in the orientation VL-linker-VH or VH-linker-VL. In some embodiments, an scFv may be engineered to comprise disulfide bonds between the VH, the VL and the linker.

[0044] The term “VHH,” as used herein, refers to single chain antibody binding domain devoid of light chain. In some cases, a VHH is derived from an antibody of the type that can be found in Camelidae or cartilaginous fish which are naturally devoid of light chains or to a13NAI-5001911280synthetic and non-immunized VHH which can be constructed accordingly. Each heavy chain comprises a variable region encoded by V-, D- and J exons. A VHH, in some cases, is a natural VHH, such as a Camelid derived VHH, or a recombinant protein comprising a heavy chain variable domain. In some embodiments, the VHH is derived from a species selected from the group consisting of camels, llamas, vicugnas, guanacos, and cartilaginous fish (such as, but not limited to, sharks). In another embodiment, the VHH is derived from an alpaca (such as, but not limited to, a Huacaya alpaca or a Suri alpaca).

[0045] As used herein, “identity” or “sequence identity” refers to the degree to which the amino acid residues of two polypeptides or the bases of two nucleic acids are the same (z.e., identical) at the equivalent positions when a query sequence is optimally aligned over the length of a reference sequence, introducing gaps as necessary if the reference and query sequence do not have the same length to achieve a maximum percent identity (called a “global alignment”). For this disclosure, a reference sequence is always an amino acid or nucleic acid sequence specifically disclosed herein, and a query sequence is any other sequence aligned to the reference sequence. Sequence identity is expressed as a percent sequence identity (% sequence identity or % identity). The global alignment and calculation of the percent identity is performed over a contiguous block of residue positions for the entire reference sequence. If the query sequence is longer than the reference sequence, then the percent identity is determined only using the residue positions of the reference sequence. Any residues of the query sequence with positions beyond the first and last positions of the reference sequence after an initial global alignment are removed and the reference and query sequences are re-aligned to determine percent identity. A query sequence has 100% identity to a reference sequence when the residues of both sequences are identical at the equivalent positions over the length of the reference sequence. Similarly, a query sequence has 50% identity to a reference sequence when 50% of the residues of the two amino acid sequences are identical at the equivalent positions over the length of the reference sequence.

[0046] A global alignment can be created using the global alignment tool “Needle” from the online European Molecular Biology Open Software Suite (EMBOSS) or the global alignment tool “BLAST® » Global Alignment” from the National Center for Biotechnology Information (NCBI). Both of these global alignment tools incorporate the Needleman- Wunsch algorithm (Needleman, S.B. & Wunsch, C.D., (1970) J. Mol. Biol. 48:443-453). A global alignment of nucleotide sequences using BLAST Global Alignment in this disclosure uses the following default parameters: match score = 2; mismatch score = -3; Gap Cost Existence score = 5; Gap Cost Extension Score = 2. A global alignment of protein sequences14NAI-5001911280in this disclosure using BLAST Global Alignment uses the following default parameters: Gap Cost Existence = 11; Gap Cost Extension = 1. A global alignment of nucleotide sequences using EMBOSS Needle in this disclosure uses the following default parameters: Output Format = pair; Matrix = DNAfull; Gap Open = 10; Gap Extend = 0.5; End Gap Penalty = false; End Gap Open = 10; End Gap Extend = 0.5. A global alignment of protein sequences using EMBOSS Needle in this disclosure uses the following default parameters: Output Format = pair; Matrix = BLOSUM62; Gap Open = 10; Gap Extend = 0.5; End Gap Penalty = false; End Gap Open = 10; End Gap Extend = 0.5.

[0047] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0048] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule.

[0049] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0050] The term “antibody-drug conjugate” or “ADC” refers to a conjugate comprising an antibody conjugated to one or more cytotoxic agents, optionally through one or more15NAI-5001911280linkers. The terms “anti-human B7-H3 antibody-drug conjugate,” “anti-human B7-H3 ADC” are used interchangeably and refer to a conjugate comprising an anti-human B7-H3 antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers.

[0051] As used herein, the term “functional fragment” of an antibody is also called “antigen binding fragment” of a human B7-H3 antibody, and is used to mean a partial fragment of the antibody having binding activity against human B7-H3, and includes, but not limited to, Fab, F(ab’)2, scFv, a diabody, a linear antibody and a multi-specific antibody formed from antibody fragments. In some embodiments, Fab’, which is a monovalent fragment of antibody variable regions obtained by treating F(ab’)2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. The antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has B7-H3-binding ability. These antigen-binding fragments include not only those obtained by treating a full-length molecule of an antibody protein with an appropriate enzyme, but proteins produced in appropriate host cells using a genetically engineered antibody gene.

[0052] The term “cytotoxic agent,” as used herein, refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. The cytotoxic agent can be an anti-angiogenic agent, a pro-apoptotic agent, an anti-mitotic agent, an anti-kinase agent, an alkylating agent, a hormone, a hormone agonist, a hormone antagonist, a chemokine, a drug, a prodrug, a toxin, an enzyme, an antimetabolite, an antibiotic, an alkaloid, or a radioactive isotope. Exemplary cytotoxic agents include calicheamycin, camptothecin, carboplatin, irinotecan, SN-38, camptothecan, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, etoposide, idarubicin, topotecan, vinca alkaloid, maytansinoid, maytansinoid analog, pyrrolobenzodiazepine, taxoid, duocarmycin, dolastatin, auristatin, and derivatives thereof.

[0053] A “linker” refers to a molecule that connects one composition to another, e.g., an antibody to an agent. Linkers described herein can conjugate an antibody to a cytotoxic agent. Exemplary linkers include a labile linker, an acid labile linker, a photolabile linker, a charged linker, a disulfide-containing linker, a peptidase-sensitive linker, a P-glucuronide-linker, a dimethyl linker, a thio-ether linker, and a hydrophilic linker. A linker can be cleavable or non-cleavable.

[0054] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology.16NAI-5001911280Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the term “treating” or any grammatical variation thereof refers to reducing and / or ameliorating the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) improvement or enhancement of the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein).

[0055] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans. Additionally or alternatively, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit risk ratio.

[0056] The term “pharmaceutically acceptable carrier” includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil / water emulsions, various types of wetting agents, and sterile solutions. Such carriers can be formulated by conventional methods and can be administered to the subject at a suitable dose. Preferably, the compositions are sterile. These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.

[0057] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., those described herein individually or in combination) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent,17NAI-5001911280including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance / molecule / agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule / agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0058] As used herein, the term “concurrently” means at the same time. For example, if two treatment regimens for a single patient are being conducted concurrently, then they are being conducted at the same time. It will be understood that two treatment regimens happening at the same time, does not necessarily mean that actual delivery of two drugs happens at the same time, as each regimen may call for a different dosing schedule and / or different delivery modes.

[0059] As used herein, the term “dosing cycle” refers to a period of treatment followed by an optional period of rest (no treatment) that is repeated on a regular schedule. The period of treatment may include a single drug or a combination of drugs. In some embodiments, the dosing cycle does not include a period of rest. As one non-limiting example, in some embodiments, a dosing cycle as described herein may be about 3 weeks or 21 days long. As referred to herein, “Day 1” is the first day of a dosing cycle. As referred to herein, “Day 1 of Cycle 1” or “Cycle 1 Day 1” or “C1D1” is the first day of the first dosing cycle. As referred to herein, “Day 8 of Cycle 1” or “Cycle 1 Day 8” or “ C1D8” is the eighth day of the first dosing cycle. As referred to herein, “Day 15 of Cycle 1” or “Cycle 1 Day 15” or “ C1D15” is the fifteenth day of the first dosing cycle. As referred to herein, “Day 1 of Cycle 2” or “Cycle 2 Day 1” or “ C2D1” is the first day of the second dosing cycle.

[0060] As used herein, the term “induction therapy” or “induction treatment” refers to the initial treatment given for a disease. The term “induction phase” or “induction” refers to a period of treatment wherein the subject is treated with induction therapy.18NAI-5001911280

[0061] As used herein, the term “maintenance therapy” or “maintenance treatment” refers to the treatment given for a disease after the initial therapy. The term “maintenance phase” or “maintenance” refers to a period of treatment wherein the subject is treated with maintenance therapy.

[0062] As used herein, the terms “subject” or “patient” are used interchangeably and mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human (e.g., an adult human, z.e., greater than or equal to 18 years of age). In some embodiments, the subject has a disease or condition that can be treated with an agent provided herein. In some embodiments, the disease or condition is a cancer.

[0063] Cancer” refers to any physiological condition in mammals characterized by unregulated cell growth; in particular, cellular-proliferative disease states. As used herein, “tumor” refers to any neoplastic cell growth or proliferation, whether malignant or benign, and to all pre-cancerous and cancerous cells and tissues. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is extensive-stage small cell lung cancer (ES-SCLC).

[0064] The term “administering” refers to the act of delivering a combination or composition described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration may be local or systemic. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).

[0065] As used herein, in some embodiments, the terms “administration in combination with” and “administered in combination” are used to represent a form of drug administration in which a plurality of active ingredients are contained or encapsulated in different preparations and administered simultaneously (a person skilled in the art would naturally understand that “simultaneously” or “at the same time” may be or may not be at about the same time) or separately or sequentially in any order at different times, or both contained or encapsulated in the same preparation and administered, unless the context otherwise requires and unless technically inconsistent.19NAI-5001911280

[0066] In the present disclosure, the term “anti-human B7-H3 antibody” refers to an antibody which binds specifically to B7-H3 (also known as: B cell antigen #7 homolog 3, PD-L3, or CD276), and preferably has an activity of internalization in B7-H3 -expressing cells by binding to B7-H3. In some embodiments, B7-H3 is human B7-H3.

[0067] As used herein, the terms “MK-6070” or “gocatamig” refer to the DLL3 targeting trispecific protein described herein comprising (a) a first domain (A) which specifically binds to human CD3; (b) a second domain (B) which specifically binds to human serum albumin; and (c) a third domain (C) which specifically binds to DLL3 (e.g., human DLL3). Gocatamig is also described in Proposed INN: List 130, WHO Drug Information, Vol. 37, No. 4, 2023 and in U.S. Patent No. 10,815,311, each of which is incorporated herein by reference in its entirety.

[0068] As used herein, the term “I-DXd” is an antibody-drug conjugate (ADC) comprising a B7 homolog 3 (B7-H3) immunoglobulin G1 monoclonal antibody, which is covalently linked to a cytotoxic payload, exatecan, or more preferably, an exatecan derivative deruxtecan (“DXd”). Exatecan is a topoisomerase I inhibitor that leads to apoptosis of the target cells. In some embodiments, I-DXd is ifinatamab deruxtecan.

[0069] As used herein, the term “ifinatamab deruxtecan” is an antibody-drug conjugate (ADC) comprising the anti-B7-H3 antibody immunoglobulin G1 monoclonal antibody ifinatamab, which is covalently linked to deruxtecan. In pre-clinical models, ifinatamab deruxtecan exerted potent antitumor activity in high B7-H3 expressing tumors with an acceptable pharmacokinetic and safety profile (Yamato, M., et. al., (2022). Mol Cancer Ther, 21(4), 635-646). Ifinatamab and ifinatamab deruxtecan are described, e.g., in WHO Drug Information, Vol. 36, No. 3, 2022 (Recommended INN: List 88). Deruxtecan is also described, e.g., in WHO Drug Information, Vol. 30, No. 4, 2016 (Proposed INN List 116).

[0070] As used herein, “atezolizumab”, alternatively referred to herein as “atezo,” is a humanized anti-programmed death-ligand 1 (PD-L1) IgGl monoclonal antibody. Atezolizumab has been approved by the U.S. FDA as described in the Prescribing Information for TECENTRIQ® (Genentech). Atezolizumab is also described, e.g., in WHO Drug Information, Vol. 29, No. 3, 2015 (Recommended INN: List 74).

[0071] The term “packaging material” refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, and the like).20NAI-5001911280

[0072] In general, the nomenclature used in this application is based on naming conventions adopted by the international union of pure and applied chemistry (IUPAC). Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.2. Methods of Treatment

[0073] Provided herein are combinational therapies based on a DLL3 targeting trispecific protein and an anti-human B7-H3 antibody-drug conjugate, detailed description of each of which is provided in sections below.

[0074] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and21NAI-5001911280(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26 or SEQ ID NO: 34.

[0075] In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0076] In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of atezolizumab.

[0077] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(I) administering to the subject a first therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises22NAI-5001911280(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and(II) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:23NAI-5001911280(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26 or SEQ ID NO: 34.

[0078] In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In one embodiment, the method further comprises administering to the subject a third therapeutically effective amount of atezolizumab.

[0079] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and24NAI-5001911280wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26 or SEQ ID NO: 34.

[0080] In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0081] In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of atezolizumab.

[0082] In another aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:25NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26 or SEQ ID NO: 34; wherein the subject has been previously administered with a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and26NAI-5001911280(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH.

[0083] In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0084] In one embodiment, the method further comprises administering to the subject a therapeutically effective amount of atezolizumab.

[0085] In one aspect, provided is a method for treating a small cell lung cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of atezolizumab; and wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26 or SEQ ID NO: 34; and27NAI-5001911280a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH.

[0086] In another aspect, provided is a method for treating cancer in a subject in need thereof, wherein the method comprises: (A) administering to the subject a first therapeutically effective amount of a DLL3 targeting protein; and (B) administering to the subject a second therapeutically effective amount of an anti-human B7-H3 antibody-drug conjugate.

[0087] In another aspect, provided is a method for treating cancer in a subject in need thereof, wherein the method comprises: (A) administering to the subject a therapeutically effective amount of a DLL3 targeting protein; and (B) administering to the subject a therapeutically effective amount of an anti-human B7-H3 antibody-drug conjugate. In some embodiments, the drug in the anti-human B7-H3 antibody-drug conjugate is a topoisomerase I inhibitor. In some embodiments, the DLL3 targeting protein may be tarlatamab, ZL-1310, BI764532, RO7616789 (ALPS12), or QLS31904. In some embodiments, the drug represented by the following formula is released to express an antitumor activity:28NAI-5001911280Formula IV

[0088] In another aspect, provided is a method wherein an antitumor compound represented by the following formula is conjugated to an anti-human B7-H3 antibody through a linker with the nitrogen atom of the amino group at position 1 as the connecting position:Formula III

[0089] In some embodiments, the antitumor compound is conjugated to the anti-human B7-H3 antibody through the linker via a thioether bond which is formed at a disulfide bond moiety present in the anti-human B7-H3 antibody. In some embodiments, the linker comprises a tetrapeptide residue of -Gly-Gly-Phe-Gly- (SEQ ID NO: 35).

[0090] In some embodiments of any of the above methods, the DLL3 targeting trispecific protein comprises the amino acid sequence of SEQ ID NO: 1.

[0091] In some aspects, the method provided herein may further comprise administering a therapeutically effective amount of a PD-1 inhibitor or PD-L1 inhibitor to the subject (PD- [L]l inhibitor or PD-1 / PD-L1 inhibitors or anti-PD-l / anti-PD-Ll), and optionally further comprise administering a therapeutically effective amount of carboplatin. In some aspects, the method provided herein may further comprise administering a therapeutically effective amount of an anti -PD-1 antibody or an anti-PD-Ll antibody to the subject, and optionally further comprise administering a therapeutically effective amount of carboplatin to the subject. In various embodiments of the method, the anti -PD-1 antibody is pembrolizumab, cemiplimab, dostarlimab, toripalimab, retifanlimab, tislelizumab, camrelizumab, sintilimab,29NAI-5001911280or nivolumab. In various embodiments of the method, the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or cosibelimab.

[0092] In some aspects, the method provided herein may further comprise administering a therapeutically effective amount of pembrolizumab (also known as KEYTRUDA®) or atezolizumab (also known as TECENTRIQ®) to the subject.

[0093] In some aspects, the method provided herein may further comprise administering a therapeutically effective amount of pembrolizumab (also known as KEYTRUDA®) to the subject.

[0094] In some aspects, the method provided herein may further comprise administering a therapeutically effective amount of atezolizumab (also known as TECENTRIQ®) to the subject.

[0095] In another aspect, provided is a method for treating small cell lung cancer in a subject in need thereof, wherein the method comprises: (A) administering to the subject a therapeutically effective amount of an anti-human B7-H3 antibody-drug conjugate; and (B) administering to the subject a therapeutically effective amount of a DLL3 targeting protein; and (C) administering to the subject a therapeutically effective amount of atezolizumab.

[0096] In one aspect, the method provided herein is a method for treating a cancer. In some embodiments, the cancer is a cancer associated with DLL3 expression (“DLL3+ tumor types”). In one aspect, the method provided herein is for treating small cell lung cancer (SCLC). In one aspect, the method provided herein is for treating extensive-stage small cell lung cancer (ES-SCLC). In one aspect, the method provided herein is for treating SCLC that is relapsed or refractory. In one aspect, the method provided herein is for treating ES-SCLC that is relapsed or refractory. In one embodiment, the ES-SCLC is Stage IV (T any, N any, Mla / b / c) as assessed by the American Joint Committee on Cancer Staging Manual, Eighth Edition. In another aspect, the method provided herein is for treating a neuroendocrine cancer. In some embodiments, the neuroendocrine cancer is melanoma, small cell bladder cancer, or prostate cancer (e.g., metastatic castration resistant prostate cancer).

[0097] In some embodiments, the method provided herein is for treating a neoplastic condition. Neoplastic conditions, in some embodiments, are benign or malignant; solid tumors or other blood neoplasia. In one embodiment, the neoplastic condition is a cancer. In one embodiment, the neoplastic condition is lung cancers (small cell carcinoma, adenocarcinoma, non-squamous cell carcinoma, squamous cell carcinoma, large cell carcinoma and the like). In some embodiments, the neoplastic condition (e.g., cancer) is associated with DLL3 expression.30NAI-5001911280

[0098] In certain embodiments, the combination therapy provided herein is used to treat subjects that have previously been treated (with anti-cancer agent) and have relapsed or determined to be refractory to the previous treatment. In some embodiments, the combination therapy of the present disclosure is used to treat subjects that have recurrent tumors.

[0099] In certain embodiments, the combination therapy provided herein is used to treat subjects that have histologically or cytologically confirmed SCLC that is extensive-stage (ES).

[0100] In one embodiment, the combination therapy provided herein is used to treat subjects that have previously been treated with at least one prior line of systemic therapy. In one embodiment, the prior line of systemic therapy includes platinum-based chemotherapy. In one embodiment, the prior line of systemic therapy includes platinum-based chemotherapy with or without PD-1 / PD-L1 inhibitors.

[0101] In other embodiment, the combination therapy provided herein is used to treat subjects that have previously been treated with only one prior line of platinum-based chemotherapy. In one embodiment, the prior line of platinum-based chemotherapy included platinum-based chemotherapy with or without PD-1 / PD-L1 inhibitors.

[0102] In other embodiment, the combination therapy provided herein is used to treat subjects that have received no prior line of systemic treatment for extensive-stage small cell lung cancer.

[0103] In one embodiment, the method provided herein is used to treat a subject that has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and an anti-PD-l / anti-PD-Ll treatment for extensive-stage small cell lung cancer. In one embodiment, the subject has not had evidence of progressive disease in the prior therapy.

[0104] In certain embodiments, the combination therapy of the disclosure reduces the growth of tumor cells in vivo when administered to a subject who has tumor cells that express DLL3. Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., computed tomography (CT) or magnetic resonance imaging (MRI)) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like.

[0105] In specific embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%,31NAI-5001911280with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-100%, about 75-100% or about 90-100%. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100%.

[0106] In one embodiment, the subject is a human subject. In one embodiment, the human subject is an adult, z.e., greater than or equal to 18 years of age.

[0107] In one aspect, provided herein is use of a DLL3 targeting trispecific protein and an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for the manufacture of a medicament for treating small cell lung cancer. In another aspect, provided herein is use of a DLL3 targeting trispecific protein for the manufacture of a medicament in combination with an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for treating small cell lung cancer. In yet another aspect, provided herein is use of an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for the manufacture of a medicament in combination with an DLL3 targeting trispecific protein for treating small cell lung cancer.

[0108] In one aspect, provided herein is use of a DLL3 targeting trispecific protein, antihuman B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) and atezolizumab for the manufacture of a medicament for treating small cell lung cancer. In another aspect, provided herein is use of a DLL3 targeting trispecific protein and anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) in combination with atezolizumab for treating small cell lung cancer. In yet another aspect, provided herein is use of an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for the manufacture of a medicament in combination with an DLL3 targeting trispecific protein and atezolizumab for treating small cell lung cancer.

[0109] In one aspect, provided herein is use of a DLL3 targeting trispecific protein and an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for the manufacture of a medicament for treating extensive-stage small cell lung cancer. In another aspect, provided herein is use of a DLL3 targeting trispecific protein for the manufacture of a medicament in combination with an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for treating extensive-stage small cell lung cancer. In yet another aspect, provided herein is use of an anti -human B7-H3 antibody-drug conjugate (e.g.,32NAI-5001911280ifinatamab deruxtecan) for the manufacture of a medicament in combination with an DLL3 targeting trispecific protein for treating extensive-stage small cell lung cancer.

[0110] In one aspect, provided herein is use of a DLL3 targeting trispecific protein, antihuman B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) and atezolizumab for the manufacture of a medicament for treating extensive-stage small cell lung cancer. In another aspect, provided herein is use of a DLL3 targeting trispecific protein and anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) in combination with atezolizumab for treating extensive-stage small cell lung cancer. In yet another aspect, provided herein is use of an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for the manufacture of a medicament in combination with an DLL3 targeting trispecific protein and atezolizumab for treating extensive-stage small cell lung cancer.

[0111] In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) in treating cancer in a subject in need thereof. In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) in treating extensive-stage small cell lung cancer in a subject in need thereof.

[0112] In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an antihuman B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) and atezolizumab in treating extensive- stage small cell lung cancer in a subject in need thereof.

[0113] In one aspect, provided herein is an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein in treating cancer in a subject in need thereof. In one aspect, provided herein is an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is an anti-human B7-H3 antibody-drug conjugate33NAI-5001911280(e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein in treating extensive-stage small cell lung cancer in a subject in need thereof.

[0114] In one aspect, provided herein is an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is an anti -human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is an anti-human B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan) for use in combination with a DLL3 targeting trispecific protein and atezolizumab in treating extensive-stage small cell lung cancer in a subject in need thereof.

[0115] In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti-human B7-H3 antibody-drug conjugate in treating cancer in a subject in need thereof, wherein the DLL3 targeting trispecific protein comprises:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is an scFv, and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH- CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH- CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH- CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH- CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)- (C)-COOH; and wherein the anti-human B7-H3 antibody-drug conjugate comprises an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:34NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL- CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26. In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the method provided herein further includes use of atezolizumab.

[0116] In one aspect, provided herein is a DLL3 targeting trispecific protein for use in combination with an anti-human B7-H3 antibody-drug conjugate in treating cancer in a subject in need thereof, wherein the DLL3 targeting trispecific protein comprises the amino acid sequence of SEQ ID NO: 1; and wherein the anti-human B7-H3 antibody-drug conjugate comprises an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:35NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26. In some embodiments, a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the method provided herein further includes use of atezolizumab.

[0117] In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating a neuroendocrine cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan in treating a neuroendocrine cancer in a subj ect in need thereof.36NAI-5001911280

[0118] In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab in treating extensive-stage small cell lung cancer in a subject in need thereof.

[0119] In one aspect, provided herein is tarlatamab for use in combination with an antihuman B7-H3 antibody-drug conjugate, in particular, “YL201” disclosed in US20240108745A1 (or WO2022 / 170971) in treating cancer such as small cell lung cancer or extensive-stage small cell lung cancer in a subject in need thereof. In a further aspect, provided herein is tarlatamab for use in combination with an anti-human B7-H3 antibodydrug conjugate, in particular, “YL201” disclosed in US20240108745A1 (or WO2022 / 170971), in addition to either atezolizumab or pembrolizumab, in treating cancer such as small cell lung cancer or extensive-stage small cell lung cancer in a subject in need thereof.

[0120] In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises administration of gocatamig to the subject once every two weeks and administration of ifinatamab deruxtecan to the subject once every two weeks. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises administration of gocatamig to the subject once every three weeks and administration of ifinatamab deruxtecan to the subject once every three weeks. In some embodiments, the subject has received only one prior line of treatment. In some embodiments, the subject has received at least one prior line of treatment. In some embodiments, the one prior line of treatment is a systemic therapy.

[0121] In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in 37NAI-5001911280treating cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating extensive- stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating a neuroendocrine cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan, pembrolizumab or atezolizumab, and further optionally carboplatin in treating a neuroendocrine cancer in a subject in need thereof.

[0122] In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and pembrolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and pembrolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is gocatamig for use in combination with ifinatamab38NAI-5001911280deruxtecan and atezolizumab in treating a neuroendocrine cancer in a subject in need thereof. In one aspect, provided herein is MK-6070 for use in combination with ifinatamab deruxtecan and atezolizumab in treating a neuroendocrine cancer in a subject in need thereof.

[0123] In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 in treating a neuroendocrine cancer in a subject in need thereof.

[0124] In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab in treating extensive-stage small cell lung cancer in a subject in need thereof.

[0125] In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises administration of ifinatamab deruxtecan to the subject once every two weeks and administration of gocatamig to the subject once every two weeks. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises administration of39NAI-5001911280ifinatamab deruxtecan to the subject once every three weeks and administration of gocatamig to the subject once every three weeks. In some embodiments, the subject has received only one prior line of treatment. In some embodiments, the subject has received at least one prior line of treatment. In some embodiments, the one prior line of treatment is a systemic therapy.

[0126] In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and pembrolizumab or atezolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and pembrolizumab or atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and pembrolizumab or atezolizumab, and further optionally carboplatin in treating extensive- stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and pembrolizumab or atezolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and pembrolizumab or atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and pembrolizumab or atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is go ifinatamab deruxtecan for use in combination with MK-6070 in treating a neuroendocrine cancer in a subject in need thereof. In one aspect, provided herein is go ifinatamab deruxtecan for use in combination with gocatamig in treating a neuroendocrine cancer in a subject in need thereof.

[0127] In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab, and further optionally carboplatin in treating small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab, and further optionally carboplatin in treating cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab, and further optionally carboplatin in treating40NAI-5001911280small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab, and further optionally carboplatin in treating extensive-stage small cell lung cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab, and further optionally carboplatin in treating a neuroendocrine cancer in a subject in need thereof. In one aspect, provided herein is ifinatamab deruxtecan for use in combination with MK-6070 and atezolizumab, and further optionally carboplatin in treating a neuroendocrine cancer in a subject in need thereof.

[0128] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein, and a therapeutically effective amount of the antibodydrug conjugate as defined herein (e.g., ifinatamab deruxtecan) in combination. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein, in combination with a therapeutically effective amount of the antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan). In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan), in combination with a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is a neuroendocrine cancer.

[0129] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein, and a therapeutically effective amount of the antibodydrug conjugate as defined herein (e.g., ifinatamab deruxtecan), and a therapeutically effective amount of atezolizumab in combination. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein, in combination with a therapeutically effective amount of the antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan), and a therapeutically effective amount of atezolizumab. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer,41NAI-5001911280comprising a therapeutically effective amount of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) as defined herein, in combination with a therapeutically effective amount of the DLL3 targeting trispecific protein as defined herein, and a therapeutically effective amount of atezolizumab. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is a neuroendocrine cancer.

[0130] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of gocatamig, in combination with a second therapeutically effective amount of ifinatamab deruxtecan. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of ifinatamab deruxtecan, in combination with a second therapeutically effective amount of gocatamig.

[0131] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a therapeutically effective amount of ifinatamab deruxtecan. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory.

[0132] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a therapeutically effective amount of ifinatamab deruxtecan, and a therapeutically effective amount of atezolizumab. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig, and a therapeutically effective amount of atezolizumab. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory.42NAI-5001911280

[0133] In some embodiments, provided herein is a use of the DLL3 targeting trispecific protein as defined herein for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan). In some embodiments, provided herein is a use of the antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan) for the preparation of a medicament for treating cancer, by administration in combination with the DLL3 targeting trispecific protein as defined herein. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory.

[0134] In some embodiments, provided herein is a use of a DLL3 targeting trispecific protein as defined herein (e.g., gocatamig) for the preparation of a medicament for treating cancer, by administration in combination with an antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan) and atezolizumab. In some embodiments, provided herein is a use of an antibody-drug conjugate as defined herein (e.g., ifinatamab deruxtecan) for the preparation of a medicament for treating cancer, by administration in combination with a DLL3 targeting trispecific protein as defined herein (e.g., gocatamig) and atezolizumab. In some embodiments, the cancer is small cell lung cancer. In other embodiments, the small cell lung cancer is relapsed or refractory. In some embodiments, the cancer is extensive-stage small cell lung cancer. In other embodiments, the extensive-stage small cell lung cancer is relapsed or refractory.

[0135] Any suitable dose(s) of the DLL3 targeting trispecific protein may be used in the methods, compositions, and kits described herein.

[0136] In some embodiments, for example, relevant to any method as disclosed herein, the therapeutically effective amount of the DLL3 targeting trispecific protein is administered according to a dosing schedule comprising the following steps: (i) administration of a priming dose of the DLL3 targeting trispecific protein, and (ii) administration of a target dose of the DLL3 targeting trispecific protein, wherein the target dose is either the same or higher than the priming dose.

[0137] In one embodiment, the method herein comprises administration of one priming dose of the DLL3 targeting trispecific protein. In some embodiments, for example, relevant to any method as disclosed herein, the priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of Cycle 1 of the dosing schedule.43NAI-5001911280

[0138] In one embodiment, the method herein comprises administration of two priming doses of the DLL3 targeting trispecific protein. In one embodiment, the two priming doses comprise a first priming dose and a second priming dose.

[0139] In some embodiments, for example, relevant to any method as disclosed herein, the priming dose of the DLL3 targeting trispecific protein is about 1 mg. In some embodiments, the priming dose of the DLL3 targeting trispecific protein is a dose of about 0.5 mg, about 1 mg, about 1.5 mg, or about 2 mg.

[0140] In some embodiments, for example, relevant to any method as disclosed herein, the first priming dose of the DLL3 targeting trispecific protein is about 1 mg. In some embodiments, the first priming dose of the DLL3 targeting trispecific protein is a dose of about 0.5 mg, about 1 mg, about 1.5 mg, or about 2 mg. In some embodiments, for example, relevant to any method as disclosed herein, the second priming dose of the DLL3 targeting trispecific protein is about 12 mg. In some embodiments, the second priming dose of the DLL3 targeting trispecific protein is a dose of about 10 mg, about 11 mg, about 12 mg, about 12.5 mg, or about 13 mg.

[0141] In one embodiment, the first priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of Cycle 1 of the dosing schedule. In one embodiment, the second priming dose of the DLL3 targeting trispecific protein is administered on Day 8 of Cycle 1 of the dosing schedule.

[0142] In some embodiments, for example, relevant to any method as disclosed herein, the first priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of the dosing schedule. In one embodiment, the second priming dose of the DLL3 targeting trispecific protein is administered on Day 8 of the dosing schedule.

[0143] In some embodiments, for example, relevant to any method as disclosed herein, the priming dose of the DLL3 targeting trispecific protein is administered once a week.

[0144] In some embodiments, for example, relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is from about 24 mg to about 100 mg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is a dose of about 12 mg, about 24 mg, about 36 mg, about 48 mg, about 50 mg, about 75 mg, or about 100 mg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is a dose of 12 mg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is a dose of 24 mg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is a dose of 36 mg. In other embodiments, the target dose of the DLL3 targeting trispecific protein is a dose of 48 mg.44NAI-5001911280

[0145] In some embodiments, for example, relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is administered for from about 1 week to about 6 weeks. In one embodiment, the priming dose (e.g., the first priming dose or the last priming dose) and the first target dose will be administered 1 week apart.

[0146] In one embodiment, the first target dose of the DLL3 targeting trispecific protein is administered on Day 8 of Cycle 1 of the dosing schedule. In one embodiment, the first target dose of the DLL3 targeting trispecific protein is administered on Day 15 of Cycle 1 of the dosing schedule. In one embodiment, the first target dose of the DLL3 targeting trispecific protein is administered on Day 19 of Cycle 1 of the dosing schedule. In one embodiment, the first target dose of the DLL3 targeting trispecific protein is administered on Day 22 of Cycle 1 of the dosing schedule. In another embodiment, the second target dose of the DLL3 targeting trispecific protein is administered on Day 29 of Cycle 1 of the dosing schedule.

[0147] In some embodiments, for example, relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is administered once every week, once every two weeks or once every three weeks. In some embodiments, the target dose of the DLL3 targeting trispecific protein is administered once every week. In some embodiments, the target dose of the DLL3 targeting trispecific protein is administered once every two weeks. In some embodiments, the target dose of the DLL3 targeting trispecific protein is administered once every three weeks. In one aspect, the target dose of the DLL3 targeting trispecific protein is maintained to the end of the dosing schedule after the administration of the priming dose of the DLL3 targeting trispecific protein.

[0148] In some embodiments, for example, relevant to any method as disclosed herein, the DLL3 targeting trispecific protein is administered intravenously (“IV”). In one embodiment, the DLL3 targeting trispecific protein is administered via a 60 ± 10 minute IV fusion.

[0149] In some embodiments, for example, relevant to any method as disclosed herein, the priming dose and target dose of the DLL3 targeting trispecific protein is administered intravenously (“IV”). In one embodiment, the priming dose and target dose of the DLL3 targeting trispecific protein is administered via a 60 ± 10 minute IV fusion.

[0150] Any suitable dose(s) of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) may be used in the methods, compositions, and kits described herein.

[0151] In some embodiments, for example, relevant to any method as disclosed herein, the therapeutically effective amount of the antibody-drug conjugate (e.g., ifinatamab45NAI-5001911280deruxtecan) is administered according to a dosing schedule comprising the following steps: (i) administration of a first dose of the antibody-drug conjugate, and (ii) administration of a second dose of the antibody-drug conjugate.

[0152] In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 4.5 mg / kg. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 4.5 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 4.8 mg / kg. In one embodiment, the first dose of the antibodydrug conjugate (e.g., ifinatamab deruxtecan) is a dose of 4.8 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 6.4 mg / kg. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 6.4 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 8 mg / kg. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 8 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 10 mg / kg. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 10 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 12 mg / kg. In one embodiment, the first dose of the antibodydrug conjugate (e.g., ifinatamab deruxtecan) is a dose of 12 mg / kg. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose ranging from about 4 mg / kg to about 12 mg / kg.

[0153] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 4.5 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 4.5 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 4.8 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 4.8 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 6.4 mg / kg. In one46NAI-5001911280embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 6.4 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 8 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 8 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 10 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 10 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 12 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of 12 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose ranging from about 4 mg / kg to about 12 mg / kg.

[0154] In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose ranging from about 8 mg / kg to about 12 mg / kg. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is a dose of about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, or about 12.0 mg / kg.

[0155] In some embodiments, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) are the same. In some embodiments, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) are different.

[0156] In some embodiments, for example, relevant to any method as disclosed herein, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered concurrently with a priming dose (e.g., the first priming dose) of the DLL3 targeting trispecific protein. In another embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered before a priming dose (e.g., the first priming dose) of the DLL3 targeting trispecific protein. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered on Day 1 of the dosing schedule. In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered 1 day before a priming dose (e.g., the first priming dose) of the DLL3 targeting trispecific protein.47NAI-5001911280

[0157] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every two weeks. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every three weeks.

[0158] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered twenty -two (22) days after the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan). In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered on Day 22 of the dosing schedule. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered for from about 1 week to about 6 weeks.

[0159] In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered fifteen (15) days after the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan). In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered on Day 15 of the dosing schedule. In some embodiments, for example, relevant to any method as disclosed herein, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered for from about 1 week to about 6 weeks.

[0160] In some embodiments relevant to any method as disclosed herein, the administration of the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is maintained to the completion of the administration of the target dose of the DLL3 targeting trispecific protein.

[0161] In some embodiments relevant to any method as disclosed herein, the antibodydrug conjugate (e.g., ifinatamab deruxtecan) is administered before administration of the DLL3 targeting trispecific protein. In some embodiments relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered 24 hours before administration of the DLL3 targeting trispecific protein. In some embodiments, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered at least 6 hours before administration of the DLL3 targeting trispecific protein. In some embodiments, the antibodydrug conjugate (e.g., ifinatamab deruxtecan) is administered at least 30 minutes before administration of the DLL3 targeting trispecific protein.48NAI-5001911280

[0162] In some embodiments of this disclosure, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered intravenously (“IV”). In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 30 ± 5 minute IV fusion. In one embodiment, the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 90 ± 10 minute IV fusion.

[0163] In some embodiments of this disclosure, the first dose and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered intravenously (“IV”). In one embodiment, the first dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 30 ± 5 minute IV fusion. In one embodiment, the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered via a 90 ± 10 minute IV fusion. In one embodiment, the first dose of the antibody-drug conjugate is administered via a 90 ± 10 minute IV fusion. In one embodiment, the second dose of the antibody-drug conjugate is administered via a 30 ± 15 minute IV fusion.

[0164] In some embodiments relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is administered once every two weeks and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every two weeks. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 12 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 5.4 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 12 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 8 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 24 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 5.4 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 24 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 8 mg / kg.

[0165] In some embodiments relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is administered once every three weeks and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every three weeks. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 18 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 8 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 18 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 12 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 36 mg and the second dose of the antibody-drug conjugate49NAI-5001911280(e.g., ifinatamab deruxtecan) is 8 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 36 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 12 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 36 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 10 mg / kg.

[0166] In some embodiments relevant to any method as disclosed herein, the target dose of the DLL3 targeting trispecific protein is administered once every two weeks and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is administered once every three weeks. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 12 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 8 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 12 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 12 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 24 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 8 mg / kg. In some embodiments, the target dose of the DLL3 targeting trispecific protein is 24 mg and the second dose of the antibody-drug conjugate (e.g., ifinatamab deruxtecan) is 12 mg / kg.

[0167] In some embodiments of the various methods, pharmaceutical compositions for use or uses provided herein, a PD-1 or PD-L1 inhibitor (e.g., pembrolizumab or atezolizumab) is further used in combination.

[0168] Any suitable dose(s) of atezolizumab may be used in the methods, compositions, and kits described herein.

[0169] In some embodiments, for example, relevant to any method as disclosed herein, atezolizumab is administered at a dose of about 100 mg to about 2500 mg. In an embodiment, atezolizumab is administered at a dose of about 200 mg. In an embodiment, atezolizumab is administered at a dose of about 400 mg. In an embodiment, atezolizumab is administered at a dose of about 600 mg. In an embodiment, atezolizumab is administered at a dose of about 800 mg. In an embodiment, atezolizumab is administered at a dose of about 1000 mg. In an embodiment, atezolizumab is administered at a dose of about 1200 mg. In an embodiment, atezolizumab is administered at a dose of 1200 mg. In an embodiment, atezolizumab is administered at a dose of about 1400 mg. In an embodiment, atezolizumab is administered at a dose of about 1600 mg. In an embodiment, atezolizumab is administered at a dose of about 1800 mg. In an embodiment, atezolizumab is administered at a dose of about 2000 mg. In an embodiment, atezolizumab is administered at a dose of about 2000 mg. In an embodiment,50NAI-5001911280atezolizumab is administered at a dose of about 2200 mg. In an embodiment, atezolizumab is administered at a dose of about 2400 mg.

[0170] In one embodiment, the atezolizumab is administered prior to administration of the DLL3 targeting trispecific protein. In one embodiment, the atezolizumab is administered at least 30 minutes prior to administration of the DLL3 targeting trispecific protein.

[0171] In some embodiments, for example, relevant to any method as disclosed herein, atezolizumab is administered intravenously (“IV”). In one embodiment, atezolizumab is administered via a 30 ± 10 minute IV infusion. In one embodiment, atezolizumab is administered via a 30 ± 5 minute IV infusion. In one embodiment, atezolizumab is administered via a 60 ± 15 minute IV infusion.

[0172] In some embodiments, for example, relevant to any method as disclosed herein, the atezolizumab is administered once every three weeks. In some embodiments, for example, relevant to any method as disclosed herein, the next dose of atezolizumab is administered twenty-two (22) days after the previous dose of atezolizumab. In one embodiment, the atezolizumab is administered on Day 22 of the dosing cycle.

[0173] Any suitable dose(s) of carboplatin may be used in the methods, compositions, and kits described herein.

[0174] In some embodiments, for example, relevant to any method as disclosed herein, carboplatin is administered at a dose of area under the curve (“AUC”) 5 mg / mL / min. In some embodiments, carboplatin is administered at a dose of AUC 4 mg / mL / min. In some embodiments, carboplatin is administered at a dose of AUC 3 mg / mL / min. In some embodiments, the maximum dose of carboplatin is 750 mg. In some embodiments, the maximum dose of carboplatin is 600 mg. In some embodiments, the maximum dose of carboplatin is 450 mg.

[0175] In some embodiments, for example, relevant to any method as disclosed herein, carboplatin is administered intravenously. In one embodiment, carboplatin is administered via a 30 to 60 minute IV infusion.

[0176] In some embodiments, for example, relevant to any method as disclosed herein, the carboplatin is administered once every three weeks. In some embodiments, for example, relevant to any method as disclosed herein, the next dose of carboplatin is administered twenty -two (22) days after the previous dose of carboplatin. In one embodiment, carboplatin is administered on Day 22 of the dosing cycle. In some embodiments, carboplatin is administered for four dosing cycles.51NAI-5001911280

[0177] In one embodiment, the atezolizumab is administered prior to administration of carboplatin. In one embodiment, the atezolizumab is administered at least 30 minutes prior to administration of carboplatin.

[0178] Any suitable dose(s) of etoposide may be used in the methods, compositions, and kits described herein.

[0179] In some embodiments, for example, relevant to any method as disclosed herein, etoposide is administered at a dose of about 50 mg / m2to about 150 mg / m2. In some embodiments, etoposide is administered at a dose of about 50 mg / m2. In some embodiments, etoposide is administered at a dose of about 60 mg / m2. In some embodiments, etoposide is administered at a dose of about 70 mg / m2. In some embodiments, etoposide is administered at a dose of about 80 mg / m2. In some embodiments, etoposide is administered at a dose of about 90 mg / m2. In some embodiments, etoposide is administered at a dose of about 100 mg / m2. In some embodiments, etoposide is administered at a dose of about 110 mg / m2. In some embodiments, etoposide is administered at a dose of about 120 mg / m2. In some embodiments, etoposide is administered at a dose of about 130 mg / m2. In some embodiments, etoposide is administered at a dose of about 140 mg / m2. In some embodiments, etoposide is administered at a dose of about 150 mg / m2.

[0180] In some embodiments, for example, relevant to any method as disclosed herein, etoposide is administered intravenously. In one embodiment, etoposide is administered via a 30 to 60 minute IV infusion.

[0181] In some embodiments, for example, relevant to any method as disclosed herein, the etoposide is administered once every three weeks. In some embodiments, etoposide is administered administered on Day 1, Day 2, and Day 3 of the dosing schedule. In some embodiments, etoposide is administered for four dosing cycles.

[0182] In one embodiment, the atezolizumab is administered first, followed by administration of carboplatin, which is followed by administration of etoposide. In one embodiment, there is a minimum time of 30 minutes between each administration.

[0183] In some embodiments, the method provided herein may include administering a therapeutically effective amount of a CRS / IRR prophylaxis medication (e.g., pre-infusion dexamethasone, acetaminophen, diphenhydramine, post-dose dexamethasone and intravenous fluids) to the subject. In one embodiment, the subject is premedicated with one or more of tocilizumab, an antihistamine, acetaminophen, 5-HT3 receptor antagonist, NK-1 receptor antagonist and / or a corticosteroid. In one embodiment, the corticosteroid comprises dexamethasone.52NAI-5001911280

[0184] In one aspect, provided herein is a method for treating extensive-stage small cell lung cancer in a subject in need thereof, wherein the method comprises: (i) administering to the subject in Cycle 1 of the dosing schedule: 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and (ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule: a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously. In one embodiment, the subject has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and an anti-PD-l / anti-PD-Ll treatment for extensive-stage small cell lung cancer. In one embodiment, the subject has not had evidence of progressive disease in the prior therapy.

[0185] In one aspect, provided herein is a method for treating extensive-stage small cell lung cancer in a subject in need thereof, wherein the method comprises: (i) administering to the subject in Cycle 1 of the dosing schedule: 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and (ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule: a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously. In one embodiment, the subject has received no prior line of systemic treatment for extensive-stage small cell lung cancer.

[0186] In one aspect, provided herein is a method for treating extensive-stage small cell lung cancer in a subject in need thereof, wherein the method comprises: (i) administering to the subject in Cycle 1 of the dosing schedule: 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; (ii) following completion of step (i), administering to53NAI-5001911280the subject for Cycles 2-4 of the dosing schedule: a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and (iii) following completion of step (ii), administering to the subject for subsequent cycles of the dosing schedule: a therapeutically effective amount of atezolizumab at a dose of about 1200 mg, once every three weeks, intravenously; and concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously. In one embodiment, the subject has received no prior line of systemic treatment for extensive-stage small cell lung cancer.

[0187] In one aspect, provided herein is a method for treating extensive-stage small cell lung cancer in a subject in need thereof, wherein the method comprises: (i) administering to the subject for four cycles of the dosing schedule: a therapeutically effective amount of atezolizumab at a dose of about 1200 mg, once every three weeks, intravenously; a therapeutically effective amount of carboplatin at a dose of about AUC 5 mg / mL / min, once every three weeks, intravenously; and a therapeutically effective amount of etoposide at a dose of about 100 mg / m2on Day 1, Day 2 and Day 3 of each cycle of the dosing schedule, every three weeks, intravenously; (ii)following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule a therapeutically effective amount of atezolizumab at a dose of about 1200 mg, once every three weeks, intravenously. In one embodiment, the subject has received no prior line of systemic treatment for extensive-stage small cell lung cancer.3. DLL3 Targeting Trispecific Protein

[0188] In one aspect, for example, relevant to any method as disclosed herein, the DLL3 targeting trispecific protein (also referred to herein as a DLL3 binding trispecific protein, a DLL3 trispecific protein, or a DLL3 TriTAC™) comprises (a) a first domain (A) which specifically binds to human CD3; (b) a second domain (B) which specifically binds to human serum albumin; and (c) a third domain (C) which specifically binds to DLL3 (e.g., human DLL3). The three domains in DLL3 targeting trispecific proteins are arranged in the order H2N-(A)-(B)-(C)-COOH.

[0189] In some embodiments, domain A, domain B, and domain C of the trispecific binding protein of this disclosure, are independently antigen-specific binding domain54NAI-5001911280polypeptides that specifically bind to targets, such as targets on diseased cells, or targets on other cells that support the diseased state, such as targets on stromal cells that support tumor growth or targets on immune cells that support disease-mediated immunosuppression.

[0190] The DLL3 targeting trispecific proteins described herein are designed to allow specific targeting of cells expressing DLL3 by recruiting cytotoxic T cells. In some embodiments, this improves efficacy compared to ADCC (antibody dependent cell-mediated cytotoxicity), which is using full length antibodies directed to a sole antigen and is not capable of directly recruiting cytotoxic T cells. In contrast, by engaging CD3 molecules expressed specifically on these cells, the DLL3 targeting trispecific proteins can crosslink cytotoxic T cells with cells expressing DLL3 in a highly specific fashion, thereby directing the cytotoxic potential of the T cell towards the target cell. The DLL3 targeting trispecific proteins described herein engage cytotoxic T cells via binding to the surface-expressed CD3 proteins, which form part of the T cell receptor (TCR). Simultaneous binding of several DLL3 trispecific antigen-binding protein to CD3 and to DLL3 expressed on the surface of particular cells causes T cell activation and mediates the subsequent lysis of the particular DLL3 expressing cell. Thus, DLL3 targeting trispecific proteins are contemplated to display strong, specific and efficient target cell killing. In some embodiments, the DLL3 targeting trispecific proteins described herein stimulate target cell killing by cytotoxic T cells to eliminate pathogenic cells (e.g., tumor cells expressing DLL3). In some of such embodiments, cells are eliminated selectively, thereby reducing the potential for toxic side effects.

[0191] The DLL3 targeting trispecific proteins described herein have extended pharmacokinetic elimination half-time due to having a half-life extension domain such as a domain that specifically binds to a serum albumin protein (e.g., a human serum albumin protein, HSA). In this respect, the DLL3 targeting trispecific proteins described herein have an extended serum elimination half-time of about two, three, about five, about seven, about 10, about 12, or about 14 days in some embodiments.

[0192] Another feature of the DLL3 targeting trispecific proteins described herein is that they are of a single-polypeptide design with flexible linkage of their domains. This allows for facile production and manufacturing of the DLL3 targeting trispecific proteins as they can be encoded by single cDNA molecule to be easily incorporated into a vector. Further, because the DLL3 targeting trispecific proteins described herein are a monomeric single polypeptide chain, there are no chain pairing issues or a requirement for dimerization. It is contemplated that the DLL3 targeting trispecific proteins described herein have a reduced tendency to55NAI-5001911280aggregate unlike other reported molecules such as bispecific proteins with Fc-gamma immunoglobulin domains.

[0193] In the DLL3 targeting trispecific proteins described herein, the domains are, in some embodiments, linked by internal linkers LI and L2, where LI links the first and second domain of the DLL3 targeting trispecific proteins and L2 links the second and third domains of the DLL3 targeting trispecific proteins. Linkers LI and L2 have an optimized length and / or amino acid composition. In some embodiments, linkers LI and L2 are the same length and amino acid composition. In other embodiments, LI and L2 are different. In certain embodiments, internal linkers LI and / or L2 are “short,” i.e., consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acid residues. Thus, in certain instances, the internal linkers consist of about 12 or less amino acid residues. In the case of 0 amino acid residues, the internal linker is a peptide bond. In certain embodiments, internal linkers LI and / or L2 are “long,” i.e., consist of 15, 20 or 25 amino acid residues. In some embodiments, these internal linkers consist of about 3 to about 15, for example 8, 9 or 10 contiguous amino acid residues.Regarding the amino acid composition of the internal linkers LI and L2, peptides are selected with properties that confer flexibility to the DLL3 targeting trispecific proteins, do not interfere with the binding domains as well as resist cleavage from proteases. For example, glycine and serine residues generally provide protease resistance. Examples of internal linkers suitable for linking the domains in the DLL3 targeting trispecific proteins include but are not limited to GGGGSGGGS (SEQ ID NO: 27) or GGGGSGGGGSGGGGS (SEQ ID NO: 31). In another embodiment, internal linker LI and / or L2 is GGGGSGGGS (SEQ ID NO: 27).

[0194] In some embodiments, for example, relevant to any method as disclosed herein, the DLL3 targeting trispecific proteins comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the DLL3 targeting trispecific proteins comprises a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 1.

[0195] In some embodiments, the DLL3 targeting trispecific proteins provided herein may undergo post-translational modifications as known in the art. Examples of post- translational modifications include, but are not limited to, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and56NAI-5001911280others known in the art. See, Liu, et. al., J. Pharma. Sci. vol. 97, no. 7, pp. 2426-2447 (2008). Other types of modifications include noncovalent interaction, conformational heterogeneity, and aggregation. Id.

[0196] In some embodiments, an N-terminal E or Q of a DLL3 targeting trispecific protein provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of a DLL3 targeting trispecific protein provided herein is removed. In other embodiments, an N-terminal E or Q of a DLL3 targeting trispecific protein provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the DLL3 targeting trispecific protein (e.g., heavy chain C-terminal amino acid) is removed. The present disclosure includes any of the above described post-translational modifications of any of the DLL3 targeting trispecific proteins provided herein.3.1. CD3 binding domain

[0197] The specificity of the response of T cells is mediated by the recognition of antigen (displayed in context of a major histocompatibility complex, MHC) by the TCR. As part of the TCR, CD3 is a protein complex that includes a CD3y (gamma) chain, a CD35 (delta) chain, and two CD3s (epsilon) chains which are present on the cell surface. CD3 associates with the a (alpha) and P (beta) chains of the TCR as well as CD3^ (zeta) altogether to comprise the complete TCR. Clustering of CD3 on T cells, such as by immobilized anti-CD3 antibodies leads to T cell activation similar to the engagement of the T cell receptor but independent of its clone-typical specificity.

[0198] In one aspect, for example, relevant to any method as disclosed herein, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to CD3 (e.g., human CD3). In one aspect, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to human CD3. In some embodiments, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to CD3y. In some embodiments, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to CD35. In some embodiments, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to CD3s. In certain embodiments, the CD3 binding domain of the DLL3 targeting trispecific proteins described herein exhibit not only potent CD3 binding affinities with human CD3, but show also excellent cross reactivity with the respective cynomolgus monkey CD3 proteins.57NAI-5001911280

[0199] In some embodiments, for example, relevant to any method as disclosed herein, the CD3 binding domain of the DLL3 trispecific antigen-binding protein can be any domain that binds to CD3 including but not limited to domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody. In some instances, it is beneficial for the CD3 binding domain to be derived from the same species in which the DLL3 trispecific antigen-binding protein will ultimately be used in. For example, for use in humans, it may be beneficial for the CD3 binding domain of the DLL3 trispecific antigen-binding protein to comprise human or humanized residues from the antigen binding domain of an antibody or antibody fragment. Thus, in one aspect, the antigen-binding domain comprises a humanized or human antibody or an antibody fragment, or a murine antibody or antibody fragment.

[0200] In one embodiment, the anti-CD3 binding domain is a single chain variable fragment (scFv) comprising a light chain and a heavy chain of an amino acid sequence provided herein. In an embodiment, the anti-CD3 binding domain comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided herein, or a sequence with 95-99% identity with an amino acid sequence provided herein; and / or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided herein, or a sequence with 95-99% identity to an amino acid sequence provided herein. In some embodiments, for example, relevant to any method as disclosed herein, the anti-CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 2, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 2.

[0201] In some embodiments, for example, relevant to any method as disclosed herein, the anti-CD3 binding domain comprises three heavy chain CDRs (VH-CDR1, VH-CDR2, and VH-CDR3), and three light chain CDRs (VL-CDR1, VL-CDR2, and VL-CDR3). In some embodiments, the VH-CDR1 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 5, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 5. In some embodiments, the VH-CDR2 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 6, or a sequence comprising one58NAI-5001911280or more modifications or substitutions in SEQ ID NO: 6. In some embodiments, the VH- CDR3 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 7, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 7. In some embodiments, the VL-CDR1 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 8, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 8. In some embodiments, the VL-CDR2 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 9, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 9. In some embodiments, the VL-CDR3 of the CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 10, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 10.

[0202] In one embodiment, the humanized or human anti-CD3 binding domain is an scFv, and a light chain variable region (VL) comprising an amino acid sequence described herein, is attached to a heavy chain variable region (VH) comprising an amino acid sequence described herein, via an scFv linker. In some embodiments, linkers in an scFv comprise glycine and serine residues. In one embodiment, the scFv linker comprises the amino acid sequence of (GGGGS)3 (SEQ ID NO: 31).

[0203] In some embodiments, for example, relevant to any method as disclosed herein, the anti-CD3 binding domain comprises as a VH, the amino acid sequence of SEQ ID NO: 3, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 3. In some examples, the anti-CD3 binding domain comprises as a VL, the amino acid sequence of SEQ ID NO: 4, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-CD3 binding domain comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3. In other embodiments, the anti-CD3 binding domain comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL- CDR3, respectively, within SEQ ID NO: 4.

[0204] In some embodiments, for example, relevant to any method as disclosed herein, CD3 binding domain of DLL3 targeting trispecific antigen-binding protein has an affinity to CD3 on CD3 expressing cells with a KD of 1000 nM or less, 500 nM or less, 200 nM or less,59NAI-5001911280100 nM or less, 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, or 0.5 nM or less. In some embodiments, the CD3 binding domain of DLL3 targeting trispecific antigen-binding protein has an affinity to CD3s, y, or 5 with a KD of 1000 nM or less, 500 nM or less, 200 nM or less, 100 nM or less, 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, or 0.5 nM or less. In further embodiments, CD3 binding domain of DLL3 targeting trispecific antigen-binding protein has low affinity to CD3, i.e., about 100 nM or greater.

[0205] In some embodiments, the CD3 binding domain provided herein may undergo post-translational modifications as known in the art. Examples of post-translational modifications include, but are not limited to, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art. See, Liu, et. al., supra. Other types of modifications include noncovalent interaction, conformational heterogeneity, and aggregation. Id.

[0206] In some embodiments, an N-terminal E or Q of the CD3 binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C- terminal K of the CD3 binding domain provided herein is removed. In other embodiments, an N-terminal E or Q of the CD3 binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the CD3 binding domain is removed. The present disclosure includes any of the above-described post-translational modifications of any of the CD3 binding domains provided herein.3.2. Human Serum Albumin (HSA) binding domain

[0207] Contemplated herein are domains which extend the half-life of an antigen-binding domain. Such domains are contemplated to include but are not limited to albumin binding domains, Fc domains, small molecules, and other half-life extension domains known in the art.

[0208] Human serum albumin (HSA) (molecular mass 67 kDa) is the most abundant protein in plasma, present at about 50 mg / ml (600 pM), and has a half-life of around 20 days in humans. HSA serves to maintain plasma pH, contributes to colloidal blood pressure, functions as carrier of many metabolites and fatty acids, and serves as a major drug transport protein in plasma. Noncovalent association with albumin extends the elimination half-time of short lived proteins.60NAI-5001911280

[0209] In one aspect, for example, relevant to any method as disclosed herein, the DLL3 targeting trispecific proteins described herein comprise a domain which specifically binds to HSA. In some embodiments, the HSA binding domain of the DLL3 targeting trispecific antigen-binding protein can be any domain that binds to HSA including but not limited to domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody. In some embodiments, the HSA binding domain is a single chain variable fragments (scFv), single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived single-domain antibody, peptide, ligand or small molecule entity specific for HSA. In certain embodiments, the HSA binding domain is a single-domain antibody.

[0210] In some embodiments, the half-life extension domain of HSA has a high binding affinity. In other embodiments, the half-life extension domain of HSA has a medium binding affinity. In yet other embodiments, the half-life extension domain of HSA has a low or marginal binding affinity. Exemplary binding affinities include KD concentrations at 10 nM or less (high), between 10 nM and 100 nM (medium), and greater than 100 nM (low).

[0211] In some embodiments, for example, relevant to any method as disclosed herein, the HSA binding domain comprises the amino acid sequence of SEQ ID NO: 11, or a sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identical to SEQ ID NO: 11. In some embodiments, for example, relevant to any method as disclosed herein, the HSA binding domain comprises three heavy chain CDRs and three light chain CDRs. In some examples, the HSA binding domain comprises three heavy chain CDRs or three light chain CDRs. The heavy chain CDR1 (VH-CDR1) of the HSA binding domain, in some embodiments, comprises the amino acid sequence of SEQ ID NO: 12, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 12. The heavy chain CDR2 (VH-CDR2) of the HSA binding domain, in some embodiments, comprises the amino acid sequence of SEQ ID NO: 13, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 13. The heavy chain CDR3 (VH-CDR3) of the HSA binding domain, in some embodiments, comprises the amino acid sequence of SEQ ID NO: 14, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 14.

[0212] In some embodiments, for example, relevant to any method as disclosed herein, the HSA binding domain is a VHH domain, comprising a heavy chain variable region (VH) comprising an amino acid sequence described herein. In some examples, the HSA binding domain comprises as a VH, the amino acid sequence of SEQ ID NO: 11, or a sequence that is61NAI-5001911280at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the HSA binding domain comprises a VH-CDR1, a VH-CDR2, and a VH- CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH- CDR3, respectively, within SEQ ID NO: 11.

[0213] In some embodiments, for example, relevant to any method as disclosed herein, the HSA binding domain provided herein may undergo post-translational modifications as known in the art. Examples of post-translational modifications include, but are not limited to, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible crosslinking, truncation and others known in the art. See, Liu, et. al., supra. Other types of modifications include noncovalent interaction, conformational heterogeneity, and aggregation. Id.

[0214] In some embodiments, an N-terminal E or Q of the HSA binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C- terminal K the HSA binding domain provided herein is removed. In other embodiments, an N-terminal E or Q of the HSA binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the HSA binding domain is removed. The present disclosure includes any of the above-described post-translational modifications of any of the HSA binding domains provided herein.3.3. DLL3 binding domain

[0215] DLL3 (also known as Delta-like Ligand 3 or SCDO1) is a member of the Deltalike family of Notch DSL ligands. Representative DLL3 protein orthologs include, but are not limited to, human (Accession Nos. NP_058637 and NP_982353), chimpanzee (Accession No. XP_003316395), mouse (Accession No. NP_031892), and rat (Accession No.NP 446118). In humans, the DLL3 gene consists of 8 exons spanning 9.5 kbp located on chromosome 19ql 3. Alternate splicing within the last exon gives rise to two protein isoforms that share overall 100% identity across their extracellular domains and their transmembrane domains, differing only in that the longer isoform contains an extended cytoplasmic tail containing 32 additional residues at the carboxy terminus of the protein. The extracellular region of the DLL3 protein, comprises six EGF-like domains, the single DSL domain and the62NAI-5001911280N-terminal domain. The DLL3 binding domain of the DLL3 targeting trispecific proteins of the present disclosure are, in some embodiments, engineered fabricated and / or selected to react with both isoforms of DLL3 or a single isoform of the protein or, conversely, comprise a pan-DLL binding domain that reacts or associates with at least one additional DLL family member in addition to DLL3. In some embodiments, the DLL3 binding domain associates or binds to a specific epitope, portion, motif or domain of DLL3.

[0216] The design of the DLL3 targeting trispecific proteins described herein allows the binding domain to DLL3 to be flexible in that the binding domain to DLL3 can be any type of binding domain, including but not limited to, domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody. In some embodiments, the DLL3 binding domain of the DLL3 targeting trispecific protein is a single-domain antibody such as a heavy chain variable domain (VH), a variable domain (VHH) of a llama derived sdAb, a peptide, a ligand or a small molecule entity specific for DLL3. In certain embodiments, the DLL3 binding domain is a single-domain antibody. In some embodiments, for example, relevant to any method as disclosed herein, the anti-DLL3 single-domain antibody comprises heavy chain variable complementarity determining regions (CDR), VH-CDR1, VH-CDR2, and VH-CDR3.

[0217] In some embodiments, for example, relevant to any method as disclosed herein, the DLL3 binding domain comprises an amino acid sequence of SEQ ID NO: 15. In various embodiments, the DLL3 binding domain of the present disclosure is at least about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence of SEQ ID NO: 15. In another embodiment, the DLL3 binding domain is an sdAb, wherein the sdAb comprises a VH- CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15.

[0218] In some embodiments, for example, relevant to any method as disclosed herein, CDR1 of the DLL3 binding domain comprises an amino acid sequence of SEQ ID NO: 16, or a variant having one, two, three, four, five, six, seven, eight, or nine amino acid substitutions in an amino acid sequence of SEQ ID NO: 16. In some embodiments, CDR2 comprises an amino acid sequence of SEQ ID NO: 17, or a variant having one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions in an amino acid sequence of SEQ ID NO:63NAI-500191128017. In some embodiments, the CDR3 comprises an amino acid sequence of SEQ ID NO: 18, or a variant having one, two, three, four, five, six, seven, or eight amino acid substitutions in an amino acid sequence of SEQ ID NO: 18.

[0219] In some embodiments, for example, relevant to any method as disclosed herein, the DLL3 binding domain of the DLL3 targeting tri specific binding protein is cross-reactive with human and cynomolgus DLL3. In some embodiments, the DLL3 binding domain is specific for human DLL3. In certain embodiments, the DLL3 binding domain disclosed herein binds to human DLL3 with a human Kd (hKd). In certain embodiments, the DLL3 binding domain disclosed herein binds to cynomolgus DLL3 with a cynomolgus Kd (cKd). In certain embodiments, the DLL3 binding domain disclosed herein binds to both cynomolgus DLL3 and a human DLL3, with a cyno Kd (cKd) and a human Kd, respectively (hKd). In some embodiments, the DLL3 binding protein binds to human and cynomolgus DLL3 with comparable binding affinities (z.e., hKd and cKd values do not differ by more than ± 10%). In some embodiments, the hKd and the cKd range from about 0.001 nM to about 500 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 450 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 400 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 350 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 300 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 250 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 200 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 150 nM. In some embodiments, the hKd and the cKd range from about 0.001 nM to about 100 nM. In some embodiments, the hKd and the cKd range from about 0. 1 nM to about 90 nM. In some embodiments, the hKd and the cKd range from about 0. 2 nM to about 80 nM. In some embodiments, the hKd and the cKd range from about 0. 3 nM to about 70 nM. In some embodiments, the hKd and the cKd range from about 0. 4 nM to about 50 nM. In some embodiments, the hKd and the cKd range from about 0.5 nM to about 30 nM. In some embodiments, the hKd and the cKd range from about 0.6 nM to about 10 nM. In some embodiments, the hKd and the cKd range from about 0.7 nM to about 8 nM. In some embodiments, the hKd and the cKd range from about 0.8 nM to about 6 nM. In some embodiments, the hKd and the cKd range from about 0.9 nM to about 4 nM. In some embodiments, the hKd and the cKd range from about 1 nM to about 2 nM.

[0220] In certain embodiments, for example, relevant to any method as disclosed herein, the DLL3 binding domains of the present disclosure preferentially bind membrane bound64NAI-5001911280DLL3 over soluble DLL3. Membrane bound DLL3 refers to the presence of DLL3 in or on the cell membrane surface of a cell that expresses DLL3. Soluble DLL3 refers to DLL3 that is no longer on in or on the cell membrane surface of a cell that expresses or expressed DLL3. In certain instances, the soluble DLL3 is present in the blood and / or lymphatic circulation in a subject in need thereof. In one embodiment, the DLL3 binding proteins bind membrane-bound DLL3 at least 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold greater than soluble DLL3. In one embodiment, the antigen binding proteins of the present disclosure preferentially bind membrane-bound DLL3 30-fold greater than soluble DLL3. Determining the preferential binding of an antigen binding protein to membrane bound DLL3 over soluble DLL3 can be readily determined using assays well known in the art.

[0221] In some embodiments, any of the foregoing DLL3 binding domains are affinity peptide tagged for ease of purification. In some embodiments, for example, relevant to any method as disclosed herein, the affinity peptide tag is six consecutive histidine residues, also referred to as 6X-his (SEQ ID NO: 28).

[0222] In some embodiments, for example, relevant to any method as disclosed herein, the DLL3 binding domain provided herein may undergo post-translational modifications as known in the art. Examples of post-translational modifications include, but are not limited to, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, C-terminal lysine processing (such that lysine is removed), deamidation, isomerization, oxidation, glycation, peptide bond cleavage, non-reducible crosslinking, truncation and others known in the art. See, Liu, et. al., supra. Other types of modifications include noncovalent interaction, conformational heterogeneity, and aggregation. Id.

[0223] In some embodiments, an N-terminal E or Q of the DLL3 binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K the DLL3 binding domain provided herein is removed. In other embodiments, an N-terminal E or Q of the DLL3 binding domain provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K of the DLL3 binding domain is removed. The present disclosure includes any of the above described post- translational modifications of any of the DLL3 binding domains provided herein.3.4. Polynucleotides Encoding DLL3 targeting trispecific proteins65NAI-5001911280

[0224] Also provided, in some embodiments, are polynucleotide molecules encoding an anti-DLL3 trispecific binding protein described herein. In some embodiments, the polynucleotide molecules are provided as a DNA construct. In other embodiments, the polynucleotide molecules are provided as a messenger RNA transcript.

[0225] The polynucleotide molecules are constructed by known methods such as by combining the genes encoding the three binding domains either separated by peptide linkers or, in other embodiments, directly linked by a peptide bond, into a single genetic construct operably linked to a suitable promoter, and optionally a suitable transcription terminator, and expressing it in bacteria or other appropriate expression system such as, for example CHO cells.

[0226] In some embodiments, the polynucleotide is inserted into a vector, preferably an expression vector, which represents a further embodiment. This recombinant vector can be constructed according to known methods. Vectors of particular interest include plasmids, phagemids, phage derivatives, viruses (e.g., retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, lentiviruses, and the like), and cosmids. A variety of expression vector / host systems may be utilized to contain and express the polynucleotide encoding the polypeptide of the described trispecific antigen-binding protein. Thus, the DLL3 targeting trispecific proteins as described herein, in some embodiments, are produced by introducing a vector encoding the protein as described above into a host cell and culturing said host cell under conditions whereby the protein domains are expressed, may be isolated and, optionally, further purified.4. Anti-human B7-H3 antibody-drug conjugate

[0227] Antibody-drug conjugates (ADCs) are targeted cancer therapies which comprise or consist of monoclonal antibodies (mAbs) conjugated via a linker component to cytotoxic agents (payloads). The antibody component of the ADC is directed towards a tumor- associated antigen, allowing for tumor specificity and targeted drug delivery to the tumor site. This approach is expected to result in reduced exposure of non-target tissues to the cytotoxic agent and enhanced antitumor potency. Due to the reduced toxicity of ADC-mediated drug delivery, the therapeutic window may be broadened in comparison to traditional chemotherapy.

[0228] B7-H3, one of the B7 family members expressed in antigen-presenting cells as a co-stimulator, is considered to act on receptors on T cells and enhance or suppress immune effect. B7-H3 is a single transmembrane protein and has two variants. B7-H3 variant 1 (41g-66NAI-5001911280B7-H3) contains two each of V- or C- like Ig domains, and B7-H3 variant 2 (2Ig-B7-H3) contains one each of V- or C -like Ig domain. Amino acid sequences of these variants are known in the art. The amino acid sequence of human 4Ig-B7-H3 is for example shown in UniProt accession number Q5ZPR3-1 (2004-11-23 vl) or GenBank accession number: NP 001019907.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP 001019907.1. The amino acid sequence of human 2Ig-B7-H3 is for example shown in UniProt accession number Q5ZPR3-2, or GenBank accession number: NP 001316557.1 or NP 079516.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP 001316557.1 or NP 079516.1. B7- H3 protein has a very limited expression on normal tissues because of its post-transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types.

[0229] Anti-human B7-H3 antibody-drug conjugates used in the present disclosure are known in the art. Examples of such anti-human B7-H3 antibody-drug conjugates include, but are not limited to, vobramitamab duocarmazine (MGC018), mirzotamab clezutoclax (ABBV- 155), BAT8009, HS-20093, MHB088C, 7MW3711, and DB-1311. Anti-human B7-H3 antibody-drug conjugates are also described in WO2014 / 057687, WO2023 / 061457, US11,685, 742B2, US20210347894A, US20220233708A, WO2024 / 022372, WO2022 / 117040, W02024 / 061306, W02024 / 037503, WO2024 / 052685, WO2024 / 052684, WO2023 / 236949, US20240148892A, WO2023 / 241663, US20240108745A1 (or WO2022 / 170971), WO2024 / 140932, WO2024 / 140935, and WO2024 / 211235, W02025 / 049270, CN119569879A, W02025 / 049270, CN119925631 A, WO2025 / 087323, W02025 / 061110, and WO2024 / 251149, each of which is incorporated herein by reference in its entirety.

[0230] In one aspect of the method provided herein, the method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:67NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof and a drug-linker is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0231] In one aspect of the present disclosure, the anti-human B7-H3 antibody-drug conjugate is an anti-human B7-H3 antibody-drug conjugate, in which a drug-linker is represented by the following formula:Formula II wherein A represents a connecting position to an anti-human B7-H3 antibody or a functional fragment thereof; is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0232] In some embodiments of the methods provided above, the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.68NAI-5001911280

[0233] In one aspect of the present disclosure, n represents the drug-to-antibody ratio (DAR). DAR as used herein: (i) when referring to a composition of the antibody-drug conjugates, is the average number of drug molecules (or units of a drug-linker) that are conjugated to the anti-human B7-H3 antibody or functional fragment thereof in the antibodydrug conjugate, and (ii) when referring to a single antibody-drug conjugate, is the discrete integer of drug molecules (or units of a drug-linker) that are conjugated to the anti-human B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate. Methods to determine DAR are well known to the skilled person and include methods using reverse phase chromatography, or HPLC-MS.

[0234] In some embodiments of the methods provided herein, with respect to a composition of antibody-drug conjugates, n (e.g., the number of drug-linkers of Formula II) is from about 2 to about 8, from about 3 to about 5, from about 3.5 to about 4.5, or about 4. In the present disclosure, in some embodiments, the term “about 4” is from 3.8 to 4.2, from 3.9 to 4.1, or 4. In other embodiments, the number of the drug or the drug-linker conjugated per antibody molecule in the anti-human B7-H3 antibody-drug conjugate in the instant method is an integer in the range from 2 to 8, for example, 2, 4, 6, or 8. In a specific embodiment, the number of the drug or the drug-linker conjugated per antibody molecule in the anti-human B7-H3 antibody-drug conjugate is 4. In a specific embodiment, the number of drug-linkers of Formula II conjugated per antibody molecule in the anti-human B7-H3 antibody-drug conjugate is 4.

[0235] In the present disclosure, the partial structure consisting of a linker and a drug in the anti-human B7-H3 antibody-drug conjugate is referred to as a “drug-linker.” The druglinker is connected to a thiol group (ie., the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0236] In particular embodiments, the drug-linker of the present disclosure includes a derivative of exatecan as a component. Exatecan (IUPAC name: (lS,9S)-l-amino-9-ethyl-5- fluoro- 1 ,2,3 ,9, 12, 15-hexahydro-9-hydroxy-4-m ethyl- 1 OH, 13H- benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-10,13-dione, (also expressed as chemical name: (lS,9S)-l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3 ',4' : 6,7]indolizino[ 1 ,2-b]quinolin- 10,13 (9H, 15H)-dione)), a camptothecin derivative having an antitumor effect, is a topoisomerase I inhibitor.

[0237] Exatecan is represented by the following formula:69NAI-5001911280Formula III

[0238] In some embodiments, after internalization into cancer cells, the anti-human B7- H3 antibody-drug conjugate used in the present disclosure releases a compound represented by the following Formula IV, and thereby exerts an antitumor effect.Formula IV

[0239] The aforementioned compound is inferred to be the original source of the antitumor activity of the anti-human B7-H3 antibody-drug conjugate used in the present disclosure, and has a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016; 22(20):5097-5108).

[0240] In some embodiments, the anti-human B7-H3 antibody-drug conjugate used in the present disclosure has a bystander effect (Ogitani Y. et al., Cancer Science, 2016; 107, 1039- 1046). The bystander effect is considered to be exerted through a process such that the antihuman B7-H3 antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target and the aforementioned compound is released and then exerts an antitumor effect also on nearby cancer cells not expressing the target.4.1. Anti-human B7-H3 antibody

[0241] In one aspect, for example, relevant to any method as disclosed herein, the antihuman B7-H3 antibody (e.g., anti-human B7-H3 antibody) or a functional fragment thereof in the anti-human B7-H3 antibody-drug conjugate used in the present disclosure may be derived from any species, but is preferably an antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the70NAI-5001911280present disclosure may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. Examples of anti-human B7-H3 antibodies include, but are not limited to, M30-H1-L4 described in WO2014 / 057687 or those described in W02024 / 061306, each of which is incorporated herein by reference in its entirety.

[0242] In the anti-human B7-H3 antibody in the anti-human B7-H3 antibody-drug conjugate relevant to any method as disclosed herein, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O- linked carbohydrate chain, and the like. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.

[0243] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted or “clipped” (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted and a proline residue newly located at the carboxyl terminus can be amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence typically do not affect the antigenbinding affinity and the effector function (e.g., complement activation or antibody-dependent cellular cytotoxicity) of the antibody. Therefore, in the anti-human B7-H3 antibody according to the present methods, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants (for example, a heavy chain in which the carboxyl terminal proline71NAI-5001911280residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom.

[0244] In some embodiments, an N-terminal E or Q of the anti-human B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of the anti-human B7-H3 antibody provided herein is removed. In other embodiments, an N-terminal E or Q of the anti-human B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K (e.g., heavy chain C-terminal amino acid) of the anti-human B7-H3 antibody is removed. The present disclosure includes any of the above described post-translational modifications of any of the anti-human B7-H3 antibody provided herein.

[0245] All isotypes of the antibody according to the present disclosure, for example, IgG (IgGl, IgG2, IgG3, IgG4) are exemplified, and IgGl or IgG2 are exemplified preferably.

[0246] In an embodiment, the anti-human B7-H3 antibody comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided herein, or a sequence with 95-99% identity with an amino acid sequence provided herein; and / or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided herein, or a sequence with 95-99% identity to an amino acid sequence provided herein. In some embodiments, for example, relevant to any method as disclosed herein, the anti-B7-H3 binding domain comprises three heavy chain CDRs (VH-CDR1, VH-CDR2, and VH-CDR3), and three light chain CDRs (VL-CDR1, VL-CDR2, and VL-CDR3). In some embodiments, the VH-CDR1 of the anti-human B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 19, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 19. In some embodiments, the VH-CDR2 of the anti-human B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 20, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 20. In some embodiments, the VH-CDR3 of72NAI-5001911280the anti-human B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 21, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 21. In some embodiments, the VL-CDR1 of the anti-human B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 22, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 22. In some embodiments, the VL-CDR2 of the anti-human B7- H3 antibody comprises the amino acid sequence of SEQ ID NO: 23, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 23. In some embodiments, the VL-CDR3 of the anti-human B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 24, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 24.

[0247] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human B7-H3 antibody comprises as a VH, the amino acid sequence of SEQ ID NO: 25, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 25. In some examples, the anti-human B7-H3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 26, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 26. In some examples, the anti-human B7-H3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 34, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 34.

[0248] In one aspect, for example, relevant to any method as disclosed herein, the antihuman B7-H3 antibody comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 25;. In one aspect, for example, relevant to any method as disclosed herein, the anti-human B7-H3 antibody comprises: a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL- CDR3, respectively, within SEQ ID NO: 26, or a sequence that is at least about 60%, about73NAI-500191128070%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 26. In some embodiments, the antihuman B7-H3 antibody comprises: a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 34, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 34.

[0249] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human B7-H3 antibody comprises as a heavy chain (HC), the amino acid sequence of SEQ ID NO: 29, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 29. In some examples, the anti -human B7-H3 antibody comprises as a light chain (LC), the amino acid sequence of SEQ ID NO: 30, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 30.

[0250] In some embodiments, the HC of the anti-human B7-H3 antibody of the present disclosure comprises a signal sequence at the N-terminus. In one embodiment, the signal sequence comprises the amino acid sequence of SEQ ID NO: 32. In some embodiments, the LC of the anti-human B7-H3 antibody of the present disclosure comprises a signal sequence at the N-terminus. In one embodiment, the signal sequence comprises the amino acid sequence of SEQ ID NO: 33.5. Pharmaceutical Compositions

[0251] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising an anti-DLL3 trispecific binding protein described herein, a vector comprising the polynucleotide encoding the polypeptide of the DLL3 targeting trispecific proteins or a host cell transformed by this vector and at least one pharmaceutically acceptable carrier. A further embodiment provides one or more of the above described DLL3 targeting trispecific proteins packaged in lyophilized form, or packaged in an aqueous medium.74NAI-5001911280

[0252] In some embodiments of the pharmaceutical compositions, the DLL3 targeting trispecific proteins described herein are encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments of the pharmaceutical compositions, the DLL3 targeting trispecific protein is attached to liposomes. In some instances, the DLL3 targeting trispecific proteins are conjugated to the surface of liposomes. In some instances, the DLL3 trispecific antigen-binding protein are encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome.

[0253] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising the anti-human B7-H3 ADC (e.g., ifinatamab deruxtecan) described herein. The pharmaceutical composition of the present disclosure may comprise a plurality of anti-human B7-H3 ADCs as disclosed herein.

[0254] The pharmaceutical composition of the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection. In the case that the pharmaceutical composition of the present disclosure is an aqueous injection, it can be preferably diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.

[0255] In the case that the pharmaceutical composition of the present disclosure is a lyophilized injection, it can be preferably dissolved in water for injection, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.

[0256] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising atezolizumab. Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising atezolizumab as described herein, and at least one pharmaceutically acceptable carrier. A further embodiment provides the atezolizumab packaged in lyophilized form, or packaged in an aqueous medium. In some embodiments of the pharmaceutical compositions, atezolizumab is encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots,75NAI-5001911280superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments of the pharmaceutical compositions, atezolizumab is attached to liposomes. In some instances, the atezolizumab is conjugated to the surface of liposomes. In some instances, the atezolizumab is encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome.

[0257] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising carboplatin. Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising carboplatin as described herein, and at least one pharmaceutically acceptable carrier. A further embodiment provides the carboplatin packaged in lyophilized form, or packaged in an aqueous medium. In some embodiments of the pharmaceutical compositions, the carboplatin is encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments of the pharmaceutical compositions, carboplatin is attached to liposomes. In some instances, the carboplatin is conjugated to the surface of liposomes. In some instances, the carboplatin is encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome.

[0258] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising etoposide. Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising etoposide as described herein, and at least one pharmaceutically acceptable carrier. A further embodiment provides the etoposide packaged in lyophilized form, or packaged in an aqueous medium. In some embodiments of the pharmaceutical compositions, etoposide is encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments of the pharmaceutical compositions, etoposide is attached to liposomes. In some instances, the etoposide is conjugated to the surface of liposomes. In some instances, the etoposide is encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome.

[0259] Administration of the DLL3 targeting trispecific protein of the present disclosure, the antibody-drug conjugate (e.g., ifinatamab deruxtecan), atezolizumab, carboplatin and / or etoposide may be effected by different ways, by intravenous, intraperitoneal, subcutaneous,76NAI-5001911280intramuscular, topical or intradermal administration. In some embodiments, the route of administration depends on the kind of therapy and the kind of compound contained in the pharmaceutical composition. The dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any one patient depends on many factors, including the patient’s size, body surface area, age, sex, the particular compound to be administered, time and route of administration, the kind of therapy, general health and other drugs being administered concurrently.6. Kits

[0260] Also provided herein is a kit comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, and (ii) an antihuman B7-H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0261] Provided herein is a kit comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, (ii) an anti-human B7- H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, and (iii) instructions for use, e.g., in any of the methods disclosed herein.

[0262] Also provided herein are kits comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, and (ii) an antihuman B7-H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, either or both of which are packaged into suitable packaging material. A kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.

[0263] Also provided herein is a kit comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, (ii) an antihuman B7-H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, and (iii) atezolizumab, or a pharmaceutical composition comprising the same.

[0264] Provided herein is a kit comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, (ii) an anti-human B7- H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically77NAI-5001911280acceptable salt thereof, or the pharmaceutical composition comprising same, (iii) atezolizumab, or a pharmaceutical composition comprising the same, and (iv) instructions for use, e.g., in any of the methods disclosed herein.

[0265] Also provided herein are kits comprising (i) a DLL3 targeting trispecific protein (such as gocatamig), or a pharmaceutical composition comprising the same, (ii) an antihuman B7-H3 ADC as disclosed herein (such as ifinatamab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, (iii) atezolizumab, or a pharmaceutical composition comprising the same, either one, either two or all three of which are packaged into suitable packaging material. A kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.

[0266] Any of the kits disclosed herein may further include a PD-1 inhibitor, a PD-L1 inhibitor, or a pharmaceutical composition comprising the same. Any of the kits disclosed herein may further include pembrolizumab and optionally carboplatin or a pharmaceutical composition comprising the same.

[0267] Kits provided herein can include labels or inserts. Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampoule, tube, or vial containing a kit component. Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic / optical storage media, FLASH media, or memory type cards. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date.

[0268] Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage.7. Illustrative Embodiments

[0269] Provided below is a list of non-limiting illustrative embodiments according to the present disclosure:

[0270] Embodiment 1. A method for treating cancer in a subject in need thereof, wherein the method comprises:78NAI-5001911280(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I79NAI-5001911280wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

[0271] Embodiment 2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH- CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)-(B)-(C)- COOH; and80NAI-5001911280(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate, wherein the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula II wherein A represents a connecting position to the anti-human B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

[0272] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the scFv in the first domain (A) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0273] Embodiment 4. The method of any one of embodiments 1-3, wherein the sdAb in the second domain (B) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 12,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and81NAI-5001911280(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0274] Embodiment 5. The method of any one of embodiments 1-4, wherein the sdAb in the third domain (C) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 18.

[0275] Embodiment 6. The method of any one of embodiments 1-5, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 19,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 20,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 21,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 22,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 24.

[0276] Embodiment 7. The method of any one of embodiments 1-6, wherein the scFv in the first domain (A) comprises a heavy chain variable region (“VH”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 3, and a light chain variable region (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.

[0277] Embodiment 8. The method of any one of embodiments 1-7, wherein the sdAb in the second domain (B) comprises a VHH domain comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 11.

[0278] Embodiment 9. The method of any one of embodiments 1-8, wherein the sdAb in the third domain (C) comprises a VHH domain comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 15.

[0279] Embodiment 10. The method of any one of embodiments 1-9, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises a VH comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 25, and a VL comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 26.

[0280] Embodiment 11. The method of any one of embodiments 1-10, wherein the scFv in the first domain (A) comprises a VH comprising the amino acid sequence of SEQ ID NO: 3, and a VL comprising the amino acid sequence of SEQ ID NO: 4.82NAI-5001911280

[0281] Embodiment 12. The method of any one of embodiments 1-11, wherein the sdAb in the second domain (B) comprises a VHH domain comprising the amino acid sequence of SEQ ID NO: 11.

[0282] Embodiment 13. The method of any one of embodiments 1-12, wherein the sdAb in the third domain (C) comprises a VHH domain comprising the amino acid sequence of SEQ ID NO: 15.

[0283] Embodiment 14. The method of any one of embodiments 1-13, wherein the antihuman B7-H3 antibody is an IgGl.

[0284] Embodiment 15. The method of any one of embodiments 1-14, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 25, and a VL comprising the amino acid sequence of SEQ ID NO: 26.

[0285] Embodiment 16. The method of any one of embodiments 1-15, wherein the antihuman B7-H3 antibody comprises a heavy chain (“HC”) comprising the amino acid sequence of SEQ ID NO: 29, and a light chain (“LC”) comprising the amino acid sequence of SEQ ID NO: 30.

[0286] Embodiment 17. The method of any one of embodiments 1-16, wherein the antibody-drug conjugate is ifinatamab deruxtecan.

[0287] Embodiment 18. The method of any one of embodiments 1-17, wherein a linker LI links the first and second domains of the DLL3 targeting trispecific protein, and a linker L2 links the second and third domains of the DLL3 targeting trispecific protein.

[0288] Embodiment 19. The method of any one of embodiments 1-18, wherein the linkers LI and L2 both comprise the sequence of SEQ ID NO: 27.

[0289] Embodiment 20. The method of any one of embodiments 1-19, wherein the DLL3 targeting trispecific protein comprises the amino acid sequence of SEQ ID NO: 1.

[0290] Embodiment 21. The method of any one of embodiments 1-20, wherein the DLL3 targeting trispecific protein is gocatamig.

[0291] Embodiment 22. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising the amino acid sequence of SEQ ID NO: 1; and(ii) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:83NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

[0292] Embodiment 23. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising the amino acid sequence of SEQ ID NO: 1; and(ii) administering to the subject a therapeutically effective amount of an antibodydrug conjugate, wherein the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula II84NAI-5001911280wherein A represents a connecting position to the anti-human B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

[0293] Embodiment 24. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a therapeutically effective amount of gocatamig; and(ii) administering to the subject a therapeutically effective amount of ifinatamab deruxtecan.

[0294] Embodiment 25. The method of any one of embodiments 1-24, wherein a lysine residue at the carboxyl terminus of the HC of the anti-human B7-H3 antibody is deleted.

[0295] Embodiment 26. The method of any one of embodiments 1-25, wherein the drug to antibody ratio is in the range of from 3 to 5, optionally wherein the drug to antibody ratio is 4.

[0296] Embodiment 27. The method of any one of embodiments 1-26, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered according to a dosing schedule comprising the following steps:(i) administering a priming dose of the DLL3 targeting trispecific protein; and(ii) administering a target dose of the DLL3 targeting trispecific protein, wherein the target dose is either the same or higher than the priming dose.

[0297] Embodiment 28. The method of any one of embodiment 27, wherein the priming dose of the DLL3 targeting trispecific protein is about 1 mg.

[0298] Embodiment 29. The method of any one of embodiment 27 or embodiment 28, wherein the priming dose of the DLL3 targeting tri specific protein is administered on Day 1 of Cycle 1 of the dosing schedule.

[0299] Embodiment 30. The method of any one of embodiments 27-29, wherein the priming dose of the DLL3 targeting trispecific protein is administered once a week.85NAI-5001911280

[0300] Embodiment 31. The method of any one of embodiments 1-27, wherein the method comprises two priming doses of the DLL3 targeting trispecific protein, wherein the two priming doses comprise a first priming dose and a second priming dose.

[0301] Embodiment 32. The method of embodiment 31, wherein the first priming dose of the DLL3 targeting trispecific protein is about 1 mg.

[0302] Embodiment 33. The method of embodiment 31 or embodiment 32, wherein the first priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of Cycle 1 of the dosing schedule.

[0303] Embodiment 34. The method of any one of embodiments 31-33, wherein the second priming dose of the DLL3 targeting trispecific protein is about 12 mg.

[0304] Embodiment 35. The method of any one of embodiments 31-34, wherein the second priming dose of the DLL3 targeting trispecific protein is administered on Day 8 of Cycle 1 of the dosing schedule.

[0305] Embodiment 36. The method of any one of embodiments 27-35, wherein the target dose of the DLL3 targeting trispecific protein is about 24 mg.

[0306] Embodiment 37. The method of any one of embodiments 27-35, wherein the target dose of the DLL3 targeting trispecific protein is about 24 mg.

[0307] Embodiment 38. The method of any one of embodiments 27-35, wherein the target dose of the DLL3 targeting trispecific protein is a dose of about 12 mg, about 24 mg, about 36 mg, or about 48 mg.

[0308] Embodiment 39. The method of any one of embodiments 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered on Day 15 of Cycle 1 of the dosing schedule.

[0309] Embodiment 40. The method of any one of embodiments 27-37, wherein the target dose of the DLL3 targeting trispecific protein is administered for from about 1 week to about 6 weeks.

[0310] Embodiment 41. The method of any one of embodiments 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every week, once every two weeks or once every three weeks.

[0311] Embodiment 42. The method of any one of embodiments 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every two weeks.

[0312] Embodiment 43. The method of any one of embodiments 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every three weeks.86NAI-5001911280

[0313] Embodiment 44. The method of any one of embodiments 27-43, wherein the target dose of the DLL3 targeting trispecific protein is maintained to the end of the dosing schedule after the administration of the priming dose of the DLL3 targeting trispecific protein.

[0314] Embodiment 45. The method of any one of embodiments 1-44, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered intravenously (“IV”).

[0315] Embodiment 46. The method of embodiment 45, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered via a 60 ± 10 minute IV fusion.

[0316] Embodiment 47. The method of any one of embodiments 1-46, wherein the therapeutically effective amount of the antibody-drug conjugate is administered according to a dosing schedule comprising the following steps:(i) administering a first dose of the antibody-drug conjugate; and(ii) administering a second dose of the antibody-drug conjugate.

[0317] Embodiment 48. The method of embodiment 46, wherein the first dose of the antibody-drug conjugate is a dose of about 8 mg / kg to about 12 mg / kg.

[0318] Embodiment 49. The method of embodiment 47 or embodiment 48, wherein the second dose of the antibody-drug conjugate is a dose ranging from about 8 mg / kg to about 12 mg / kg.

[0319] Embodiment 50. The method of embodiment 47 or embodiment 48, wherein the second dose of the antibody-drug conjugate is a dose of about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about11.5 mg / kg, or about 12.0 mg / kg.

[0320] Embodiment 51. The method of embodiment 47, wherein the first dose of the antibody-drug conjugate or the second dose of the antibody-drug conjugate is a dose of about4.5 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.4 mg / kg, about 8 mg / kg, about 10 mg / kg, or about 12 mg / kg.

[0321] Embodiment 52. The method of any one of embodiments 47-51, wherein the first dose of the antibody-drug conjugate is administered concurrently with the priming dose of the DLL3 targeting trispecific protein or before the priming dose of the DLL3 targeting trispecific protein.87NAI-5001911280

[0322] Embodiment 53. The method of any one of embodiments 47-52, wherein the second dose of the antibody-drug conjugate is administered for from about 1 week to about 6 weeks.

[0323] Embodiment 54. The method of any one of embodiments 47-53, wherein the second dose of the antibody-drug conjugate is administered once every two weeks.

[0324] Embodiment 55. The method of embodiment 54, wherein the second dose of the antibody-drug conjugate is administered fifteen (15) days after the first dose of the antibodydrug conjugate.

[0325] Embodiment 56. The method of any one of embodiments 47-53, wherein the second dose of the antibody-drug conjugate is administered once every three weeks.

[0326] Embodiment 57. The method of embodiment 55, wherein the second dose of the antibody-drug conjugate is administered twenty-two (22) days after the first dose of the antibody-drug conjugate.

[0327] Embodiment 58. The method of any one of embodiments 47-57, wherein the administration of the second dose of the antibody-drug conjugate is maintained to the completion of the administration of the target dose of the DLL3 targeting trispecific protein.

[0328] Embodiment 59. The method of any one of embodiments 1-58, wherein the antibody-drug conjugate is administered before administration of the DLL3 targeting trispecific protein.

[0329] Embodiment 60. The method of embodiment 59, wherein the antibody-drug conjugate is administered 24 hours before administration of the DLL3 targeting trispecific protein.

[0330] Embodiment 61. The method of embodiment 59, wherein the antibody-drug conjugate is administered at least 6 hours before administration of the DLL3 targeting trispecific protein.

[0331] Embodiment 62. The method of embodiment 59, wherein the antibody-drug conjugate is administered at least 30 minutes before administration of the DLL3 targeting trispecific protein.

[0332] Embodiment 63. The method of any one of embodiments 1-62, wherein the antibody-drug conjugate is administered intravenously (“IV”).

[0333] Embodiment 64. The method of embodiment 63, wherein the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.

[0334] Embodiment 65. The method of embodiment 63, wherein the antibody-drug conjugate is administered via a 60 ± 10 minute IV fusion.88NAI-5001911280

[0335] Embodiment 66. The method of embodiment 63, wherein the antibody-drug conjugate is administered via a 90 ± 10 minute IV fusion.

[0336] Embodiment 67. The method of any one of embodiments 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every two weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every two weeks.

[0337] Embodiment 68. The method of embodiment 67, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and (ii) the second dose of the antibody-drug conjugate is 5.4 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 5.4 mg / kg; or(IV) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and (ii) the second dose of the antibody-drug conjugate is 8 mg / kg.

[0338] Embodiment 69. The method of any one of embodiments 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every three weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every three weeks.

[0339] Embodiment 70. The method of embodiment 69, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 18 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 18 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(IV) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg; or(V) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and(ii) the second dose of the antibody-drug conjugate is 10 mg / kg.89NAI-5001911280

[0340] Embodiment 71. The method of any one of embodiments 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every two weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every three weeks.

[0341] Embodiment 72. The method of embodiment 71, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg; or(IV) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and (ii) the second dose of the antibody-drug conjugate is 12 mg / kg.

[0342] Embodiment 73. The method of any one of embodiments 1-72, further comprising administering to the subject a therapeutically effective amount of atezolizumab.

[0343] Embodiment 74. The method of embodiment 73, wherein the atezolizumab is administered prior to administration of the DLL3 targeting trispecific protein.

[0344] Embodiment 75. The method of embodiment 74, wherein the atezolizumab is administered at least 30 minutes prior to administration of the DLL3 targeting trispecific protein.

[0345] Embodiment 76. The method of any one of embodiments 73-75, wherein the atezolizumab is administered at a dose of about 100 mg to about 2500 mg.

[0346] Embodiment 77. The method of embodiment 76, wherein the atezolizumab is administered at a dose of 1200 mg.

[0347] Embodiment 78. The method of any one of embodiments 73-77, wherein the atezolizumab is administered once every three weeks.

[0348] Embodiment 79. The method of any one of embodiments 73-78, wherein the atezolizumab is administered intravenously (“IV”).

[0349] Embodiment 80. The method of embodiment 79, wherein the atezolizumab is administered via a 30 ± 5 minute IV infusion or 30 ± 10 minute IV infusion.

[0350] Embodiment 81. The method of embodiment 79, wherein the atezolizumab is administered via a 60 ± 15 minute IV infusion.90NAI-5001911280

[0351] Embodiment 82. The method of any one of embodiments 1-81, wherein the cancer is a cancer associated with DLL3 expression.

[0352] Embodiment 83. The method of any one of embodiments 1-82, wherein the cancer is small cell lung cancer or a neuroendocrine cancer.

[0353] Embodiment 84. The method of any one of embodiments 1-83, wherein the cancer is extensive-stage small cell lung cancer (“ES-SCLC”).

[0354] Embodiment 85. The method of embodiment 84, wherein the ES-SCLC is Stage IV (T any, N any, Mla / b / c) as assessed by the American Joint Committee on Cancer Staging Manual, Eighth Edition.

[0355] Embodiment 86. The method of any one of embodiments 82-84, wherein the cancer is relapsed or refractory.

[0356] Embodiment 87. The method of any one of embodiments 1-86, wherein the method is used as induction therapy for a subject in need thereof.

[0357] Embodiment 88. The method of any one of embodiments 1-86, wherein the method is used as maintenance therapy for a subject in need thereof.

[0358] Embodiment 89. The method of any one of embodiments 1-88, wherein the subject has received only one prior line of treatment.

[0359] Embodiment 90. The method of any one of embodiments 1-88, wherein the subject has received at least one prior line of treatment.

[0360] Embodiment 91. The method of embodiment 89 or embodiment 90, wherein the one prior line of treatment is a systemic therapy.

[0361] Embodiment 92. The method of any one of embodiments 84-91, wherein the subject has received no prior line of systemic treatment for ES-SCLC.

[0362] Embodiment 93. The method of any one of embodiments 84-92, wherein the subject has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and anti-PD-l / anti-PD-Ll treatment for ES-SCLC; optionally wherein the subject has not had evidence of progressive disease in the prior therapy.

[0363] Embodiment 94. The method of any one of embodiments 1-93, wherein the antihuman B7-H3 antibody or functional fragment thereof is an antibody.

[0364] Embodiment 95. The method of any one of embodiments 1-94, wherein the antihuman B7-H3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.91NAI-5001911280

[0365] Embodiment 96. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:(i) administering to the subject in Cycle 1 of the dosing schedule: a) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; b) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and c) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and(ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule: a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and wherein the subject has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and anti-PD-l / anti-PD-Ll treatment for ES-SCLC; optionally wherein the subject has not had evidence of progressive disease in the prior therapy.

[0366] Embodiment 97. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:(i) administering to the subject in Cycle 1 of the dosing schedule: a) 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; b) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; c) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and d) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and(ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule:92NAI-5001911280a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and wherein the subject has received no prior line of systemic treatment for ES-SCLC.

[0367] Embodiment 98. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:(i) administering to the subject in Cycle 1 of the dosing schedule: a) 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; b) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; c) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and d) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule;(ii) following completion of step (i), administering to the subject for Cycles 2-4 of the dosing schedule: a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and(iii) following completion of step (ii), administering to the subject for subsequent cycles of the dosing schedule: a) a therapeutically effective amount of atezolizumab at a dose of about 1200 mg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and wherein the subject has received no prior line of systemic treatment for ES-SCLC.93NAI-5001911280

[0368] Embodiment 99. The method of any one of embodiments 1-98, wherein the subject is premedicated with one or more of tocilizumab, an antihistamine, acetaminophen, 5- HT3 receptor antagonist, NK-1 receptor antagonist and / or a corticosteroid, optionally wherein the corticosteroid comprises dexamethasone.

[0369] Embodiment 100. The method of any one of embodiments 1-99, wherein the subject is a human subject.

[0370] Embodiment 101. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26, and a therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-26 in combination, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72.

[0371] Embodiment 102. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26, in combination with a therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72.

[0372] Embodiment 103. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26, in combination with a therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-26, and a therapeutically effective amount of atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72, and / or the atezolizumab is optionally administered as defined in any one of embodiments 73-81.

[0373] Embodiment 104. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a therapeutically effective amount of ifinatamab deruxtecan.

[0374] Embodiment 105. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a94NAI-5001911280therapeutically effective amount of ifinatamab deruxtecan, and a therapeutically effective amount of atezolizumab.

[0375] Embodiment 106. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig.

[0376] Embodiment 107. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig, and a therapeutically effective amount of atezolizumab.

[0377] Embodiment 108. The pharmaceutical composition for use of any one of embodiments 101-107 wherein the cancer is as defined in any one of embodiments 82-86.

[0378] Embodiment 109. Use of the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined in any one of embodiments 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibodydrug conjugate is optionally administered as defined in any one of embodiments 47-72.

[0379] Embodiment 110. Use of the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined in any one of embodiments 1-26 and atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72, and / or the atezolizumab is optionally administered as defined in any one of embodiments 73-81.

[0380] Embodiment 111. Use of the antibody-drug conjugate as defined in any one of embodiments 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the DLL3 targeting trispecific protein as defined in any one of embodiments 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibodydrug conjugate is optionally administered as defined in any one of embodiments 47-72.

[0381] Embodiment 112. Use of the antibody-drug conjugate as defined in any one of embodiments 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the DLL3 targeting trispecific protein as defined in any one of95NAI-5001911280embodiments 1-26 and atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72, and / or the atezolizumab is optionally administered as defined in any one of embodiments 73-81.

[0382] Embodiment 113. The use of any one of embodiments 109-112, wherein the cancer is as defined in any one of embodiments 82-86.

[0383] Embodiment 114. A DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 in treating cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72.

[0384] Embodiment 115. A DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 in treating small cell lung cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47- 72.

[0385] Embodiment 116. A DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 and atezolizumab in treating small cell lung cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 47-72, and / or the atezolizumab is optionally administered as defined in any one of embodiments 73-81.

[0386] Embodiment 117. An anti -human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 in treating cancer in a subject in need thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of embodiments 47-72 and / or the DLL3 targeting trispecific protein is optionally administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75.96NAI-5001911280

[0387] Embodiment 118. An anti-human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 in treating small cell lung cancer in a subject in need thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of embodiments 47-72 and / or the DLL3 targeting trispecific protein is optionally administered as defined in any one of embodiments 27-46, 58-62, 67-72, 74, or 75.

[0388] Embodiment 119. An anti -human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of embodiments 1-26 and atezolizumab in treating small cell lung cancer in a subject in need thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of embodiments 47-72 and / or the DLL3 targeting trispecific protein is optionally administered as defined in any one of embodiments 27-46, 58- 62, 67-72, 74, or 75, and / or the atezolizumab is optionally administered as defined in any one of embodiments 73-81.

[0389] Embodiment 120. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof.

[0390] Embodiment 121. Gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab in treating small cell lung cancer in a subject in need thereof.

[0391] Embodiment 122. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof.

[0392] Embodiment 123. Ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab in treating small cell lung cancer in a subject in need thereof.

[0393] Embodiment 124. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of gocatamig to the subject once every two weeks; and(ii) administration of ifinatamab deruxtecan to the subject once every two weeks.

[0394] Embodiment 125. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of ifinatamab deruxtecan to the subject once every two weeks; and(ii) administration of gocatamig to the subject once every two weeks.

[0395] Embodiment 126. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of gocatamig to the subject once every three weeks; and(ii) administration of ifinatamab deruxtecan to the subject once every three weeks.97NAI-5001911280

[0396] Embodiment 127. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of ifinatamab deruxtecan to the subject once every three weeks; and(ii) administration of gocatamig to the subject once every three weeks.

[0397] Embodiment 128. Gocatamig or ifinatamab deruxtecan for use of any one of embodiments 120-127, wherein the subject has received only one prior line of treatment.

[0398] Embodiment 129. Gocatamig or ifinatamab deruxtecan for use of any one of embodiments 120-127, wherein the subject has received at least one prior line of treatment.

[0399] Embodiment 130. Gocatamig or ifinatamab deruxtecan for use of embodiment 128 or 129, wherein the one prior line of treatment is a systemic therapy.

[0400] Embodiment 131. A kit comprising (i) an DLL3 targeting trispecific protein as defined in any one of embodiments 1-26, or a pharmaceutical composition comprising the same, and (ii) an anti-human B7-H3 antibody-drug conjugate as defined in any one of embodiments 1-26, or a pharmaceutical composition comprising the same, optionally further comprising instructions for treating cancer in a subject in need thereof according to the method of any one of embodiments 1-100.

[0401] Embodiment 132. The kit of embodiment 131, further comprising (iii) atezolizumab or a pharmaceutical composition comprising the same.

[0402] Embodiment 133. The kit of embodiment 131, further comprising (iii) pembrolizumab or a pharmaceutical composition comprising the same.EXAMPLES

[0403] The following are examples of methods and compositions of the disclosure. It is understood that various other embodiments may be practiced, given the general description provided herein. Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, and the like), but some experimental error and deviation should, of course, be allowed for.98NAI-5001911280Example 1: Production of Ifinatamab Deruxtecan (I-DXd)

[0404] In accordance with a production method described in WO2014 / 057687 or WO2022 / 014698, for example, ifinatamab deruxtecan (I-DXd) can be produced. The average number of units of a drug-linker that are conjugated to the anti-human B7-H3 antibody in ifinatamab deruxtecan is, in one embodiment, 4 as determined by a high-performance liquid chromatography (HPLC) method.Example 2: Clinical trial protocol for administration of the DLL3 targeting trispecific protein and Ifinatamab Deruxtecan (I-DXd) to patients with small cell lung cancer (SCLC)

[0405] This is a Phase 1 / 2 clinical trial for studying DLL3 targeting trispecific protein (e.g., gocatamig) with ifinatamab deruxtecan (referred to throughout this Example as I-DXd) as a treatment for SCLC. It is an open-label, multicenter study to evaluate the safety, PK, and pharmacodynamics of the combination therapy.

[0406] Primary Objectives'. (1) Assess safety and tolerability at increasing dose levels of the DLL3 targeting trispecific protein administered in combination with I-DXd, in successive cohorts of patients. (2) Estimate the maximum tolerated dose (MTD) and / or select Recommended Dose(s) for Expansion (RDE) of the DLL3 targeting trispecific protein administered in combination with I-DXd. (3) Characterize the PK of the DLL3 targeting trispecific protein and I-DXd following IV administration in combination.

[0407] Secondary Objectives'. (1) Evaluate the preliminary efficacy of the DLL3 targeting trispecific protein administered as in combination with I-DXd. (2) Evaluate the immunogenicity of the DLL3 targeting trispecific protein in combination with I-DXd.

[0408] Exploratory Objectives'. Characterize the impact of the DLL3 targeting trispecific protein in combination with I-DXd on peripheral blood mononuclear cells (PBMC) and soluble serum cytokines including, but not limited to, IFNy, IL-6, and TNFa.

[0409] Target Population'. Only patients with SCLC, which is relapsed / refractory following at least one prior line of systemic therapy that included platinum-based chemotherapy will be enrolled.

[0410] Number of Patients'. Up to 30 patients with SCLC will be enrolled.99NAI-50019112802.1 DLL3 tarsetins trispecific protein dose escalation in combination with I- DXd

[0411] Patient cohorts will be enrolled using a BOIN design with step dosing as described below. SCLC patients will be treated with a combination regimen of DLL3 targeting trispecific protein and I-DXd. DLL3 targeting trispecific protein will be administered once every two weeks (q2w) via IV infusion during each 42-day cycle. I-DXd will be administered one every three weeks (q3w) on Day 1 and Day 22 of each 42-day cycle.

[0412] Pre-infusion medications will be administered according to treatment regimen determined prior to opening of each cohort to enrollment. On dosing days where both the DLL3 targeting trispecific protein and I-DXd are administered, I-DXd will be given prior to the DLL3 trispecific antigen-binding protein. Pre-medications, when indicated, will be administered prior to I-DXd.

[0413] The first cohort treated with DLL3 trispecific antigen-binding protein / I-DXd combination will receive a target dose of the DLL3 targeting trispecific protein up to, but no higher than, one dose level below the current highest monotherapy dose level deemed to be safe and tolerable. If MTD for the combination regimen is not reached, the next cohort may be enrolled with up to 2x increase in the DLL3 targeting trispecific protein target dose for each subsequent BOIN combination treatment cohort. The MTD of DLL3 targeting trispecific protein in combination with I-DXd cannot be higher than the MTD of the DLL3 targeting trispecific protein administered q2w in monotherapy (if reached). The DLL3 targeting trispecific protein will be administered as a 1-hour (±10 minute) IV infusion at a flat dose. Dosing frequency varies as shown in Table 2.

[0414] The starting dose for I-DXd will be 8 mg / kg q3w and the maximum dose will be 12 mg / kg q3w, which is the recommended Phase 2 dose (RP2D). An initial dose of I-DXd will be infused for 90 ± 10 minutes. If there is no infusion-related reaction (IRR) during or after the initial dose, the subsequent doses of I-DXd may be infused for 30 ± 5 minutes. A post-infusion observation period should be observed for the monitoring of potential IRR as per the investigator’s judgment. When administered on the same day as the DLL3 trispecific antigen-binding protein, at least 30 minutes will separate the two infusions.

[0415] Dose escalation will proceed per BOIN criteria and may continue until the MTD for the DLL3 targeting trispecific protein given in combination with I-DXd is declared or RDE(s) is identified. The DLL3 targeting trispecific protein and I-DXd will be sequentially dose escalated as required based on the totality of PK, safety, and efficacy data.100NAI-5001911280

[0416] Patients may continue the DLL3 targeting trispecific protein and I-DXd treatment in 42-day cycles per protocol until disease progression, unacceptable toxicity, withdrawal of consent by the patient from the study, or until marketing approval (whichever is earlier). Dose modification / discontinuation rules are independent for the DLL3 targeting trispecific protein and I-DXd. Patients who discontinue I-DXd due to toxicity may be eligible to continue the DLL3 targeting trispecific protein treatment. Similarly, patients who discontinue DLL3 targeting trispecific protein due to toxicity may be eligible to continue I-DXd treatment.

[0417] To allow for further exploration of the safety and pharmacology of a dose or dosing schedule and identification of potential RDE(s), additional patients may be enrolled and treated at dose levels previously determined to be safe (z.e., backfilling previously cleared dose levels). Backfill cohorts may also be used to evaluate other aspects of dosage, for example to explore intermediate or lower dose levels or different dosing schedules (e.g., split dosing), modified premedication use, or other modifications to step dosing (e.g., modification of Priming Dose level or additional Priming Doses) based on emergent safety and available PK, ADA and pharmacodynamic data, or to collect additional biomarker data (e.g., tumor biopsies). Each backfill cohort in may initially enroll up to 12 patients.2.2 Statistical Methods

[0418] Descriptive statistics will be used to summarize baseline characteristics, study treatments, safety variables, and preliminary efficacy. Categorical or nominal variables will be summarized by frequency and percentage. Continuous variables will be summarized using standard summary statistics (N, mean, standard deviation, median, minimum, and maximum). Where appropriate, 95% confidence intervals around point estimates will be presented.

[0419] Pharmacokinetic Analysis: Individual and mean (by time) PK concentrations versus time will be plotted for each dose on both linear and natural logarithm scales for a) DLL3 targeting trispecific protein therapy in combination with I-DXd (three analytes: I-DXd [intact], total anti-human B7-H3 antibody, and DXd [released payload]). PK parameters will be estimated and summarized by dose and visit.2.3 Concomitant Medication

[0420] All patients will receive cytokine release syndrome (CRS) / IRR prophylaxis medications (for example, pre-infusion dexamethasone, acetaminophen, diphenhydramine, post-dose dexamethasone and intravenous fluids) for initial doses of the DLL3 targeting101NAI-5001911280trispecific protein and I-DXd. Additional CRS / IRR prophylaxis medications may be added. When administered on the same day as the DLL3 targeting trispecific protein, pre-medication will be administered before administration of I-DXd, which will be administered first. The detailed regimen for each cohort will be informed by available safety, PK, and pharmacodynamic data.2.4 Bayesian Optimal Interval (BOIN} design Dose Escalation Cohorts

[0421] Dose-escalation and de-escalation decisions are based on the Bayesian Optimal Interval (BOIN) design and depend on the number of participants enrolled and number of participants with at least 1 DLT observed at the current dose level.

[0422] A minimum of 3 participants are required at each dose. However, depending on the accrual rate, 3, 4, 5, or 6 participants may be enrolled at the opening of a dose cohort. In Table 1, the columns indicate the numbers of participants treated at the current dose level, and the rows indicate the numbers of participants experiencing DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 0 of 3 participants at a given dose level develop a DLT, then the dose can escalate to the next level. If 2 of 3 participants develop a DLT, the dose will be de-escalated to the next lower dose level. If 3 of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be de-escalated, and the current dose will not be explored further. If 1 of 3 participants at a given dose level develop a DLT, then additional participants should be enrolled at that dose level following the rules below.

[0423] When adding participants to a dose level, the number of additional participants to be enrolled is capped to minimize the exposure to a dose that may be unacceptably toxic (denoted as DU in Table 1). To determine how many more participants can be enrolled at the dose level, one can count steps in diagonal direction (down and to the right) from the current cell to the first cell marked DU. For example, if 1 of 3 participants have experienced a DLT at a given dose level, no more than an additional 3 participants should be enrolled at this dose level until additional DLT data are available. This is because this dose level would be considered unacceptably toxic if all 3 of the additional participants experience a DLT (z.e., 4 / 6 participants with DLT in Table 1).

[0424] A D or DU decision at the lowest dose level will stop the study. An E decision at the highest dose level will result in staying at that level. During dose finding, it may be102NAI-5001911280acceptable to de-escalate to an intermediate dose that was not predefined and not previously studied if evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new participants may be enrolled at the new intermediate dose, and the aforementioned rules should be used to determine further enrollment at this dose level.

[0425] After 10 participants have been enrolled at any of the tested doses (including intermediate doses), dose finding will stop if the BOIN table indicates “S” for staying at current dose.

[0426] After dose finding stops, the dose with an estimated DLT rate closest to 30% will be treated as a preliminary MTD. However, the totality of the data will be considered before deciding on the dose(s) to carry forward to dose expansion and the escalation schedule may be adjusted based on data emerging throughout the study.

[0427] Note that although 30% was the target DLT rate used to generate the guidelines in Table 2, the observed rate of participants with DLTs at the MTD may be slightly above or below 30%.

[0428] Table 1: Dose-finding Rules per BOIN Design with Target DLT Rate 30%BOIN=Bayesian optimal interval; D=Deescalate to the next lower dose; DLT=dose-limiting toxicity; DU=The current dose is unacceptably toxic; E=Escalate to the next higher dose; S=Stay at the current dose.2.5 Dose Limiting Toxicity (DLT}

[0429] The severity of adverse events (AEs) will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for events of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which will be graded per American Society for Transplant103NAI-5001911280and Cellular Therapy (ASTCT) criteria (Lee, D.W. et al., Biol Blood Marrow Transplant; 2019; 25(4), 625-638).

[0430] Any one of the AEs listed below occurring within the DLT assessment period that is attributable to the DLL3 targeting trispecific protein or I-DXd will be classified as a DLT, regardless of whether the target dose has been administered. The DLT assessment period is C1D1 through C1D21. For individual patients who have dose delays for non-DLT adverse events following either of the priming doses, the DLT window will be extended until 7 days after the administration of the first target dose.(i) Hematological'.• Grade >4 neutropenia for >7 days• Grade >3 neutropenia with clinically significant infection• Grade >3 febrile neutropenia (absolute neutrophil count [ANC] <1.0 x 109 / L with fever > 38.3 °C or > 38°C for more than 1 hour)• Grade >3 thrombocytopenia with clinically significant bleeding• Grade >4 anemia unrelated to underlying disease(ii) Non-hemalo logical• Grade >3 non-hematological toxicities are considered DLTs with the following exceptions:- Grade 3 nausea, diarrhea, or vomiting that persists <72 hours (or > 72 hours in the absence of maximal medical therapy) are NOT considered a DLT- Grade 3 fatigue lasting <7 days is NOT considered a DLT- Grade 3 rash that is not associated with clinically significant systemic symptoms or other organ toxicity is not considered a DLT- Non-hematologic laboratory Grade 3 AE that is asymptomatic and / or rapidly reversible (returned to baseline or to Grade <1 within 7 days) unless identified as clinically relevant is NOT considered a DLT- Events of increased or decreased blood pressure are not considered DLTs if associated with symptoms of CRS / IRR and resolve in concordance with CRS symptom resolution and do not result in additional safety events- Grade 4 vomiting / diarrhea (life-threatening consequences, urgent intervention indicated) of any duration• Serum chemistry values consistent with Hy’s Law (FDA, Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 2009)104NAI-5001911280• Grade >3 CRS (per ASTCT; Lee. D. W., et aL, supra) I IRR [per CTCAE], with or without pre- infusion medication and regardless of duration are considered DLTs• Symptomatic congestive heart failure, 1. Left ventricular ejection fraction (LVEF) decline to <40%, absolute >20% drop from baseline LVEF, LVEF decline leading to discontinuation• Grade >2 interstitial lung disease (ILD) or pneumonitis

[0431] In this Dose Escalation study, clinically important or persistent toxi cities (e.g., toxicities responsible for significant dose delay) that are not included in the above criteria may also be considered DLTs. To be considered a DLT, the AE must represent a clinically significant shift from baseline and must be considered related or suspected to be related to study drug (DLL3 targeting trispecific protein and LDXd).2.6 Study Duration and Dates

[0432] Patient participation includes Pre-screening (if required for confirmation of DLL3 expression), Screening (28 days), Treatment (ongoing in 42-day cycles; see Table 2), End of Treatment Visit (EOT; within 7 days after of the decision to end study treatment), and Safety Follow-up (SFU). All AEs will be reported to the sponsor until 28 days (+7 days) after the final dose of study drug. Serious adverse events (SAEs) and immune-mediated adverse events (imAEs) will continue to be reported until 40 days (+7 days) after the final dose of study drug(s). After completion of study treatment, patients will have long term follow-up (LTFU) for survival. Duration of the study depends on the dose escalation and length of treatment for each patient; the entire study is expected to last approximately 38 months until the last patient completes the safety follow-up (SFU).105NAI-5001911280

[0433] Table 2: Study Treatment, Dosing Schedule, and Duration of TreatmentCyclec For initial dose escalation, the DLL3 targeting trispecific protein will be administered on Study Day 2. P=priming dose of DLL3 trispecific antigen-binding protein; T=target dose of DLL3 trispecific antigenbinding protein; I=I-DXd; q2w+ = continuing once every 2 weeks; q3w+ = continuing once every 3 weeks

[0434] The present disclosure believes that the combination of DLL3 targeting trispecific protein (e.g., gocatamig) with an anti-B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan (I-DXd)) may be more efficacious than either treatment alone. Additionally, the present disclosure believes that the combination may not result in cumulative toxicities such that it will be better tolerated than existing therapies.Example 3: Clinical trial protocol for administration of the DLL3 targeting trispecific protein and Ifinatamab Deruxtecan (I-DXd) in combination with a PD-1 or PD-L1 inhibitor

[0435] Clinical study is conducted to evaluate administration of the DLL3 targeting trispecific protein and ifinatamab deruxtecan (referred to throughout this Example as I-DXd) in combination with a PD-1 or PD-L1 inhibitor (such as pembrolizumab or atezolizumab) as a first line therapy to newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) patients. Participants of this study have treated brain metastases or small, asymptomatic brain metastases. The participants have neither autoimmune or paraneoplastic syndromes nor pneumonitis or interstitial lung disease.

[0436] Participants are treated according to Cohorts 1-5 depicted in FIG. 1.

[0437] For Cohorts 1-3, participants complete 4 cycles of SoC chemo-anti -PD-1 or anti- PD-L1 prior to enrollment, without evidence of PD.

[0438] The above described study (including participant selection criteria and the study design for each cohorts) is also conducted using pembrolizumab in replacement of atezolizumab.106NAI-5001911280Example 4: Clinical trial protocol for administration of the DLL3 targeting trispecific protein and Ifinatamab Deruxtecan (I-DXd) to patients with small cell lung cancer (SCLC)

[0439] This is a Phase 1 / 2 open-label clinical study to evaluate the safety and efficacy of DLL3 targeting trispecific protein (e.g., MK-6070 or gocatamig) and ifinatamab deruxtecan (referred to throughout this Example as I-DXd) in participants with relapsed / refractory extensive- stage SCLC.

[0440] Primary Objectives: (1) To assess safety and tolerability of the DLL3 targeting trispecific protein administered in combination with I-DXd administered at various schedules. (2) To evaluate objective response rate (ORR, per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1)), of the DLL3 targeting trispecific protein in combination with I-DXd administered at various schedules.

[0441] Secondary Objectives: (1) To evaluate duration of response (DOR, per RECIST 1.1), of the DLL3 targeting trispecific protein in combination with I-DXd administered at various schedules. (2) To evaluate progression-free survival (PFS, per RECIST 1.1), of the DLL3 targeting trispecific protein in combination with I-DXd administered at various schedules. (3) To characterize the pharmacokinetic (PK) profile of the DLL3 targeting trispecific protein and I-DXd in combination. (4) To evaluate the immunogenicity of the DLL3 targeting trispecific protein and I-DXd in combination.

[0442] Tertiary / Exploratory Objectives: (1) To identify molecular (genomic, metabolic, and / or proteomic) biomarkers that may be indicative of clinical response / resistance, safety, pharmacodynamic activity, and / or the mechanism of action of the DLL3 targeting trispecific protein and / or I DXd administered at various schedules. (2) To evaluate overall survival (OS) of MK-6070 in combination with I-DXd administered at various schedules.

[0443] Target Population: Participants must be at least 18 years of age. Participants with histologically or cytologically confirmed SCLC that is extensive-stage (defined as Stage IV (T any, N any, Mla / b / c) by AJCC, 8th Edition) following:- Part 1 Arm 1 Safety Run-In and Arm 3b Safety Run-In: at least 1 prior line of systemic therapy that included platinum-based chemotherapy (with or without PD- 1 / PD-L1 inhibitors) (i.e., second-line or later (2L+)).Part 1 Arm 1 Dose Expansion, Arm 2 Dose Expansion, and Arm 3b Dose Expansion: only 1 prior line of platinum-based chemotherapy (with or without PD-1 / PD-L1 inhibitors) i.e., second-line (2L)).107NAI-5001911280- Participants treated with a platinum-based line of therapy (with or without consolidation PD-1 / PD-L1 inhibitors) for prior limited stage (LS)-SCLC may be eligible for the study if the disease has progressed; the platinum based line of therapy will be considered as first-line (IL) of therapy.4.1 Study Design

[0444] This study will evaluate the safety, tolerability, and efficacy of MK-6070 / I-DXd administered on q3w / q3w (Arm 1), q2w / q3w (Arm 2), and q2w / q2w (Arm 3b) schedules, respectively. See study schema depicted in FIG. 2.

[0445] Evaluation of new MK-6070 / I-DXd combination schedules will begin with Safety Run-Ins per Bayesian Optimal Interval (BOIN) with robust dose-limiting toxicity (DLT) evaluations (z.e., q3w / q3w for Arm 1 and q2w / q2w for Arm 3b, n=10). Dose escalation per BOIN for Arm 2 (q2w / q3w) is being evaluated in a prior Phase 1 study. The Safety Run-In portions of Arms 1 and 3b may be dose deescalated per BOIN (n=10 per Arm). Each Arm will also have an optional dose expansion part (n=15) (see, FIG. 2 and Table 3).

[0446] Whereas the study population in the initial safety cohorts are participants with 2L and beyond (2L+) SCLC, the study population for the dose expansion portion will be strictly 2L in order to reduce heterogeneity. Based on the totality of emerging safety, PK, and efficacy data, the Safety Run-In of Arm 3b (MK-6070 / I-DXd q2w / q2w) or the subsequent dose expansion portion of any arm may be initiated.

[0447] Table 3: Descriptions of Study Parts108NAI-5001911280

[0448] MK-6070 is administered with initial priming doses of 1 mg on Cycle 1 Day 1(C1D1) followed by a 12 mg dose on Cycle 1 Day 8 (C1D8). Target doses are administered on Cycle 1 Day 15 (CID 15), and the timing of subsequent doses are dependent on the administration schedule. For example, the subsequent target dose for the MK-6070 q3w schedule is on Cycle 1 Day 22 (C1D22), whereas the subsequent target dose for the MK-6070 q2w schedule is on Cycle 1 Day 19 (CID 19). The scheduled administration may vary in the setting of 24 hour stagger of the initial administrations of MK-6070 and I-DXd, dosage modifications, or dose delays.

[0449] Based on the results from the prior Phase 1 q2w / q3w schedule, those doses will be converted to projected q3w / q3w and q2w / q2w doses per Table 4.

[0450] Table 4: Projected MK-6070 and I-DXd Doses4.2 Sample Size

[0451] In Arm 1, approximately up to 10 participants will be enrolled in the Safety Run- in Phase to evaluate the safety / tolerability / PK / efficacy of MK-6070 in combination with I- DXd administered q3w. If the initial dose level is not tolerated, the dose of I-DXd will be deescalated by one dose level (e.g., 8 mg / kg6.4 mg / kg or 6.4 mg / kg4.8 mg / kg) without changing the MK-6070 dose. Approximately up to 10 participants may be enrolled to this lower dose level and the DLT evaluation will be repeated. If the dose level has been cleared per BOIN criteria (i.e., an E or S decision is reached after evaluating 10 participants; see above), an additional 15 participants may be enrolled to further evaluate the efficacy of this dose level in the Dose Expansion Phase. Participants treated at the same dose level in the Safety Run-in Phase and the Dose Expansion Phase may be pooled for the efficacy analyses.109NAI-5001911280

[0452] In Arm 2, approximately up to 15 participants may be enrolled to further evaluate the efficacy of MK-6070 in combination with I-DXd administered at q2w / q3w, if this dose level has been cleared during the dose escalation in the prior Phase 1 study.

[0453] In Arm 3b, approximately up to 10 participants will be enrolled in the Safety Run- in Phase to evaluate the safety / tolerability / PK / efficacy of MK-6070 in combination with I- DXd administered q2w. If the initial dose level is not tolerated, the dose of I-DXd will be deescalated by one dose level (e.g., 8 mg / kg6.4 mg / kg or 6.4 mg / kg 4.8 mg / kg) without changing the MK-6070 dose. Approximately up to 10 participants may be enrolled to this lower dose level and the DLT evaluation will be repeated. If the dose level has been cleared per BOIN criteria (z.e., an E or S decision is reached after evaluating 10 participants; see above), an additional 15 participants may be enrolled to further evaluate the efficacy of this dose level in the Dose Expansion Phase. Participants treated at the same dose level in the Safety Run-in Phase and the Dose Expansion Phase may be pooled for the efficacy analyses.4.3 Administration of MK-6070 and I-DXd

[0454] MK-6070 will be administered as a 1-hour (±10 minute) IV infusion at a flat dose.Dosing will be administered q3w or q2w.

[0455] Participants will be administered I-DXd IV, at q2w or q3w intervals, until unacceptable toxicity, disease progression, or withdrawal of consent. The initial dose of I- DXd will be infused for 90 (±10 minutes). If there is no infusion-related reaction (IRR) during or after the initial dose, the subsequent doses of I-DXd may be infused for 30 (±5 minutes).

[0456] Before each dose of I-DXd, it is mandatory to premedicate participants for prevention of nausea and vomiting with a 2- or 3-drug combination regimen (e.g., corticosteroids with either a 5-HT3 receptor antagonist (e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g., aprepitant, casopitant, netupitant, or rolapitant) as well as other drugs as indicated) according to local or standard practice guidelines.

[0457] When administered on the same day as MK-6070, I-DXd will be administered first, followed by MK-6070. MK-6070 will be administered at least 30 minutes after the end of I-DXd administration.110NAI-50019112804.4 Dose-limitins Toxicity

[0458] All toxicities will be graded using the National Cancer Institute (NCI) common terminology criteria for adverse events, version 5.0 (CTCAE, version 5.0). Each treatment cycle is 42 days. The DLT window of observation will be from C1D1 to C1D21 for Arms 1 and 3b Safety Run-In parts.

[0459] The occurrence of any of the following toxicities during the DLT observation window will be considered a DLT, if possibly, probably, or definitely related to study intervention administration.• Grade 4 hematologic toxicity lasting > 7 days, except thrombocytopenia: o Grade 4 thrombocytopenia of any duration. o Grade 3 thrombocytopenia associated with clinically significant bleeding.• Febrile neutropenia Grade 3 or Grade 4: o Grade 3 is defined as absolute neutrophil count (ANC) < 1000 / mm3with a single temperature of >38.3 °C (101 °F) or a sustained temperature of > 38 °C (100.4 °F) for more than 1 hour. o Grade 4 is defined as ANC <1000 / mm3with a single temperature of >38.3 °C (101 °F) or a sustained temperature of > 38 °C (100.4 °F) for more than 1 hour, with life threatening consequences and urgent intervention indicated.• Grade 4 nonhematologic toxicity (not laboratory).• Any nonhematologic adverse event (AE) > Grade 3 in severity should be considered a DLT, with the following exceptions: o Grade 3 fatigue lasting < 7 days. o Grade 3 diarrhea, nausea, or vomiting <72 hours. o Grade 3 diarrhea, nausea, or vomiting >72 hours and <120 hours without use of antiemetics or antidiarrheals per standard of care (SOC). o Grade 3 rash without use of corticosteroids or anti-inflammatory agents per SOC. o Grade 3 or 4 events of increased or decreased blood pressure if associated with symptoms of cytokine release syndrome / infusion-related reaction (CRS / IRR) and resolve in concordance with CRS symptom resolution and do not result in additional safety events.111NAI-5001911280o Grade 3 or 4 nonhematologic laboratory that is asymptomatic and / or rapidly reversible (returned to baseline or to Grade 1 within < 7 days) unless identified as clinically relevant is not considered a DLT.• Drug-induced liver injury (DILI) defined as serum chemistry values and clinical presentation consistent with Hy’s Law with the following features: o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN); o Total bilirubin (TBL) > 2 x ULN; o Alkaline phosphatase < 2 x ULN; and o no other cause for abnormalities, such as viral hepatitis A, B, C, preexisting or acute liver disease, or another drug capable of causing the observed injury.• Grade > 2 interstitial lung disease (ILD) or pneumonitis.• Grade 5 toxicity.4.5 Dose Modification of I-DXd

[0460] No dose modification is required for Grade 1 or Grade 2 events, unless specified.

[0461] For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) should be performed frequently and at an interval of no greater than 7 days until the adverse event (AE) is determined to be resolving or back to baseline.

[0462] If a dose reduction is required, after resolution of the toxicity, the participant can resume treatment with I-DXd at a dose level as outlined in Table 5. Once the dose of I-DXd has been reduced because of toxicity, all subsequent doses should be administered at that lower dose level unless further dose reduction is required. More than 2 dose reductions are not allowed. The participant will be withdrawn from the study treatment if further toxicity meeting the requirement for dose reduction occurs. Once the dose of I-DXd is reduced, no dose reescalation is permitted.

[0463] Table 5: I-DXd Dose Reduction Guidelines112NAI-50019112804.6 Prophylaxis Medication for CRS / IRR

[0464] Participants will receive cytokine release syndrome / infusion-related reaction (CRS / IRR) prophylaxis medication to reduce the risk and severity of hypersensitivity reactions. CRS / IRR prophylaxis medications include, for example, acetaminophen, dexamethasone and diphenhydramine.

[0465] The sequence of administration will be premedication followed by I-DXd, followed by MK-6070. Prophylactic medications should be administered 1 hour before I DXd administration.

[0466] The present disclosure believes that the combination of DLL3 targeting trispecific protein (e.g., MK-6070 or gocatamig) with an anti-B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan (I-DXd)) may be more efficacious than either treatment alone.Additionally, the present disclosure believes that the combination may not result in cumulative toxicities such that it will be better tolerated than existing therapies.Example 5: Clinical trial protocol for administration of the DLL3 targeting trispecific protein and Ifinatamab Deruxtecan (I-DXd) to patients with Extensive Stage small cell lung cancer (ES-SCLC)

[0467] This is a Phase lb / 2 open-label clinical study evaluating different combinationbased regimens with DLL3 targeting trispecific protein (e.g., MK-6070 or gocatamig; referred to throughout this Example as MK-6070) and ifinatamab deruxtecan (referred to throughout this Example as I-DXd) in first-line extensive stage small cell lung cancer (ES- SCLC). This study will evaluate the safety, tolerability, and preliminary efficacy of different MK-6070 and I-DXd based combinations in maintenance only (Arm 1) or induction and maintenance (Arms 2 and 3) in first line ES-SCLC. Arm 4 represents current standard of care (SOC) and serves as a control arm for Arms 2 and 3.

[0468] Primary Objectives: (1) To evaluate the safety and tolerability of different MK- 6070 and I-DXd combination-based regimens. (2) To evaluate ORR of different MK-6070 and I-DXd combination-based regimens per RECIST 1.1 as assessed by blinded independent central review (BICR).

[0469] Secondary Objectives: (1) To evaluate duration of response (DOR, per RECIST 1.1), of different MK-6070 and I-DXd combination-based regimens. (2) To evaluate progression-free survival (PFS, per RECIST 1.1), of different MK-6070 and I-DXd combination-based regimens. (3) To evaluate overall survival (OS) of different MK-6070 and113NAI-5001911280I-DXd combination-based regimens. (4) To characterize the pharmacokinetic (PK) profile of MK-6070 and I-DXd. (4) To evaluate the immunogenicity of MK-6070, I-DXd, and atezolizumab.

[0470] Tertiary / Expl oratory Objectives: (1) To identify molecular (genomic, metabolic, and / or proteomic) biomarkers that may be indicative of clinical response / resistance, safety, pharmacodynamic activity, and / or the mechanism of action of MK-6070 and I DXd. (2) To evaluate the duration of disease control (DDC) of different MK-6070 and I-DXd combination-based regimens per RECIST 1.1 as assessed by BICR. (3) To evaluate ORR and disease control rate (DCR), PFS, DOR, DDC of different MK-6070 and I-DXd combinationbased regimens per RECIST 1.1. (4) To characterize the PK profile of atezolizumab.

[0471] Target Population: Participants must be at least 18 years of age. Participants with histologically or cytologically confirmed diagnosis of ES-SCLC defined as Stage IV (T any, N any, Mla / b / c) by AJCC, 8th Edition or T3-T4 due to multiple lung nodules that are too extensive or have tumor / nodal volume that is too large to be encompassed in a tolerable radiation plan (see also, Table 6).Arm 1 Part A and B: completed 3 to 4 cycles of platinum + etoposide chemotherapy with concurrent anti-PD-l / anti-PD-Ll as first-line treatment of ES-SCLC within 8 weeks prior to enrollment, without radiological disease progression per RECIST 1.1, per investigator assessment. Prior systemic therapy for ES-SCLC other than the aforementioned induction treatment chemo + anti-PD-l / Ll is not allowed.Rechallenge systemic therapy will be considered an additional line of therapy and as such participants who received rechallenge systemic therapy will be excluded. Arms 2 (Part A and B), 3, and 4: prior systemic treatment for ES-SCLC is not allowed.Applicable to all Arms: Participants with prior limited-stage SCLC per AJCC 8thEdition are allowed if the interval is > 6 months since the end of previous therapy and progression, and after consultation with the sponsor.5.1 Study Design and sample size

[0472] This study will evaluate the safety, tolerability, and preliminary efficacy of different MK-6070 and I-DXd based combinations in maintenance only (Arm 1) or induction and maintenance (Arms 2 and 3) in first line ES-SCLC. Arm 4 represents current standard of care (SOC) and serves as a control arm for Arms 2 and 3. See study schema depicted in and intervention groups and duration as depicted in Table 6.114NAI-5001911280

[0473] Table 6: Intervention Groups and DurationAUC=area under curve; I-DXd=ifinatamab deruxtecan; IV=intravenous (-ly) ; q3w=every 3 weeks115NAI-5001911280

[0474] The study is divided into 2 parts.

[0475] Part A consists of safety run-in for Arm 1 and 2. To be eligible, Arm 1 participants must have completed 3 to 4 cycles of SOC for ES-SCLC (etoposide + platinum + anti-PD-l / anti-PD-Ll treatment) without disease progression per investigator assessment, while Arm 2 participants must have not received prior systemic treatment for ES-SCLC (see, Table 7). In part A, patients are assigned in non-randomized fashion and per investigator choice to one of the open arms. The first cycle of maintenance treatment on Arm 1 must start within 8 weeks of completion of the last dose of SOC chemo-immunotherapy.

[0476] Table 7. Descriptions of Study Parts

[0477] During the Safety Run-in, participants in Arms 1 and 2 will receive combination treatment of MK 6070 and I-DXd q3w. DLTs for the combination of MK-6070 and LDXd in Arms 1 and 2 Part A will be assessed in a Safety Run-in according to a BOIN design with opportunity to de-escalate the entry dose level (n=3-10 per dose level, see Section 2.4 for BOIN rules).

[0478] Once the Safety run-in is completed in Part A, participants for Arm 1 Part B will be enrolled in a non-randomized fashion. For Part B induction, Arm 1 participants must have completed 3 to 4 cycles of SOC for ES-SCLC (etoposide + platinum + anti-PD-l / anti-PD-Ll116NAI-5001911280treatment) without disease progression per investigator assessment. During maintenance phase participants will receive treatment of MK-6070 and I-DXd. The first cycle of maintenance phase must start within 8 weeks.

[0479] Participants enrolled for Part B Arms 2, 3 and 4 will be randomized 1 : 1 : 1. To be eligible for Part B, participants must not have received systemic therapy for ES-SCLC. Arm 2 consists of MK-6070 + I-DXd in both induction and maintenance. Arm 3 consists of MK- 6070 + I-DXd in induction followed by MK-6070 + atezolizumab in maintenance. Arm 4 consists of SOC carboplatin + etoposide + atezolizumab in induction followed by atezolizumab maintenance. Once Arm 2 Part A DLT clears, Part B can be initiated with randomization 1 : 1 : 1 to Arms 2, 3 and 4. Similarly, once Arm 1 DLT clears in Part A, Arm 1 in Part B will open for non-randomized allocation.

[0480] In Part B, each arm can randomize up to 40 patients approximately at a tolerated dose level determined from safety run-in in Part A. Entry dose level of Arm 2 and 3 in Part B will be set by Arm 2 in Part A. Similarly, entry dose level of Arm 1 in Part B will be set by Arm 1 in Part A. The selected entry dose level and dosing frequency on Part B will not exceed the highest DLT cleared dose range on Part A. This will also be guided by the totality of data from Part A of this study alongside totality of data from prior studies. More than one dose level can be explored in Part B to generate further information on safety and efficacy, depending on emerging data from prior and current studies.5.2 Administration of MK-6070, I-DXd, Atezolizumab, Carboplatin and EtoposideMK-6070

[0481] MK-6070 is administered with initial priming doses of 1 mg on CID 1 (Cycle 1Day 1) for all arms followed by a 12 mg dose on C1D8 (Cycle 1 Day 2). The target dose is administered on C1D15 for all arms (Cycle 1 Day 15). MK-6070 q3w target dose schedule starts at C2D1 (Cycle 2 Day 1) and continues for subsequent cycles for all arms.

[0482] MK-6070 will be administered as a 1-hour (±10 minute) IV infusion at a flat dose.Dosing will be administered q3w.I-DXd

[0483] Participants in Arms 1 and 2 will be administered I-DXd IV q3w until unacceptable toxicity, disease progression, or withdrawal of consent. Participants in Arm 3 will be administered I-DXd IV q3w up to 4 cycles.117NAI-5001911280

[0484] The first dose of I-DXd will be infused for 90 (±10) minutes. If there is no IRR during or after the initial dose, the subsequent doses may be infused for 30 (±5) minutes.

[0485] Before each dose of I-DXd, it is mandatory to premedicate participants for prevention of nausea and vomiting with a 2- or 3-drug combination regimen (e.g., corticosteroids with either a 5-HT3 receptor antagonist (e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g., aprepitant, casopitant, netupitant, or rolapitant) as well as other drugs as indicated) according to local or standard practice guidelines.

[0486] When administered on the same day as MK-6070, I-DXd will be administered first, followed by MK-6070. MK-6070 will be administered at least 30 minutes after the end of I-DXd administration.

[0487] I-DXd is prepared based on the participant’s baseline body weight, defined as the last measurement before the first dose. The dose must be recalculated if the participant’s weight changes by 10% or more from baseline. After the recalculation, the updated participant’s weight will be used as the new baseline weight.Atezolizumab

[0488] Atezolizumab will be administered IV q3w. The first dose of atezolizumab will be infused over 60 (±15) minutes. If there is no IRR during or after the initial dose, the subsequent doses may be infused for 30 (±5) minutes.Carboplatin

[0489] In Arm 4 induction, carboplatin will be administered as an IV infusion over approximately 30 to 60 minutes on Day 1 for up to 4 cycles (Cycles 1-4). Carboplatin will be administered approximately 30 minutes after the completion of atezolizumab infusion. Additional premedications should be administered as per standard practice.

[0490] Carboplatin will be calculated using the Calvert formula to achieve an area under the plasma drug concentration time curve of 5 mg / mL / min. The dose should not exceed 750 mg:Total dose (mg) = (target AUC) x (CrCl + 25)The estimated CrCl in the Calvert formula should not exceed 125 mL / minMaximum carboplatin dose (mg) = target AUC 5 x (125 ± 25) = 5 x 150 = 750 mg CrCl must be calculated using the Cockcroft-Gault formula:- Men: [(140 - age (y)) x weight (kg)] / [72 x serum creatinine (mg / dL)]- Women: [(140 - age (y)) x weight (kg)] x 0.85 / [72 x serum creatinine (mg / dL)]118NAI-5001911280

[0491] Dose may be rounded to the nearest 50 mg at the discretion of the investigator and according to institutional standards.

[0492] It is recommended to use the subject’s most recent serum creatinine and body weight values for dose calculation at each visit.Etoposide

[0493] In Arm 4 induction, etoposide will be administered as an IV infusion over approximately 30 to 60 minutes on Day 1 to Day 3 for up to 4 cycles (Cycles 1-4). Days 1, 2, and 3 must be consecutive days without interruption.

[0494] Etoposide will be administered approximately 30 minutes after the completion of carboplatin infusion. Additional premedications should be administered as per standard practice.5.3 Dose-limiting Toxicity

[0495] All toxicities will be graded using NCI-CTCAE Version 5.0 based on the investigator assessment.

[0496] The DLT window of observation will be 21 days following first dose of study intervention during Safety Run-in.

[0497] The occurrence of any of the toxicities listed in Section 4.4 during Cycle 1 will be considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration.5.4 Dose Modification of I-DXd

[0498] No dose modification is required for Grade 1 or Grade 2 events, unless specified.

[0499] For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) should be performed frequently and at an interval of no greater than 7 days until the adverse event (AE) is determined to be resolving or back to baseline.

[0500] If a dose reduction is required, after resolution of the toxicity, the participant can resume treatment with I-DXd at a dose level as outlined in Table 8. Once the dose of I-DXd has been reduced because of toxicity, all subsequent doses should be administered at that lower dose level unless further dose reduction is required. More than 2 dose reductions are not allowed. The participant will be withdrawn from the study treatment if further toxicity meeting the requirement for dose reduction occurs. Once the dose of I-DXd is reduced, no dose reescalation is permitted.119NAI-5001911280

[0501] Table 8: 1-DXd Dose Reduction Guidelines5.5 Dose Modification for Carboplatin

[0502] Recommended dose reduction levels for carboplatin are provided in Table 9. A maximum of 2 dose reductions are permitted; if additional reductions are required, carboplatin must be discontinued.

[0503] Table 9: Dose Reduction Levels for CarboplatinAUC = area under the curve used to calculate the dose of carboplatin5.6 Dose Modification for Etoposide

[0504] Recommended etoposide dosing adjustments for renal impairment or hepatic dysfunction are provided in Table 10.

[0505] Table 10: Recommended Dose Modifications for EtoposideAST = aspartate aminotransferase; CrCl = creatinine clearance5. 7 Prophylaxis Medication for CRS / IRR

[0506] Participants will receive cytokine release syndrome / infusion-related reaction (CRS / IRR) prophylaxis medication to reduce the risk and severity of hypersensitivity reactions. CRS / IRR prophylaxis medications include, for example, acetaminophen, dexamethasone and diphenhydramine.120NAI-5001911280

[0507] The sequence of administration will be premedication followed by I-DXd, followed by MK-6070. Prophylactic medications should be administered 1 hour before I DXd administration.Example 6: Summary of preliminary clinical data

[0508] The combination of ifinatamab deruxtecan (I-DXd), a B7-H3 targeted ADC, and gocatamig (MK-6070), a DLL3 targeting trispecific protein, is being tested for small cell lung cancer in active trials MK-6070-001 and MK-6070-002. Efficacy in evaluable participants receiving the combination has been higher than anticipated. The preliminary confirmed ORR of >70% surpasses each of the monotherapy agents’ efficacy. This is a promising combination for treatment of DLL3+ tumor types.

[0509] The present disclosure believes that the combination of DLL3 targeting trispecific protein (e.g., MK-6070 or gocatamig) with an anti-B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan (I-DXd)) may be more efficacious than either treatment alone. The present disclosure believes that the combination of DLL3 targeting trispecific protein (e.g., MK-6070 or gocatamig) with an anti-B7-H3 antibody-drug conjugate (e.g, ifinatamab deruxtecan (I-DXd)) and atezolizumab may be more efficacious than any of the treatments alone. Additionally, the present disclosure believes that the combination may not result in cumulative toxicities such that it will be better tolerated than existing therapies.

[0510] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

[0511] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.121NAI-5001911280SEQUENCE TABLE122NAI-5001911280123NAI-5001911280

Claims

CLAIMS1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH- CDR3, comprising the amino acid sequence of the VH-CDR1, VH- CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody (“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH- CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH- CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)- (B)-(C)-COOH; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:124NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising:(a) a first domain (A) which specifically binds to human CD3, wherein the first domain (A) is a single chain variable fragment (“scFv”), and wherein the scFv comprises a VH-CDR1, a VH-CDR2, and a VH- CDR3, comprising the amino acid sequence of the VH-CDR1, VH- CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;(b) a second domain (B) which specifically binds to human serum albumin, wherein the second domain (B) is a single-domain antibody125NAI-5001911280(“sdAb”), wherein the sdAb comprises a VH-CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH- CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 11; and(c) a third domain (C) which specifically binds to human DLL3, wherein the third domain (C) is an sdAb, wherein the sdAb comprises a VH- CDR1, a VH-CDR2, and a VH-CDR3 comprising the amino acid sequence of the VH-CDR1, the VH-CDR2, and the VH-CDR3, respectively, within an sdAb comprising the amino acid sequence of SEQ ID NO: 15; wherein the first, second and third domains are linked in the order H2N-(A)- (B)-(C)-COOH; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate, wherein the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula II wherein A represents a connecting position to the anti-human B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and126NAI-5001911280(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

3. The method of claim 1 or claim 2, wherein the scFv in the first domain (A) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

4. The method of any one of claims 1-3, wherein the sdAb in the second domain (B) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 12,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 14.

5. The method of any one of claims 1-4, wherein the sdAb in the third domain (C) comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 16,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 18.

6. The method of any one of claims 1-5, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 19,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 20,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 21,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 22,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 24.127NAI-50019112807. The method of any one of claims 1-6, wherein the scFv in the first domain (A) comprises a heavy chain variable region (“VH”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 3, and a light chain variable region (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.

8. The method of any one of claims 1-7, wherein the sdAb in the second domain (B) comprises a VHH domain comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 11.

9. The method of any one of claims 1-8, wherein the sdAb in the third domain (C) comprises a VHH domain comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 15.

10. The method of any one of claims 1-9, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises a VH comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 25, and a VL comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 26.

11. The method of any one of claims 1-10, wherein the scFv in the first domain (A) comprises a VH comprising the amino acid sequence of SEQ ID NO: 3, and a VL comprising the amino acid sequence of SEQ ID NO: 4.

12. The method of any one of claims 1-11, wherein the sdAb in the second domain (B) comprises a VHH domain comprising the amino acid sequence of SEQ ID NO: 11.

13. The method of any one of claims 1-12, wherein the sdAb in the third domain (C) comprises a VHH domain comprising the amino acid sequence of SEQ ID NO: 15.

14. The method of any one of claims 1-13, wherein the anti-human B7-H3 antibody is an IgGl.128NAI-500191128015. The method of any one of claims 1-14, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 25, and a VL comprising the amino acid sequence of SEQ ID NO: 26.

16. The method of any one of claims 1-15, wherein the anti-human B7-H3 antibody comprises a heavy chain (“HC”) comprising the amino acid sequence of SEQ ID NO: 29, and a light chain (“LC”) comprising the amino acid sequence of SEQ ID NO: 30.

17. The method of any one of claims 1-16, wherein the antibody-drug conjugate is ifinatamab deruxtecan.

18. The method of any one of claims 1-17, wherein a linker LI links the first and second domains of the DLL3 targeting tri specific protein, and a linker L2 links the second and third domains of the DLL3 targeting trispecific protein.

19. The method of any one of claims 1-18, wherein the linkers LI and L2 both comprise the sequence of SEQ ID NO: 27.

20. The method of any one of claims 1-19, wherein the DLL3 targeting trispecific protein comprises the amino acid sequence of SEQ ID NO: 1.

21. The method of any one of claims 1-20, wherein the DLL3 targeting trispecific protein is gocatamig.

22. A method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising the amino acid sequence of SEQ ID NO: 1; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:129NAI-5001911280Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH- CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

23. A method for treating cancer in a subject in need thereof, wherein the method comprises:(I) administering to the subject a therapeutically effective amount of a DLL3 targeting trispecific protein comprising the amino acid sequence of SEQ ID NO: 1; and(II) administering to the subject a therapeutically effective amount of an antibodydrug conjugate, wherein the antibody-drug conjugate comprises an anti-human B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II130NAI-5001911280Formula II wherein A represents a connecting position to the anti-human B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises:(i) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 25; and(ii) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 26.

24. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a therapeutically effective amount of gocatamig; and(ii) administering to the subject a therapeutically effective amount of ifinatamab deruxtecan.

25. The method of any one of claims 1-24, wherein a lysine residue at the carboxyl terminus of the HC of the anti-human B7-H3 antibody is deleted.

26. The method of any one of claims 1-25, wherein the drug to antibody ratio is in the range of from 3 to 5, optionally wherein the drug to antibody ratio is 4.131NAI-500191128027. The method of any one of claims 1-26, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered according to a dosing schedule comprising the following steps:(i) administering a priming dose of the DLL3 targeting trispecific protein; and(ii) administering a target dose of the DLL3 targeting trispecific protein, wherein the target dose is either the same or higher than the priming dose.

28. The method of claim 27, wherein the priming dose of the DLL3 targeting trispecific protein is about 1 mg.

29. The method of claim 27 or claim 28, wherein the priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of Cycle 1 of the dosing schedule.

30. The method of any one of claims 27-29, wherein the priming dose of the DLL3 targeting trispecific protein is administered once a week.

31. The method of any one of claims 1-27, wherein the method comprises two priming doses of the DLL3 targeting trispecific protein, wherein the two priming doses comprise a first priming dose and a second priming dose.

32. The method of claim 31, wherein the first priming dose of the DLL3 targeting trispecific protein is about 1 mg.

33. The method of claim 31 or claim 32, wherein the first priming dose of the DLL3 targeting trispecific protein is administered on Day 1 of Cycle 1 of the dosing schedule.

34. The method of any one of claims 31-33, wherein the second priming dose of the DLL3 targeting trispecific protein is about 12 mg.

35. The method of any one of claims 31-34, wherein the second priming dose of the DLL3 targeting trispecific protein is administered on Day 8 of Cycle 1 of the dosing schedule.132NAI-500191128036. The method of any one of claims 27-35, wherein the target dose of the DLL3 targeting trispecific protein is about 24 mg.

37. The method of any one of claims 27-35, wherein the target dose of the DLL3 targeting trispecific protein is about 36 mg.

38. The method of any one of claims 27-35, wherein the target dose of the DLL3 targeting trispecific protein is a dose of about 12 mg, about 24 mg, about 36 mg, or about 48 mg.

39. The method of any one of claims 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered on Day 15 of Cycle 1 of the dosing schedule.

40. The method of any one of claims 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered for from about 1 week to about 6 weeks.

41. The method of any one of claims 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every week, once every two weeks or once every three weeks.

42. The method of any one of claims 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every two weeks.

43. The method of any one of claims 27-38, wherein the target dose of the DLL3 targeting trispecific protein is administered once every three weeks.

44. The method of any one of claims 27-43, wherein the target dose of the DLL3 targeting trispecific protein is maintained to the end of the dosing schedule after the administration of the priming dose of the DLL3 targeting trispecific protein.

45. The method of any one of claims 1-44, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered intravenously (“IV”).133NAI-500191128046. The method of claim 45, wherein the therapeutically effective amount of the DLL3 targeting trispecific protein is administered via a 60 ± 10 minute IV fusion.

47. The method of any one of claims 1-46, wherein the therapeutically effective amount of the antibody-drug conjugate is administered according to a dosing schedule comprising the following steps:(i) administering a first dose of the antibody-drug conjugate; and(ii) administering a second dose of the antibody-drug conjugate.

48. The method of claim 47, wherein the first dose of the antibody-drug conjugate is a dose of about 8 mg / kg to about 12 mg / kg.

49. The method of claim 47 or claim 48, wherein the second dose of the antibody-drug conjugate is a dose ranging from about 8 mg / kg to about 12 mg / kg.

50. The method of claim 47 or claim 48, wherein the second dose of the antibody-drug conjugate is a dose of about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, or about 12.0 mg / kg.

51. The method of claim 47, wherein the first dose of the antibody-drug conjugate or the second dose of the antibody-drug conjugate is a dose of about 4.5 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 6.4 mg / kg, about 8 mg / kg, about 10 mg / kg, or about 12 mg / kg.

52. The method of any one of claims 47-51, wherein the first dose of the antibody-drug conjugate is administered concurrently with the priming dose of the DLL3 targeting trispecific protein or before the priming dose of the DLL3 targeting trispecific protein.

53. The method of any one of claims 47-52, wherein the second dose of the antibody-drug conjugate is administered for from about 1 week to about 6 weeks.134NAI-500191128054. The method of any one of claims 47-53, wherein the second dose of the antibody-drug conjugate is administered once every two weeks.

55. The method of claim 54, wherein the second dose of the antibody-drug conjugate is administered fifteen (15) days after the first dose of the antibody-drug conjugate.

56. The method of any one of claims 47-53, wherein the second dose of the antibody-drug conjugate is administered once every three weeks.

57. The method of claim 56, wherein the second dose of the antibody-drug conjugate is administered twenty-two (22) days after the first dose of the antibody-drug conjugate.

58. The method of any one of claims 47-57, wherein the administration of the second dose of the antibody-drug conjugate is maintained to the completion of the administration of the target dose of the DLL3 targeting trispecific protein.

59. The method of any one of claims 1-58, wherein the antibody-drug conjugate is administered before administration of the DLL3 targeting trispecific protein.

60. The method of claim 59, wherein the antibody-drug conjugate is administered 24 hours before administration of the DLL3 targeting trispecific protein.

61. The method of claim 59, wherein the antibody-drug conjugate is administered at least 6 hours before administration of the DLL3 targeting trispecific protein.

62. The method of claim 59, wherein the antibody-drug conjugate is administered at least 30 minutes before administration of the DLL3 targeting trispecific protein.

63. The method of any one of claims 1-62, wherein the antibody-drug conjugate is administered intravenously (“IV”).

64. The method of claim 63, wherein the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.135NAI-500191128065. The method of claim 63, wherein the antibody-drug conjugate is administered via a 60 ± 10 minute IV fusion.

66. The method of claim 63, wherein the antibody-drug conjugate is administered via a 90 ± 10 minute IV fusion.

67. The method of any one of claims 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every two weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every two weeks.

68. The method of claim 67, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 5.4 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 5.4 mg / kg; or(IV) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg.

69. The method of any one of claims 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every three weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every three weeks.

70. The method of claim 69, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 18 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 18 mg; and136NAI-5001911280(ii) the second dose of the antibody-drug conjugate is 12 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and (ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(IV) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg; or(V) (i) the target dose of the DLL3 targeting trispecific protein is 36 mg; and(ii) the second dose of the antibody-drug conjugate is 10 mg / kg.

71. The method of any one of claims 1-41, 44-53 and 58-66, wherein(i) the target dose of the DLL3 targeting trispecific protein is administered once every two weeks; and(ii) the second dose of the antibody-drug conjugate is administered once every three weeks.

72. The method of claim 71, wherein:(I) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg;(II) (i) the target dose of the DLL3 targeting trispecific protein is 12 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg;(III) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 8 mg / kg; or(IV) (i) the target dose of the DLL3 targeting trispecific protein is 24 mg; and(ii) the second dose of the antibody-drug conjugate is 12 mg / kg.

73. The method of any one of claims 1-72, further comprising administering to the subject a therapeutically effective amount of atezolizumab.

74. The method of claim 73, wherein the atezolizumab is administered prior to administration of the DLL3 targeting trispecific protein.

75. The method of claim 74, wherein the atezolizumab is administered at least 30 minutes prior to administration of the DLL3 targeting trispecific protein.137NAI-500191128076. The method of any one of claims 73-75, wherein the atezolizumab is administered at a dose of about 100 mg to about 2500 mg.

77. The method of claim 76, wherein the atezolizumab is administered at a dose of 1200 mg.

78. The method of any one of claims 73-77, wherein the atezolizumab is administered once every three weeks.

79. The method of any one of claims 73-78, wherein the atezolizumab is administered intravenously (“IV”).

80. The method of claim 79, wherein the atezolizumab is administered via a 30 ± 5 minute IV infusion or 30 ± 10 minute IV infusion.

81. The method of claim 79, wherein the atezolizumab is administered via a 60 ± 15 minute IV infusion.

82. The method of any one of claims 1-81, wherein the cancer is a cancer associated with DLL3 expression.

83. The method of any one of claims 1-82, wherein the cancer is small cell lung cancer or a neuroendocrine cancer.

84. The method of any one of claims 1-83, wherein the cancer is extensive-stage small cell lung cancer (“ES-SCLC”).

85. The method of claim 84, wherein the ES-SCLC is Stage IV (T any, N any, Mla / b / c) as assessed by the American Joint Committee on Cancer Staging Manual, Eighth Edition.

86. The method of any one of claims 82-84, wherein the cancer is relapsed or refractory.138NAI-500191128087. The method of any one of claims 1-86, wherein the method is used as induction therapy for a subject in need thereof.

88. The method of any one of claims 1-86, wherein the method is used as maintenance therapy for a subject in need thereof.

89. The method of any one of claims 1-88, wherein the subject has received only one prior line of treatment.

90. The method of any one of claims 1-88, wherein the subject has received at least one prior line of treatment.

91. The method of claim 89 or claim 90, wherein the one prior line of treatment is a systemic therapy.

92. The method of any one of claims 84-91, wherein the subject has received no prior line of systemic treatment for ES-SCLC.

93. The method of any one of claims 84-92, wherein the subject has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and anti-PD-l / anti- PD-L1 treatment for ES-SCLC; optionally wherein the subject has not had evidence of progressive disease in the prior therapy.

94. The method of any one of claims 1-93, wherein the anti-human B7-H3 antibody or functional fragment thereof is an antibody.

95. The method of any one of claims 1-94, wherein the anti-human B7-H3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.

96. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:139NAI-5001911280(i) administering to the subject in Cycle 1 of the dosing schedule: a) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; b) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and c) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and(ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule: a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and wherein the subject has received three or four dosing cycles of prior therapy with etoposide, platinum therapy and anti-PD-l / anti-PD-Ll treatment for ES-SCLC; optionally wherein the subject has not had evidence of progressive disease in the prior therapy.

97. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:(i) administering to the subject in Cycle 1 of the dosing schedule: a) 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; b) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; c) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and d) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule; and(ii) following completion of step (i), administering to the subject for subsequent cycles of the dosing schedule:140NAI-5001911280a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and wherein the subject has received no prior line of systemic treatment for ES-SCLC.

98. A method for treating extensive-stage small cell lung cancer (“ES-SCLC”) in a subject in need thereof, wherein the method comprises a dosing schedule comprising the following steps:(i) administering to the subject in Cycle 1 of the dosing schedule: a) 12 mg / kg of ifinatamab deruxtecan on Day 1 of Cycle 1 of the dosing schedule; b) 1 mg of a DLL3 targeting trispecific protein on Day 1 of Cycle 1 of the dosing schedule; c) 12 mg of the DLL3 targeting trispecific protein on Day 8 of Cycle 1 of the dosing schedule; and d) 36 mg of the DLL3 targeting trispecific protein on Day 15 of Cycle 1 of the dosing schedule;(ii) following completion of step (i), administering to the subject for Cycles 2-4 of the dosing schedule: a) a therapeutically effective amount of ifinatamab deruxtecan at a dose of about 12 mg / kg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and(iii) following completion of step (ii), administering to the subject for subsequent cycles of the dosing schedule: a) a therapeutically effective amount of atezolizumab at a dose of about 1200 mg, once every three weeks, intravenously; and b) concurrently administering to the subject a therapeutically effective amount of the DLL3 targeting trispecific protein at a dose of about 36 mg / kg once every three weeks, intravenously; and141NAI-5001911280wherein the subject has received no prior line of systemic treatment for ES-SCLC.

99. The method of any one of claims 1-98, wherein the subject is premedicated with one or more of tocilizumab, an antihistamine, acetaminophen, 5-HT3 receptor antagonist, NK-1 receptor antagonist and / or a corticosteroid, optionally wherein the corticosteroid comprises dexamethasone.

100. The method of any one of claims 1-99, wherein the subject is a human subject.

101. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of claims 1-26, and a therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-26 in combination, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58- 62 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.

102. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of claims 1-26, in combination with a therapeutically effective amount of the antibodydrug conjugate as defined in any one of claims 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58- 62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.

103. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of the DLL3 targeting trispecific protein as defined in any one of claims 1-26, in combination with a therapeutically effective amount of the antibodydrug conjugate as defined in any one of claims 1-26, and a therapeutically effective amount of atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, the antibody-drug conjugate is optionally administered as defined in any one of142NAI-5001911280claims 47-72, and / or the atezolizumab is optionally administered as defined in any one of claims 73-81.

104. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a therapeutically effective amount of ifinatamab deruxtecan.

105. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of gocatamig, in combination with a therapeutically effective amount of ifinatamab deruxtecan, and a therapeutically effective amount of atezolizumab.

106. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig.

107. A pharmaceutical composition for use in treating cancer, comprising a therapeutically effective amount of ifinatamab deruxtecan, in combination with a therapeutically effective amount of gocatamig, and a therapeutically effective amount of atezolizumab.

108. The pharmaceutical composition for use of any one of claims 101-107 wherein the cancer is as defined in any one of claims 82-86.

109. Use of the DLL3 targeting trispecific protein as defined in any one of claims 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined in any one of claims 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.

110. Use of the DLL3 targeting trispecific protein as defined in any one of claims 1-26 for the preparation of a medicament for treating cancer, by administration in combination143NAI-5001911280with the antibody-drug conjugate as defined in any one of claims 1-26 and atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72, and / or the atezolizumab is optionally administered as defined in any one of claims 73-81.

111. Use of the antibody-drug conjugate as defined in any one of claims 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the DLL3 targeting trispecific protein as defined in any one of claims 1-26, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.

112. Use of the antibody-drug conjugate as defined in any one of claims 1-26 for the preparation of a medicament for treating cancer, by administration in combination with the DLL3 targeting trispecific protein as defined in any one of claims 1-26 and atezolizumab, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72, and / or the atezolizumab is optionally administered as defined in any one of claims 73-81.

113. The use of any one of claims 109-112, wherein the cancer is as defined in any one of claims 82-86.

114. A DLL3 targeting trispecific protein as defined in any one of claims 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 in treating cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.144NAI-5001911280115. A DLL3 targeting trispecific protein as defined in any one of claims 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 in treating small cell lung cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72.

116. A DLL3 targeting trispecific protein as defined in any one of claims 1-26 for use in combination with an anti-human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 and atezolizumab in treating small cell lung cancer in a subject in need thereof, wherein optionally the DLL3 targeting trispecific protein is administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, the antibody-drug conjugate is optionally administered as defined in any one of claims 47-72, and / or the atezolizumab is optionally administered as defined in any one of claims 73-81.

117. An anti -human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of claims 1-26 in treating cancer in a subject in need thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of claims 47-72 and / or the DLL3 targeting trispecific protein is optionally administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75.

118. An anti-human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of claims 1-26 in treating small cell lung cancer in a subject in need thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of claims 47-72 and / or the DLL3 targeting trispecific protein is optionally administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75.

119. An anti -human B7-H3 antibody-drug conjugate as defined in any one of claims 1-26 for use in combination with a DLL3 targeting trispecific protein as defined in any one of claims 1-26 and atezolizumab in treating small cell lung cancer in a subject in need145NAI-5001911280thereof, wherein optionally the antibody-drug conjugate is administered as defined in any one of claims 47-72, the DLL3 targeting trispecific protein is optionally administered as defined in any one of claims 27-46, 58-62, 67-72, 74, or 75, and / or the atezolizumab is optionally administered as defined in any one of claims 73-81.

120. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof.

121. Gocatamig for use in combination with ifinatamab deruxtecan and atezolizumab in treating small cell lung cancer in a subject in need thereof.

122. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof.

123. Ifinatamab deruxtecan for use in combination with gocatamig and atezolizumab in treating small cell lung cancer in a subject in need thereof.

124. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of gocatamig to the subject once every two weeks; and(ii) administration of ifinatamab deruxtecan to the subject once every two weeks.

125. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of ifinatamab deruxtecan to the subject once every two weeks; and(ii) administration of gocatamig to the subject once every two weeks.

126. Gocatamig for use in combination with ifinatamab deruxtecan in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of gocatamig to the subject once every three weeks; and(ii) administration of ifinatamab deruxtecan to the subject once every three weeks.146NAI-5001911280127. Ifinatamab deruxtecan for use in combination with gocatamig in treating small cell lung cancer in a subject in need thereof, wherein the use comprises(i) administration of ifinatamab deruxtecan to the subject once every three weeks; and(ii) administration of gocatamig to the subject once every three weeks.

128. Gocatamig or ifinatamab deruxtecan for use of any one of claims 120-127, wherein the subject has received only one prior line of treatment.

129. Gocatamig or ifinatamab deruxtecan for use of any one of claims 120-127, wherein the subject has received at least one prior line of treatment.

130. Gocatamig or ifinatamab deruxtecan for use of claim 128 or 129, wherein the one prior line of treatment is a systemic therapy.

131. A kit comprising (i) an DLL3 targeting trispecific protein as defined in any one of claims 1-26, or a pharmaceutical composition comprising the same, and (ii) an antihuman B7-H3 antibody-drug conjugate as defined in any one of claims 1-26, or a pharmaceutical composition comprising the same, optionally further comprising instructions for treating cancer in a subject in need thereof according to the method of any one of claims 1-100.

132. The kit of claim 131, further comprising (iii) atezolizumab or a pharmaceutical composition comprising the same.

133. The kit of claim 131, further comprising (iii) pembrolizumab or a pharmaceutical composition comprising the same.147NAI-5001911280

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