Engineered DLL3-binding peptides

Abstract

Provided herein are engineered DLL3-binding peptides, pharmaceutical compositions comprising the engineered DLL3-binding peptides, and methods of designing and preparing the same. The engineered DLL3-binding peptides selectively bind DLL3 with low-nanomolar or picomolar binding activity.

Description

WSGR Docket No. 70774-714.601ENGINEERED DLL3-BINDING PEPTIDESCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 748,434, filed January 23, 2025, which is entirely incorporated herein by reference.INCORPORATION BY REFERENCE

[0002] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BACKGROUND

[0003] Delta like ligand 3 (DLL3), is an inhibitory Notch ligand protein that is overexpressed in various types of cancers and in many instances, is aberrantly expressed on the cell surface. Such expression of DLL3 on the surface of cells, may be used as a biomarker for cancer. In instances of aberrant expression, certain domains of DLL3, such as the N-terminal domain, the Delta- Serrate-Lag2 (DSL) domain and one or more epidermal growth factor like (EGF) domains are extracellular while other domains located near the C-terminus remain disposed within the cell membrane or are intracellular. Although the underlying cause of the cell surface expression of DLL3 is not known, recent studies have suggested that DLL3 plays a role in tumorigenesis in several cancers including, for example, small cell lung cancer and large cell neuroendocrine carcinoma. As a result, DLL3 has emerged as an attractive target for cancer therapies, and in particular, therapies for use in the treatment and prevention of cancers.SUMMARY

[0004] Provided herein are engineered delta like ligand 3-binding peptides comprising a sequence of Formula X1X2X3X4X5X6X7X8WSGR Docket No. 70774-714.601^31^32^33^34^35^36^37^38^39^40^41^42^43^44^45^46^47^48^49^50^51^52^53^54^55^56^57X58X59X6OX61X62X63X64 )wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T; X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y;X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y; X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y; X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V; X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y; X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, V, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, T, and V; XIIis selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V; X12is selected from the group consisting of A, D, E, G, I, K, L, N, P, R, S, T, and V; X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, P, R, T, V, and Y;X14is selected from the group consisting of A, D, E, F, G, I, K, L, P, Q, R, T, and V; X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y;X16is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y;X18is selected from the group consisting of A, C, D, E, F, L, M, P, Q, R, S, T, V, W, and Y;X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y;X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y;X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V;X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y; X25is selected from the group consisting of A, C, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y; X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, S, and V; X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V; X30is selected from the group consisting of A, C, D, E, H, I, F, K, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, P, Q, R, S, and V; X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y;X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, V, and Y; X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y; X37is selected from the group consisting of A, C, D, E, F, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, D, E, F, G, H, I, L, N, P, R, S, T, V, and Y;X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W;X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W; X42is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, V, W, and Y;X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, T, V, and W;WSGR Docket No. 70774-714.601X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y;X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V;X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, W, and Y;X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V;X49is selected from the group consisting of A, C, D, E, F, H, I, L, M, N, P, Q, R, S, T, V, and Y;X50is selected from the group consisting of A, C, E, F, G, I, L, Q, R, T, V, W, and Y; X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y;X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, S, T, and V;X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y;X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y; X57is absent or selected from the group consisting of A, C, E, L, Q, R, T, V, and Y; X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, E, F, K, L, P, R, and V;X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.WSGR Docket No. 70774-714.601

[0005] Also provided herein are methods of designing and preparing engineered DLL3-binding peptides in accordance with the present technology, as well as pharmaceutical compositions comprising the same.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 is a schematic of the structure of delta like ligand 3 (DLL3).

[0007] FIGS. 2A-2B are fluorescence-activated cell sorting (FACS) dot plots showing cell populations without any added DLL3 target (FIG.2A) and after (FIG.2B) addition of 100 nM biotinylated human DLL3 protein.

[0008] FIGS. 3A-3B are graphs showing two-state reaction kinetics for determining KD values of SEQ ID NO: 2 (FIG. 3 A) and SEQ ID NO: 7 (FIG. 3B) on DLL3.

[0009] FIGS. 4A-4C show the cell surface binding of SEQ ID NOs: 2, 7, 32, and 33 on two DLL3(+) cancer cell lines (SHP77 and NCI-H82) and one DLL3(-) cancer cell line (A431).DETAILED DESCRIPTION

[0010] The present technology provides engineered delta like ligand 3 -binding (DLL3-binding) peptides. The engineered DLL3-binding peptides may selectively bind DLL3 over other Notch family ligands, such as, for example, delta like ligand 1 (DLL1), delta like ligand 4 (DLL4), jagged- 1 (JAG1), and jagged-2 (JAG2). Specifically, the engineered DLL3 -binding peptides may bind DLL3 with low nanomolar affinity. The engineered DLL3-binding peptides may bind DLL3 with low picomolar affinity.

[0011] Further, as cell surface expression of DLL3 is common in various types of cancer, such as, for example, small cell lung cancer and large cell neuroendocrine carcinoma, the engineered DLL3 -binding peptides according to the present technology may bind an extracellular domain of DLL3 expressed by a cancer cell. The engineered DLL3 -binding peptides of the present technology may be designed to selectively bind DLL3 or a specific domain of DLL3, using a combined computational experimental approach based on ligand-peptide structure predictions and in vitro data.

[0012] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended toWSGR Docket No. 70774-714.601limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0013] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that structural changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation.Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0015] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0016] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0017] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0018] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of theWSGR Docket No. 70774-714.601administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight polypeptides (less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0019] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating, and the like.

[0020] The “peptides” described herein can be (a) naturally occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0021] As used herein, the terms “host cell” and “recipient cell” are intended to include any individual cell or cell culture that can be or has / have been recipients of vectors, exogenous nucleic acid molecules, and polynucleotides encoding the polypeptide or binding agent of the present disclosure; and / or recipients of the polypeptide or binding agent itself. The introduction of the respective material into the cell is carried out by way of transformation, transfection andWSGR Docket No. 70774-714.601the like. The term “host cell” is also intended to include progeny or potential progeny of a single cell. Because certain modifications may occur in succeeding generations due to either natural, accidental, or deliberate mutation or due to environmental influences, such progeny may not, in fact, be completely identical (in morphology or in genomic or total DNA complement) to the parent cell but is still included within the scope of the term as used herein. Suitable host cells include prokaryotic or eukaryotic cells, and also include but are not limited to bacteria, yeast cells, fungi cells, plant cells, and animal cells such as insect cells and mammalian cells, e.g., murine, rat, macaque or human.

[0022] A “vector” is a nucleic acid molecule used as a vehicle to transfer (foreign) genetic material into a cell. The term “vector” encompasses — but is not restricted to — plasmids, viruses, cosmids, and artificial chromosomes. In general, engineered vectors comprise an origin of replication, a multicloning site and a selectable marker. The vector itself is generally a nucleotide sequence, commonly a DNA sequence, that comprises an insert (transgene) and a larger sequence that serves as the “backbone” of the vector. Modem vectors may encompass additional features besides the transgene insert and a backbone: promoter, genetic marker, antibiotic resistance, reporter gene, targeting sequence, protein purification tag. Vectors called expression vectors (expression constructs) specifically are for the expression of the transgene in the target cell, and generally have control sequences.

[0023] As used herein, the term “culturing” refers to the in vitro maintenance, differentiation, growth, proliferation, and / or propagation of cells under suitable conditions in a medium.

[0024] The term “expression” includes any step involved in the production of a peptide or protein of the disclosure including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion.

[0025] Transfection” is the process of deliberately introducing nucleic acid molecules or polynucleotides (including vectors) into target cells. Transfection of animal cells typically involves opening transient pores or “holes” in the cell membrane, to allow the uptake of material. Transfection can be carried out using calcium phosphate, by electroporation, by cell squeezing or by mixing a cationic lipid with the material to produce liposomes, which fuse with the cell membrane and deposit their cargo inside.

[0026] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The aminoWSGR Docket No. 70774-714.601acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with non-amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0027] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0028] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User ’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35 :287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0029] In the peptides described herein, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent ExaminingWSGR Docket No. 70774-714.601Procedure, 8th Ed. Thus, “A” is alanine; “R” is arginine; “N” is asparagine; “D” is aspartic acid; “C” is cysteine; “Q” is glutamine; “E” is glutamic acid; “G” is glycine; “H” is histidine; “I” is isoleucine; “L” is leucine; “K” is lysine; “M” is methionine; “F” is phenylalanine; “P” is proline; “S” is serine; “T” is threonine; “W” is tryptophan; “Y” is tyrosine; and “V” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof can be used. Thus, for example, “L-F” or “IF” is L-phenylalanine; “D-F” or “dF” is D-phenylalanine; “D- / L-F” or “d / lF” is D-phenylalanine, L-phenylalanine, or combinations thereof; “F” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0030] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”Engineered DLL3 -Binding Peptides

[0031] The present technology provides engineered DLL3-binding peptides, also referred to herein as “DLL3-binding peptides.” The engineered DLL-binding peptide may be selective for DLL3 (Gene ID: 10683) over other Notch family ligands, such as, for example, DLL1, DLL4, JAG1, and JAG2. In some embodiments, the engineered DLL3-binding peptide disrupts the inhibitory action of DLL3 on Notch signaling.

[0032] Although a crystal structure of DLL3 has not yet been obtained, the general structural features of DLL3, which are conserved among other Notch family ligands, are known and may be individually targeted by the engineered DLL3-binding peptides of the present technology. Specifically, DLL3 is characterized by anN-terminal domain (residues 1-175 with residues 1-26 making up the secretion sequence), a Delta- Serrate-LAG2 (DSL) domain (residues 176-215), and six epidermal growth factor-like (EGF-like) domains: EGF-like domain 1 (EGF1 domain; residues 216-249), EGF-like domain 2 (EGF2 domain; residues 274-310), EGF-like domain 3 (EGF3 domain; residues 312-351), EGF-like domain 4 (EGF4 domain; residues 353-389), EGF-like domain 5 (EGF5 domain; residues 391-427), and EGF-like domain 6 (EGF6 domain; residues 429-465), as shown in FIG. 1. The engineered DLL3-binding peptides described herein may bind one or more of the N-terminal domain, the DSL domain, and the six EGF-like domains of DLL3. In particular, the engineered DLL3-bindingWSGR Docket No. 70774-714.601peptides may bind one or more of the N-terminal domain, the DSL domain, the EGF1 domain and the EGF2 domain. As such, the engineered DLL3 -binding peptides may bind a region of DLL3 defined by any of residues 1-310.

[0033] In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3. Accordingly, in some embodiments, the engineered DLL3-binding peptides bind any of residues 1-175 of DLL3.

[0034] In some embodiments, the engineered DLL3 -binding peptides bind a region of DLL3 spanning the N-terminal domain and the DSL domain. Accordingly, in some embodiments, the engineered DLL3 -binding peptides bind any of residues 1-215 of DLL3.

[0035] In some embodiments, the engineered DLL3-binding peptide binds the DSL domain of DLL3. Accordingly, in some embodiments, the engineered DLL3-binding peptides bind any of residues 176-215 of DLL3.

[0036] In some embodiments, the engineered DLL3 -binding peptides bind a region of DLL3 spanning the DSL domain and the EGF1 domain. Accordingly, in some embodiments, the engineered DLL3-binding peptides bind any of residues 176-249 of DLL3.

[0037] In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3. Accordingly, in some embodiments, the engineered DLL3-binding peptides bind any of residues 216-249 of DLL3.

[0038] In some embodiments, the engineered DLL3 -binding peptides bind a region of DLL3 spanning the EGF1 domain and the EGF2 domain. Accordingly, in some embodiments, the engineered DLL3-binding peptides bind any of residues 216-310 of DLL3.

[0039] In some embodiments, the engineered DLL3 -binding peptide binds the EGF2 domain of DLL3. Accordingly, in some embodiments, the engineered DLL3 -binding peptides bind any of residues 274-310 of DLL3.

[0040] Whereas most normal tissues have negligible DLL3 expression, and the subset of normal tissues that do express DLL3, exhibit low, cytoplasmic expression; DLL3 is highly and homogenously expressed on the cell surface of tumors. Accordingly, the engineered DLL3-binding peptides of the present technology may bind to an extracellular domain of DLL3 expressed on a cell. Specifically, the engineered DLL3 -binding peptides may bind one or more of the N-terminal domain, the DSL domain, and the six EGF-like domains within the extracellular domain of DLL3. In some embodiments, the engineered DLL3 -binding peptidesWSGR Docket No. 70774-714.601bind the N-terminal domain, a region spanning the N-terminal domain and the DSL-domain, the EGF1 domain, the EGF2 domain, or a region spanning the EGF1 domain and the EGF2 domain within the extracellular domain of DLL3.

[0041] In some embodiments, the engineered DLL3 -binging peptides bind the N-terminal domain, a region spanning the N-terminal domain and the DSL-domain, the EGF1 domain, the EGF2 domain, or a region spanning the EGF 1 domain and the EGF2 domain within the extracellular domain of DLL3 on a cancer cell. The cancer cell may be a small cell lung cancer cell, a prostate cancer cell, or a large cell neuroendocrine carcinoma. In some embodiments, the engineered DLL3 -binging peptides bind the N-terminal domain, a region spanning the N-terminal domain and the DSL-domain, the EGF1 domain, the EGF2 domain, or a region spanning the EGF1 domain and the EGF2 domain within the extracellular domain of DLL3 on a small cell lung cancer cell. In some embodiments, the engineered DLL3 -binging peptides bind the N-terminal domain, a region spanning the N-terminal domain and the DSL-domain, the EGF1 domain, the EGF2 domain, or a region spanning the EGF1 domain and the EGF2 domain within the extracellular domain of DLL3 on a prostate cancer cell. In some embodiments, the engineered DLL3 -binging peptides bind the N-terminal domain, a region spanning the N-terminal domain and the DSL-domain, the EGF1 domain, the EGF2 domain, or a region spanning the EGF1 domain and the EGF2 domain within the extracellular domain of DLL3 on a large cell neuroendocrine carcinoma cell.

[0042] In some embodiments, the engineered DLL3 -binding peptides have a length of at least 50 amino acids. For example, the engineered DLL3-binding peptides may be about 50 amino acids to about 70 amino acids in length. In some embodiments, the engineered DLL3-binding peptides have a length of about 51 amino acids to about 68 amino acids, about 52 amino acids to about 66 amino acids, about 53 amino acids to about 64 amino acids, about 54 amino acids to about 62 amino acids, or about 55 amino acids to about 60 amino acids. In some embodiments, the engineered DLL3-binding peptides have a length of about 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 amino acids.

[0043] In some embodiments, the engineered DLL3 -binding peptide has a length of at least 53 residues, at least 54 residues, at least 55 residues, at least 56 residues, at least 57 residues, at least 58 residues, at least 59 residues, at least 60 residues, at least 61 residues, at least 62 residues, at least 63 residues, or at least 64 residues.WSGR Docket No. 70774-714.601

[0044] In some embodiments, the engineered DLL3 -binding peptide has a length of at most 53 residues, at most 54 residues, at most 55 residues, at most 56 residues, at most 57 residues, at most 58 residues, at most 59 residues, at most 60 residues, at most 61 residues, at most 62 residues, at most 63 residues, or at most 64 residues.

[0045] In some embodiments, the engineered DLL3-binding peptides comprise a sequence according to Formula (I):X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30x31x32x33x34x35x36x37x38x39x40x41x42x43x44x45x46x47x48x49x50x51x52x53x54x55x56x57X58X59X6OX61X62X63X64 )wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T; X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y;X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y; X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y; X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V; X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y; X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, V, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, T, and V; XIIis selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V; X12is selected from the group consisting of A, D, E, G, I, K, L, N, P, R, S, T, and V; X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, P, R, T, V, and Y;X14is selected from the group consisting of A, D, E, F, G, I, K, L, P, Q, R, T, and V; X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y;X16is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, S, T, V, W, and Y;WSGR Docket No. 70774-714.601X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y;X18is selected from the group consisting of A, C, D, E, F, L, M, P, Q, R, S, T, V, W, and Y;X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y;X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y;X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V;X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y; X25is selected from the group consisting of A, C, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y; X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, S, and V; X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V; X30is selected from the group consisting of A, C, D, E, H, I, F, K, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, P, Q, R, S, and V; X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y;X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, V, and Y; X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y; X37is selected from the group consisting of A, C, D, E, F, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, D, E, F, G, H, I, L, N, P, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W;X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W; X42is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, V, W, and Y;X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, T, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y;X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V;X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, W, and Y;X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V;X49is selected from the group consisting of A, C, D, E, F, H, I, L, M, N, P, Q, R, S, T, V, and Y;X50is selected from the group consisting of A, C, E, F, G, I, L, Q, R, T, V, W, and Y; X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y;X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, S, T, and V;X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y;X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y; X57is absent or selected from the group consisting of A, C, E, L, Q, R, T, V, and Y;WSGR Docket No. 70774-714.601X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, E, F, K, L, P, R, and V; X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

[0046] In some embodiments of the sequence of Formula (I), X22is E. Accordingly, in some embodiments, the engineered DLL3-binding peptide comprises a sequence of Formula (IA):x1x2x3x4x5x6x7x8x9x10x11X12X13X14X15X16X17X18X19X20X21EX23X24X25X26X27X28X29X30 x3^x32x33x34x33x3^x37x38x39x49x4^x42x43x44x43x4^x47x48x49x39x3^x32x33x34x33x3^x37X58X59X6OX61X62X63X64A)wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, P, Q, R, S, and T; X2is selected from the group consisting of C E, F, I, L, P, Q, R, S, T, V, W, and Y; X3is selected from the group consisting of A, C, E, F, K, L, Q, R, T, V, and Y;X4is selected from the group consisting of A, C, E, L, R, T, and V;X5is selected from the group consisting of A, C, E, F, H, I, L, R, T, V and Y;X6is selected from the group consisting of A, C, E, H, I, L, R, S, T, and V;X7is selected from the group consisting of A, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, E, G, L, P, Q, S, T, and V;X9is selected from the group consisting of A, D, E, F, G, L, N, P, S, and T;X10is selected from the group consisting of C, D, E, G, L, Q, R, S, T;XIIis selected from the group consisting of A, D, E, G, L, N, P, Q, and R;X12is selected from the group consisting of A, D, E, G, I, K, P, R, S, T, and V;X13is selected from the group consisting of A, D, G, K, L, M, P, R, T, and V;X14is selected from the group consisting of E, F, G, I, L, Q, R, T, and V;X15is selected from the group consisting of A, E, F, G, I, R, S, T, V, and W;X16is selected from the group consisting of A, C, E, F, I, L, P, Q, R, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, K, L, Q, R, V, W, and Y;WSGR Docket No. 70774-714.601X18is selected from the group consisting of A, D, E, P, R, S, and T;X19is selected from the group consisting of A, D, E, F, L, N, P, Q, S, and T;X20is selected from the group consisting of A, C, E, G, I, K, L, M, R, T, V, and W; X21is selected from the group consisting of A, D, E, F, G, I, P, Q, S, T, V, and Y; X23is selected from the group consisting of A, C, D, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, I, L, K, P, R, S, and V;X25is selected from the group consisting of A, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, G, I, L, P, Q, R, and S;X27is selected from the group consisting of A, C, E, F, I, L, P, R, and V;X28is selected from the group consisting of A, D, E, G, K, M, N, Q, and R;X29is selected from the group consisting of A, D, E, K, N, Q, R, S, and V;X30is selected from the group consisting of A, C, D, E, H, R, S, T, V, and Y;X31is selected from the group consisting of A, C, F, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, and V;X33is selected from the group consisting of A, C, D, E, K, L, R, S, T, V, and W; X34is selected from the group consisting of A, D, E, G, K, H, L, N, Q, R, S, T, and Y; X35is selected from the group consisting of A, C, E, G, K, N, R, and V;X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V and Y; X37is selected from the group consisting of A, C, D, E, K, L, N, P, Q, R, S, T, V, andX38is selected from the group consisting of A, C, E, F, G, H, I, L, P, R, T, V, and Y; X39is selected from the group consisting of A, C, E, I, K, L, P, R, S, T, V, and W; X40is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, and V; X41is selected from the group consisting of A, D, E, F, G, L, Q, R, S, V, W, and Y; X42is selected from the group consisting of A, D, E, H, K, N, Q, R, S, V, W, and Y; X43is selected from the group consisting of A, D, E, F, I, K, L, Q, R, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, Q, R, V, and Y; X45is selected from the group consisting of A, D, E, G, K, L, P, R, S, V, and W; X46is selected from the group consisting of A, C, D, E, G, I, K, N, Q, T, and V;X47is selected from the group consisting of A, C, E, F, G, K, L, N, Q, R, S, T, V, andX48is selected from the group consisting of A, C, D, E, I, L, N, P, S, T, and V;X49is selected from the group consisting of A, D, E, F, H, I, L, M, N, P, R, T, V, andWSGR Docket No. 70774-714.601X50is selected from the group consisting of A, C, E, G, I, L, R, T, V, and W;X51is selected from the group consisting of A, C, D, E, F, H, K, L, Q, R, T, V, and Y; X52is selected from the group consisting of A, C, E, G, I, L, P, Q, R, and V;X53is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, E, L, R, T, and V;X55is absent or selected from the group consisting of A, E, I, L, P, R, T, V, and Y; X56is absent or selected from the group consisting of A, E, H, P, R, and Y;X57is absent or selected from the group consisting of C, L, R, and V;X58is absent or selected from the group consisting of A, E, R, and V;X59is absent or selected from the group consisting of L, P, R, and V;X60is absent or selected from the group consisting of A, E, F, L, and T;X61is absent or selected from the group consisting of E, P, R, and V;X62is absent, E, or P;X63is absent or R; andX64is absent.

[0047] In some embodiments of Formula (I), X64is not E. Accordingly, in some embodiments, the engineered DLL3-binding peptide comprises a sequence of Formula (IB): X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30x31x32x33x34x35x36x37x38x39x40x41x42x43x44x45x46x47x48x49x50x51x52x53x54x55x56x57wherein:X1is selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T; X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y;X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y; X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y; X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V; X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, Q, R, S, T, and V;X11is selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V; X12is selected from the group consisting of A, D, E, G, K, L, P, R, S, T, and V;X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, N, P, R, S, T, and V;X14is selected from the group consisting of A, D, E, F, G, I, K, P, Q, R, T, and V; X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y;X16is selected from the group consisting of A, C, E, F, H, I, L, P, Q, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y;X18is selected from the group consisting of A, C, D, E, F, L, P, Q, R, S, T, V, W, and Y;X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y;X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y;X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V;X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y; X25is selected from the group consisting of A, C, D, E, K, G, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y; X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, and S; X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V; X30is selected from the group consisting of A, C, D, E, F, K, H, M, R, S, T, V, and Y; X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, Q, R, S, and V;WSGR Docket No. 70774-714.601X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y;X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, and V; X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y; X37is selected from the group consisting of A, C, D, E, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, E, F, G, H, I, L, N, P, R, S, T, V, and Y;X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W;X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W; X42is selected from the group consisting of A, D, E, H, K, L, N, Q, R, S, T, V, W, and Y;X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y;X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V;X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, and Y;X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V;X49is selected from the group consisting of A, C, D, E, F, H, I, L, N, P, Q, R, S, T, V, and Y;X50is selected from the group consisting of A, C, E, F, G, I, L, R, T, V, W, and Y; X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, T, and V;X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y;X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y; X57is absent or selected from the group consisting of C, E, L, Q, R, T, V, and Y; X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, D, E, F, K, L, P, R, and V; X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

[0048] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X64are absent. In some embodiments, X1is M or P; X3is R or L; X9is G or P; X11is R or G; X19is D or S; X22is E; X25is E or A; X30is A or Y; X35is G or A; X42is E; X46is D; X48is V or L; and X52is C or V. In further embodiments, X2is selected from L, V, and I; X4is selected from V, L, and C; X6is selected from V, I, and L; X10is selected from D, L, and G; X13is selected from V, G, and A; X14is selected from V, R, and I; X16is selected from E, Y, and L; X17is selected from A, F, and V; X18is selected from A, D, and P; X27is selected from A, L, and E; X29is selected from E, K, and R; X31is selected from C, A, and L; X32is selected from R, A, and E; X37is selected from E, T, and R; X38is selected from V, L, and I; X41is selected from L, E, and V; and X53is selected from R, A, and E. In still further embodiments, the engineered DLL3-binding peptide comprises a sequence selected from the group consisting of: MLRVTVRLGDREVVIEAADREEALERAAEACRELGGELESLEFLGDEVRARCR (SEQ ID NO: 1);MVRLVIRGPLGVGVSYFDSMEEALAALERYLRETGRELLRLERVGDTLLVEVA (SEQ ID NO: 2);WSGR Docket No. 70774-714.601MVLVHLESPLGSARWEAPSIAEGIAQARKACEARGLTVVAEEERPDSVRVQCE (SEQ ID NO: 3);PIRCIIVEGDRRGVTLVDSLAECVEGAKRYAARHGKRIVNLEVGEDNVVLTVE (SEQ ID NO: 4); and PLRLVVSGPGGRGIAEVDSLEELEAAEARALALYAGRVTGVERGADSVHIHVA (SEQ ID NO: 5).

[0049] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 1-5.

[0050] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54is present and X55-X64are absent. In further embodiments, the engineered DLL3-binding peptide comprises a sequence of: MIECEVVLGDRVGRWEADSVEECLEACRRAAALEGKRIVRVE VRPDGSVRCVLE (SEQ ID NO: 6). In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 6.

[0051] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54and X55are present and X56-X64are absent. In some embodiments, X2is selected from L, T, and E; X4is selected from V, Y, and T; X5is selected from R, V, and L; X9is N or T; X10is selected from G, S, and D; X11is selected from R, A, and L; X12is selected from E, T, and S; X14is selected from V, Q, and E; X15is selected from F, T, and E; X16is selected from P, Y, and A; X18is selected from P, V, and E; X22is selected from E, P, and A; X23is selected from G, I, and L; X25is selected from A, E, and D; X26is selected from R, F, and E; X28is selected from R, A, and E; X29is selected from A, H, and E; X30is selected from D, R, and E; X32is E or G; X33is A or W; X34is selected from L, E, and R; X35is A or V; X37is selected from A, D, and Y; X40is selected from C, V and L; X43is selected from A, E, and D; X44is selected from H, V, and G; X47is selected from G, D, and Y; X48is selected from D, Q, and I; X52is A or V; X53is selected from V, T, and R; and X55is selected from E, P and A. In some embodiments, the engineered DLL3-binding peptide is selected from the group consisting of:WSGR Docket No. 70774-714.601PLWRVRQNGREMVFPYPDTPEGRARARADVEALARDPRCRWAHWEGDEGYAVCE (SEQ ID NO: 7);ATTYVMVYNSATGQTYLVAKAPLEEFEAHREEWLAKAEAVAAEVGADQIYVVTAP(SEQ IDNO: 8);ETRVLSWLTDASEEEAAEEAAAIVERLEEEEGWEASAHILTSDGRRYIVVEVRDA(SEQ IDNO: 9);TTTVLTYPTDLSVEEAEELGEELAAEIEEESGAEVEYHVVQHEGRTYINILVTEP (SEQ ID NO: 10);EELTLSWETDLSPEEAEEEAQELVDELEEEFGWRATAHVLEHEGRTYITVHVVEA(SEQ IDNO: 11); and ETTVLSYETDLSLEEAEELGEELAAEIEAETGAEVTYTVVESDGVTYIMVEVTEE(SEQ IDNO: 12).

[0052] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID Nos: 7-12.

[0053] In further embodiments, X1is E or T; X2is T or E; X4is V or T; X5is L; X6is S or T; X7is W or Y; X9is T; X10is D; X11is A or L; X12is S; X14is E; X15is E; X16is A; X17is A or E; X18is E; X19is E or L; X20is A or G; X22is E or A; X23is I or L; X26is R or E; X27is I or L; X28is E; X29is A or E; X30is E; X32is G; X34is E or R; X37is A or Y; X38is H or T; X39is I or V; X40is V or L; X43is E or D; X44is G; X45is R or V; X46is R or T; X47is Y; X48is I; X50is V or I; X52is V; and X54is D or E. In still further embodiments, the engineered DLL3-binding peptide is selected from the group consisting of SEQ ID NOs: 9-12. In some embodiments, the engineered DLL3-binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 9-12.

[0054] Alternatively, in some embodiments, when X54and X55are present and X56-X64are absent, then at least three, at least four, or at least five of X^X10are A. In some embodiments, X2, X3, X5, X6, and X7are all A. In further embodiments, X4is L; X8is Q; X11is L; X15is V; X16is E; X17is A; X18is A; X19is L; X20is G; X21is V; X22is P; X23is V; X25WSGR Docket No. 70774-714.601is P; X26is A; X27is A; X28is V; X30is T; X33is E; X34is G; X38is A; X42is A; X44is V; X45is D; X46is G; X49is L; X51is F; and X52is S. In some embodiments, the engineered DLL3-binding peptide is:DAALAAAQAALVREVEAALGVPVEPAAVLTSPEGRTFATARAVVDGQPLVFSRLL(SEQ IDNO: 13); orEAALAAAQEDL AAR VEAALGVPVRPAAVVTNAEGEVYAMVTAEVDGRPLTF SERI(SEQ IDNO: 14).

[0055] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 13 or 14.

[0056] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X56are present and X57-X64are absent.

[0057] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X57are present and X58-X64are absent. In further embodiments, X2is V; X4is R; X5is Y; X6is A; X7is V; X9is S; X10is V; X12is A; X13 is L; X15is A; X16is L; X17is L; X19is R; X21is A; X22is D; X23is V; X24is D; X25is P; X29is A; X30is A; X31is L; X33is A; X35is V; X36is A; X39is I; X40is A; X42is R; X43is R; X44is A; X45is A; X46is G; X47is E; X48is D; X50is W; X51is V; X52is E; X53is V; X56is R; and X57is L. In still further embodiments, the engineered DLL3-binding peptide is:RVVRYAVASVEALEALLARLADVDPEERAALLARVAREIARRRAAGEDLWVEVEV RL (SEQ ID NO: 18); or AVRRYAVGSVQALQALLQREADVDPADAAALAAAVAAAIAARRAAGEDPWVEVQ IRL (SEQ IDNO: 19).

[0058] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 18 or 19.

[0059] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X58are present and X59-X64are absent.WSGR Docket No. 70774-714.601

[0060] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X59are present and X60-X64are absent. In some embodiments, the engineered DLL3-binding peptide is: MRRERLRAFDPATGEWHEFEVEIDEAAGVVVRVRAPPVPDAALLVILEAADER ARELAR (SEQ ID NO: 21). In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 21.

[0061] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X60are present and X61-X64are absent. In further embodiments, the engineered DLL3 -binding peptide is: DAALDALARRNLEAALAEARRAAGDPEAFAAFAEAALANGRLLGREAEARAAL AEIRAAA (SEQ ID NO: 23). In some embodiments, the engineered DLL3-binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 23.

[0062] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X61are present and X62-X64are absent. In some embodiments, X5is V; X7is I; X9is L; X14is G; X19is A; X31is R; X36is E; X40is L; X41is L; X42is A; X45is L; X47is A; X48is E; and X50is G. In some embodiments, X4is R or A; X10is T or R; X12is E or A; X16is V or E; X17is R or Q; X18is R or T; X20is E or T; X22is E or R; X26is P or S; X28is A or E; X30is A or V; X33is D or E; X34is G or A; X35is E or L; X37is V or L; X38is A or G; X43is A or R; X46is E or A; X49is T or D; X57is V or L; X58is R or E; and X61is R or E. In some embodiments, the engineered DLL3-binding peptide is selected from the group consisting of:PTVRVLIELTDEDGRVRRAEFETRLPEAQARREGEEVGRLLAAELAAETGQRYRLAV RLER (SEQ ID NO: 26);ARVRVLIELRGADGRVRTATFESPRPPAVARAEAEEVARLLAADLAAEDGLPYTYA VRLFE (SEQ ID NO: 27);ARFAVRITLRRADGAVQTAEAELDLSRARARVEAEEVAALLAADLEAETGVAVETA VEVTE (SEQ ID NO: 28);MRVRVHIVLRNEKGEERRAEYELEGPREAVRAEAEELAELLARYLEAEDGLRWRAE LRLEE (SEQ ID NO: 29); andWSGR Docket No. 70774-714.601PERRVVIVLRDAEGRERRAEYRDARPLAVARADALELGELLAAELEAETGLPWEVR VEFEE (SEQ ID NO: 30).

[0063] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 26-30.

[0064] In further embodiments, X5is V; X7is I; X9is L; X14is G; X19is A; X31is R; X36is E; X40is L; X41is L; X42is A; X45is L; X47is A; X48is E; and X50is G. In still further embodiments, X1is selected from P, A, and M; X4is R or V; X10is R or T; X13is selected from D, K, and E; X16is V or E; X17is R or Q; X18is T or R; X20is E or T; X22is E or R; X26is P or S; X28is A or E; X30is A or V; X32is selected from R, A, and V; X34is G or A; X35is E or L; X37is V or L; X39is selected from R, A, and E; X43is A or R; X49is D or T; X52is selected from R, A, and P; X53is selected from Y, V, and W; X54is selected from R, T, and E; X58is R or E; X59is selected from L, V, and F; X60is selected from F, T, and E; and X61is R or E. In yet further embodiments, the engineered DLL3-binding peptide is selected from the group consisting of SEQ ID NOs: 26-30.

[0065] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X62are present and X63and X64are absent. In further embodiments, X1is selected from G, P, and M; X5is A or V; X7is R or L; X8is A or T; X14is selected from E, D, and F; X19is selected from Q, T, and E; X22is selected from V, E, and D; X23is G or A; X24is E or A; X25is selected from V, A, and L; X32is S or A; X34is selected from D, I, and E; X36is selected from R, G, and P; X39is selected from V, W, and R; X40is A or P; X43is V or E; X45is selected from K, L, and A; X49is T or E; X51is K or A; X52is selected from E, A, and V; X53is E or T; X54is selected from V, L, and A; X55is selected from R, L, and D; X56is selected from R, A, and H; X58is V or A; X59is selected from P, E, and A; X60is L or A; and X61is selected from R, P, and A. In some embodiments, the engineered DLL3-binding peptide is selected from the group consisting of:GWAEAERAAEAAREELKAQGIEGEVIVNEHLSLDGRRRWASVVVKNKETGKVEVR HVVPLPP (SEQ ID NO: 32);PPRVATLTRTEEFDGHRVTVTVAAADDGRVDARIEGPAVPDEVLLRALELAEELLRQ AEARL (SEQ ID NO: 33);WSGR Docket No. 70774-714.601GPLWELTETVTLDGYEVTVTVAAASDGSVSARIEGPDVPDEVLLAALERAEELLRE AAARL (SEQ ID NO: 34); and MLTAAILTYNGEVFLKVMEEEDGELTFRTITADELPAARAEFEELGWAEQAATADA AV ALAA (SEQ ID NO: 35).

[0066] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 32-35.

[0067] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X63are present and X64is absent. In further embodiments, X3is R; X4is L; X28is E; X46is A; and X60is A. In some embodiments, the engineered DLL3-binding peptide is:ECRLSEGRDEQGKKVILRRCGDDLADAEAVLAEMKAQYPNWKVWIAQTVVNGVR HWLVVAVEQ (SEQ ID NO: 37); or PLRLRAEGTVPAEQAPELERSAADLVREEAARRGYRLLSLEVERRALPDGTVAVVAT GLAEAL (SEQ ID NO: 38).

[0068] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 37-41.

[0069] In some embodiments, in the sequence of any one of Formulae (I)-(IB), X54-X64are present. In some embodiments, the engineered DLL3-binding peptide is: GEVRLETPWVPAEEEERAVAELVERLRELCERHGCLTTSVKVLHRVDEQGREQVRA VGRVVLLP (SEQ ID NO: 41).

[0070] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 1-14, 18, 19, 21, 23, 26-30, 32-35, 37, 38, and 41. In some embodiments, the engineered DLL3-binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 1-14, 18, 19, 21, 23, 26-30, 32-35, 37, 38, or 41.WSGR Docket No. 70774-714.601

[0071] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of:WSGR Docket No. 70774-714.601WSGR Docket No. 70774-714.601WSGR Docket No. 70774-714.601WSGR Docket No. 70774-714.601WSGR Docket No. 70774-714.601

[0072] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 43-167.

[0073] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, and 43-167.

[0074] In some embodiments, the engineered DLL3 -binding peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to any one of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, or 43-167.

[0075] In some embodiments, the engineered DLL3 -binding peptide binds to an extracellular domain of DLL3 expressed on a cell. In some embodiments, the engineered DLL3-binding peptide binds to the extracellular domain of DLL3 expressed by a cancer cell. In some embodiments, the cancer cell is selected from the group consisting of a small cell lung cancer cell, a prostate cancer cell, and a large cell neuroendocrine carcinoma cell.

[0076] In some embodiments, the engineered DLL3 -binding peptide binds to an N-terminal domain, an EGF1 domain, or an EGF2 domain within the extracellular domain of DLL3.

[0077] In some embodiments, the engineered DLL3 -binding peptide binds to the N-terminal domain of DLL3.

[0078] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X5is V; X9is L; X14is G; X19is A; X36is E; X40is L; X41is L; X42is A; X47is A; X48is E; and X50is G.WSGR Docket No. 70774-714.601

[0079] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X7is I; X20is E; X30is A; X31is R; X34is A; X45is L; X57is V; and X61is E.

[0080] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X5is V; X7is I; X9is L; X14is G; X19is A; X20is E; X30is A; X31is R; X34is A; X36is E; X40is L; X41is L; X42is A; X45is L; X47is A; X48is E; X50is G; X57is V; and X61is E.

[0081] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X4is R; X5is V; X7is I; X9is L; X14is G; X17is R; X19is A; X26is P; X31is R; X36is E; X40is L; X41is L; X42is A; X45is L; X47is A; X48is E; and X50is G.

[0082] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X3is V; X4is R; X5is V; X7is I; X9is L; X10is R;X14is G; X15is R; X17is R; X18is R; X19is A; X20is E; X26is P; X28is A; X30is A; X31is R; X32is A; X33is E; X34is A; X35is E; X36is E; X40is L; X41is L; X42is A; X43is A; X45is L; X47is A; X48is E; X50is G; X51is L; X57is V; X58is R; X59is L; X60is E; and X61is E.

[0083] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X3is V; X4is R; X5is V; X7is I; X9is L; X10is R; X14is G; X15is R; X17is R; X18is R; X19is A; X20is E; X22is E; X26is P; X28is A; X30is A; X31is R; X32is A; X33is E; X34is A; X35is E; X36is E; X40is L; X41is L; X42is A; X43is A; X45is L; X47is A; X48is E; X50is G; X51is L; X57is V; X58is R; X59is L; X60is E; and X61is E.

[0084] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166.

[0085] In some embodiments, the engineered DLL3 -binding peptide that binds to the N-terminal domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ IDWSGR Docket No. 70774-714.601NOs: 23, 26, 27, 29, 30 or 33. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 23, 26, 27, 29, 30 or 33.

[0086] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, and 166. In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, and 166 and the engineered DLL3-binding peptide selectively binds the N-terminal domain (residues 1-175) of DLL3.

[0087] In some embodiments, the engineered DLL3 -binding peptide binds to the EGF1 domain.

[0088] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF1 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X5is L; X14is E; X15is E; X32is G; X44is G; and X52is V.

[0089] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF1 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X22is E; X23is L; X35is A; X43is E; andX52is V.

[0090] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF1 domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164.

[0091] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF1 domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37.

[0092] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53,WSGR Docket No. 70774-714.60159, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161, and 164. In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161, and 164 and the engineered DLL3 -binding peptide selectively binds the EGF1 domain (residues 216-249) of DLL3.

[0093] In some embodiments, the engineered DLL3 -binding peptide binds to the EGF2 domain.

[0094] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X11is G; X13is G; and X22is E.

[0095] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X6is I; X8is G; X9is P; X17is F; X19is S; X20is L; X21is E; X26is A; X30is Y; X35is G; X38is L; X39is L; X45is G; X46is D; and X52is V.

[0096] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X6is I; X8is G; X9is P; X11is G; X13is G; X17is F; X19is S; X20is L; X21is E; X22is E; X26is A; X30is Y; X35is G; X38is L; X39is L; X45is G; X46is D; and X52is V.

[0097] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X19is S; X22is E; X42is E; and X46is D.

[0098] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X3is R; X9is P; X11is G; X13is G; X18is D; X25is A; X29is R; X35is G; andX48is V.

[0099] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises the sequence of any one of Formulae (I), (IA) or (IB), wherein X3is R; X9is P; X11is G; X13is G; X18is D; X19is S; X22is E; X25is A; X29is R; X35is G; X42is E; X46is D; X48is V; and X52is V.

[0100] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs:WSGR Docket No. 70774-714.6012-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167.

[0101] In some embodiments, the engineered DLL3 -binding peptide that binds to the EGF2 domain of DLL3 comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 2-6, or 41. In some embodiments, the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, or 41.

[0102] In some embodiments, the engineered DLL3 -binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146-149, 152, 154, 156-160, 162, 163, 165, and 167. In some embodiments, the engineered DLL3-binding peptide has a sequence selected from the group consisting of SEQ ID NOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146-149, 152, 154, 156-160, 162, 163, 165, and 167 and the engineered DLL3-binding peptide selectively binds the EGF2 domain (residues 274-310) of DLL3.

[0103] In some embodiments, the engineered DLL3 -binding peptide selectively binds DLL3 with low nanomolar to picomolar affinity. For example, the engineered DLL3-binding peptides may bind DLL3 with a KD of less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, or less than about 50 nM. In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of about 1 nM to about 50 nM. In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of about 5 nM to about 50 nM, about 10 nM to about 45 nM, or about 20 nM to about 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of less than about 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of less than about 1 nM.WSGR Docket No. 70774-714.601In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, or less than 50 nM. In some embodiments, the engineered DLL3-binding peptides bind DLL3 with a KD of 1 nM to 50 nM. In some embodiments, the engineered DLL3-binding peptides bind DLL3 with a KD of 5 nM to 50 nM, 10 nM to 45 nM, or 20 nM to 40 nM. In some embodiments, the engineered DLL3-binding peptides bind DLL3 with a KD of less than 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind DLL3 with a KD of less than 1 nM. In some embodiments, the engineered DLL3 -binding peptide binds DLL3 with a KD of between about 1 pM and about 1 nM. In some embodiments, the engineered DLL3 -binding peptide binds DLL3 with a KD of less than 1 pM.

[0104] In some embodiments, the engineered DLL3 -binding peptide selectively binds the N-terminal domain of DLL3 with low nanomolar to picomolar affinity. For example, the engineered DLL3-binding peptides may bind the N-terminal domain of DLL3 with a KD of less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, or less than about 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the N-terminal domain of DLL3 with a KD of about 1 nM to about 50 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of about 5 nM to about 50 nM, about 10 nM to about 45 nM, or about 20 nM to about 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of less than about 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of less than about 1 nM. In some embodiments, the engineered DLL3 -binding peptide binds the N-terminal domain of DLL3 with a KD of between about IpM and about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the N-terminal domain of DLL3 with a KD of less than 1 pM.

[0105] In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, or less than 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the N-terminal domain of DLL3 with a KD of 1 nM to 50 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of 5 nM to 50 nM, 10 nM to 45 nM, or 20 nM to 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of lessWSGR Docket No. 70774-714.601than 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of less than 1 nM.

[0106] In some embodiments, the engineered DLL3 -binding peptide selectively binds the EGF1 domain of DLL3 with low nanomolar to picomolar affinity. For example, the engineered DLL3 -binding peptides may bind the EGF1 domain of DLL3 with aKo of less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, or less than about 50 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF1 domain of DLL3 with a KD of about 1 nM to about 50 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3 with a KD of about 5 nM to about 50 nM, about 10 nM to about 45 nM, or about 20 nM to about 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF1 domain of DLL3 with a KD of less than about 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF1 domain of DLL3 with a KD of less than about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3 with a KD of between about IpM and about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3 with a KD of less than 1 pM. In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3 with a KD of between about IpM and about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF1 domain of DLL3 with a KD of less than 1 pM.

[0107] In some embodiments, the engineered DLL3-binding peptides bind the EGF1 domain of DLL3 with a KD of less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, or less than 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the EGF1 domain of DLL3 with a KD of 1 nM to 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the EGF1 domain of DLL3 with a KD of 5 nM to 50 nM, 10 nM to 45 nM, or 20 nM to 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF1 domain of DLL3 with a KD of less than 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the N-terminal domain of DLL3 with a KD of less than 1 nM.

[0108] In some embodiments, the engineered DLL3 -binding peptide selectively binds the EGF2 domain of DLL3 with low nanomolar to picomolar affinity. For example, the engineered DLL3-binding peptides may bind the EGF2 domain of DLL3 with a KD of less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, or less than about 50 nM. In some embodiments, the engineered DLL3 -bindingWSGR Docket No. 70774-714.601peptides bind the EGF2 domain of DLL3 with a KD of about 1 nM to about 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the EGF2 domain of DLL3 with a KD of about 5 nM to about 50 nM, about 10 nM to about 45 nM, or about 20 nM to about 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF2 domain of DLL3 with a KD of less than about 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF2 domain of DLL3 with a KD of less than about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF2 domain of DLL3 with a KD of between about IpM and about 1 nM. In some embodiments, the engineered DLL3-binding peptide binds the EGF2 domain of DLL3 with a KD of less than 1 pM.

[0109] In some embodiments, the engineered DLL3 -binding peptides bind the EGF2 domain of DLL3 with a KD of less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, or less than 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the EGF2 domain of DLL3 with a KD of 1 nM to 50 nM. In some embodiments, the engineered DLL3-binding peptides bind the EGF2 domain of DLL3 with a KD of 5 nM to 50 nM, 10 nM to 45 nM, or 20 nM to 40 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF2 domain of DLL3 with a KD of less than 2 nM. In some embodiments, the engineered DLL3 -binding peptides bind the EGF2 domain of DLL3 with a KD of less than 1 nM.Engineered DLL3 -binding Peptide Design

[0110] The engineered DLL3 -binding peptides in accordance with the present technology may be designed by a combined computational-experimental approach. Generally, the engineered DLL3 -binding peptides may be designed by first preparing a library of potential binding sequences based on the sequences of target epitopes of the DLL3 domain of interest, then screening the potential binding sequences to identify one or more lead sequences, iterating on the lead sequences to optimize binding properties, and finally confirming the activity of the lead sequences on the target DLL3 domain with in vitro testing. To prepare the library of potential binding sequences, the DLL3 domain of interest, e.g., the N-terminal domain, the DSL domain, the EGF1 domain, or the EGF2 domain, may be modeled using conventional predictive structure software known in the art, as a crystal structure of DLL3 has not yet been prepared. The potential binding sequences may then be designed based on these structures and the sequences of the epitopes within each domain.WSGR Docket No. 70774-714.601

[0111] After the library of potential binding sequences has been designed, the sequences may be produced and screened using any high throughput screening method known in the art, such as, for example, yeast surface display, to identify lead sequences. The lead sequences from the library may then be iteratively optimized to arrive at optimized leads that exhibit the desired physical and chemical characteristics. FIGS. 2A and 2B show fluorescence-activated cell sorting (FACS) plots of cell populations without any added DLL3 target (FIG. 2A) and after the addition of 100 nM biotinylated human DLL3 protein (FIG. 2B) the iterative process to optimize for DLL3 binding, with the binding population shown in the boxed upper right quadrant of the plots. Finally, the optimized lead sequences are tested using a number of in vitro assays to confirm binding and selectivity, and to arrive at the engineered DL3 -binding peptides in accordance with the present technology.Engineered DLL3 -binding Peptide Production

[0112] The engineered DLL3 -binding peptides in accordance with the present technology may be produced in host cells, such as, for example, mammalian cells like CHO and HEK293 cells; bacterial strains (e.g., Escherichia coH, Lactococcus lactis , and yeast (e.g., Saccharomyces cerevisiae. Pichia pastoris), according to techniques known in the art, using transient expression or stable expression techniques. Procedures for expressing peptides and proteins are described generally in Gene Expression in Mammalian Cells and its Applications, Khan KH, Adv. Pharm. Bull. 3(2):257-63 (2013); the teachings of which are incorporated herein by reference. For example, the engineered DLL3-binding peptides may be delivered to the host cell and produced by culturing the host cell under conditions for the host cell to proliferate while allowing expression of the peptide or protein and recovering the produced peptide or protein from the culture of host cells. A host cell strain may be chosen for its ability to modulate expression of the inserted sequences or to process the expressed polypeptide in the desired fashion. Different host cells that have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and W138) are available commercially and from the American Type Culture Collection (ATCC) and may be chosen to ensure the correct modification and processing of the expressed polypeptide.

[0113] A variety of expression vector and host cell systems known to those of skill in the art may be used to express the engineered DLL3 -binding peptide sequences described herein. These include, but are not limited to, plasmid, or cosmid DNA expression vectors and animal cell systems. For long-term production of recombinant proteins in mammalian systems, stable expression in mammalian cell lines may be used. For example, nucleotide sequencesWSGR Docket No. 70774-714.601able to encode any one of the engineered DLL3 -binding peptide sequences described herein may be transformed into cell lines using expression vectors that may contain viral origins of replication and / or endogenous expression elements and a selectable or visible marker gene on the same or on a separate vector. The present disclosure is not to be limited by the vector or host cell employed. In certain embodiments, nucleic acids able to encode engineered DLL3-binding peptide sequences may be ligated into expression vectors. Cells may be transformed with the desired vector or vector sets.

[0114] In order to express the engineered DLL3 -binding peptides, nucleotide sequences able to encode the peptide sequences may be inserted into an expression vector, i.e., a vector that contains the elements for transcriptional and translational control of the inserted coding sequence in a particular host. These elements may include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5' and 3' un-translated regions. Methods that are well known to those skilled in the art may be used to construct such expression vectors. These methods include in vitro recombinant DNA techniques, synthetic techniques, in vivo genetic recombination and the like.

[0115] Due to the inherent degeneracy of the genetic code, DNA sequences that encode the same, substantially the same or a functionally equivalent amino acid sequence may be produced and used. The nucleotide sequences may be ordered or engineered using methods generally known in the art in order to alter the nucleotide sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and / or expression of the gene product. Genes encoding peptide and protein variants may be acquired as gblock gene fragments and then cloned in a plasmid, such as, for example, pet29b, with a C-terminal tag, such as a His-tag. The genes may be cloned in pet29b between Ndel and Xhol restriction sites. Alternatively, the genes may be ordered already cloned into a plasmid, e.g., pet29b. DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth. Codon-optimized nucleic acids encoding the peptide sequences described herein are encompassed by the present disclosure.

[0116] Host cells comprising nucleotide sequences may be cultured under conditions for the transcription of the corresponding RNA (mRNA, etc.) and / or the expression and secretion of the engineered DLL3 -binding peptides from cell culture. In an exemplary embodiment,WSGR Docket No. 70774-714.601expression vectors containing nucleotide sequences able to encode the engineered DLL3-binding peptides of the present technology may be designed to contain signal sequences that direct secretion of the peptide through a eukaryotic cell membrane. Expression of the engineered DLL3-binding peptides in host cells may be carried out according to known techniques, such as but not limited to, the Studier autoinduction technique.

[0117] When using recombinant techniques, the engineered DLL3 -binding peptides can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the engineered DLL3-binding peptides are produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, are removed, for example, by centrifugation or ultrafiltration. Cells may be lysed using a microfluidizer.

[0118] The engineered DLL3 -binding peptides of the present technology prepared from the host cells can be recovered or purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, affinity chromatography, and size exclusion chromatography. Other techniques for protein purification such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin SEPHAROSE™, chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chromato-focusing, SDS-PAGE, and ammonium sulfate precipitation are also available. Affinity chromatography, e.g., with a Ni-NTA column, is a common purification technique that may be used to purify the peptides and proteins described herein. The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or polystyrene-divinylbenzene allow for faster flow rates and shorter processing times than can be achieved with agarose.

[0119] The identity of engineered DLL3 -binding peptides produced according to techniques described above may be confirmed using mass spectrometry.Pharmaceutical Compositions

[0120] The present technology also provides pharmaceutical compositions comprising the engineered DLL3 -binding peptides and one or more pharmaceutically acceptable carriers and / or excipients.

[0121] In some embodiments, the engineered DLL3-binding peptide is present in a pharmaceutical composition in a therapeutically effective amount. The therapeutically effective amount may be an amount sufficient to elicit a desired response in the subject, suchWSGR Docket No. 70774-714.601as, for example, treating, preventing, mitigating, or reducing tumor cell formation and / or promoting or increasing tumor cell apoptosis.

[0122] In some embodiments, the engineered DLL3-binding peptide is present in the composition in a concentration of 0.001 mg / mL to 1000 mg / mL, relative to a total volume of the composition. For example, the engineered DLL3-binding peptide is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL, relative to a total volume of the composition. In some embodiments, the engineered DLL3-binding peptide is present in the composition in a concentration of 5 mg / mL to 100 mg / mL relative to a total volume of the composition.

[0123] In some embodiments, the pharmaceutical composition comprising the engineered DLL3 -binding peptide is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration. In some embodiments, the composition comprising the engineered DLL3 -binding peptide is administered to the subject parenterally. In some embodiments, the composition comprising the engineered DLL3-binding peptide is administered to the subject intravenously. In some embodiments, the composition comprising the engineered DLL3-binding peptide is administered to the subject subcutaneously.

[0124] Pharmaceutical compositions disclosed herein formulated for intravenous administration may be in the form of an aqueous or non-aqueous isotonic sterile injection solution or suspension. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0125] In some embodiments, the composition formulated for parenteral administration (e.g., intravenous or subcutaneous administration) comprises the engineered DLL3-binding peptide at a concentration of about 0.001 mg / mL, 0.005 mg / mL, 0.01 mg / mL, 0.02 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.25 mg / mL, 0.5 mg / mL, 1 mg / mL, 2.5 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 25 mg / mL, 50 mg / mL, 100 mg / mL, 250 mg / mL, 500 mg / mL, or 1000 mg / mL, or even more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the composition formulated for parenteral administration (e.g., intravenous or subcutaneous administration) comprises the engineered DLL3-binding peptide at a concentration of about 1 mg / mL to about 500 mg / mL. In further embodiments, theWSGR Docket No. 70774-714.601composition formulated for parenteral administration comprises the engineered DLL3-binding peptide at a concentration of about 5 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 25 mg / mL to about 170 mg / mL or about 50 mg / mL to about 150 mg / mL.

[0126] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is an animal such as a rat or a dog. In some embodiments, the subject is a human.

[0127] The pharmaceutically acceptable carriers and / or excipients may facilitate delivery (e.g., parenteral administration, in particular intravenous or subcutaneous administration) of the engineered DLL3-binding peptide to a subject. Other purposes of the pharmaceutically acceptable carriers and / or excipients include to enhance dispersion, solubility, and stability of the engineered DLL3 -binding peptide, and to reduce adverse injection site reactions.

[0128] The carriers and / or excipients of the pharmaceutical composition may generally include a pH buffered aqueous solution. In some embodiments, all components are compatible with the engineered DLL3-binding peptide (i.e., do not react or cause the engineered peptide or fusion protein to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0129] The pH buffered aqueous solution of the pharmaceutical compositions include water. The water may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0130] The pH buffered aqueous solution of the pharmaceutical composition include an organic buffer. In some embodiments, the organic buffer is selected from the group consisting of histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes, TES, HEPES, DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine. In some embodiments, the organic buffer is Tris. In some embodiments, the organic buffer is HEPES.WSGR Docket No. 70774-714.601

[0131] The buffer may be present in the pharmaceutical composition or formulation at a concentration of about 5 mM to about 100 mM. In some embodiments, the buffer is present in the pharmaceutical composition or formulation at a concentration of about 10 mM to about 100 mM, about 10 mM to about 90 mM, about 10 mM to about 80 mM, about 10 mM to about 70 mM, about 10 mM to about 6 mM, about 10 mM to about 50 mM, or about 10 mM to about 40 mM. In some embodiments, the buffer may be present in the pharmaceutical composition or formulation at a concentration of about 20 mM.

[0132] In some embodiments, the pharmaceutical composition is isotonic. In order to achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is sodium chloride. In some embodiments, the sodium chloride is present in the composition in a concentration of about 10 mM to about 300 mM, about 50 mM to about 250 mM, about 100 mM to about 200 mM, or about 150 mM.

[0133] In some embodiments, the pH buffered aqueous solution provides the pharmaceutical composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the engineered DLL3-binding peptide with enhanced stability and resistance to aggregation and degradation.

[0134] In some embodiments, the pharmaceutical composition has a pH ranging from 6.5 to 8.5. In some embodiments, the composition has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the composition has a pH of about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the composition has a pH ranging from about 7.4 to about 8.0.

[0135] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg.WSGR Docket No. 70774-714.601

[0136] In some embodiments, the pharmaceutical composition further comprises additional buffering agents, preservatives, antioxidants, surfactants, and / or sweeteners.Use of Engineered DLL3 -Binding Peptide

[0137] The engineered DLL3 -binding peptides and pharmaceutical compositions of the present technology are useful to treat, reduce, or prevent conditions associated with aberrant DLL3 expression. Specifically, the engineered DLL3 -binding peptides and pharmaceutical compositions of the present technology may be useful to treat, prevent, mitigate, or reduce tumor cell formation and / or promote or increase tumor cell apoptosis. In some embodiments, the engineered DLL3 -binding peptides are useful in the treatment, prevention, mitigation, and / or reduction of cancer, such as, for example, small cell lung cancer, prostate cancer, or large cell neuroendocrine carcinoma.Dosing and Administration

[0138] The pharmaceutical compositions of the present technology may be formulated to deliver a certain dose of the engineered DLL3 -binding peptide to a subject in need thereof. The dose may be based on the body weight of the subject. For example, in some embodiments, the pharmaceutical composition is formulated to deliver the engineered DLL3-binding peptide to the subject at a dose of about 0.01 mg / kg to about 100 mg / kg, per body weight of the subject. In some embodiments, the pharmaceutical composition is formulated to deliver a dose of the engineered DLL3-binding peptide of about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.05 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.25 mg / kg to about 10 mg / kg, about 0.5 mg / kg to about 7.5 mg / kg, about 0.75 mg / kg to about 7 mg / kg, about 1 mg / kg to about 6.5 mg / kg, or about 1 mg / kg to about 6 mg / kg, per body weight of the subject. In some embodiments, the pharmaceutical composition is formulated to deliver a dose of the engineered DLL3-binding peptide of about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 7.5 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 2.5 mg / kg, about 0.01 mg / kg to about 1.5 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 7.5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 2.5 mg / kg, or about 0.1 mg / kg to about 1.5 mg / kg, per body weight of the subject. In some embodiments, the pharmaceutical composition is formulated to deliver a dose of the engineered DLL3-binding peptide of about 0.1 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, 1 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 22.5WSGR Docket No. 70774-714.601mg / kg, or about 25 mg / kg, per body weight of the subject. In further embodiments, the pharmaceutical composition is formulated to deliver a dose of the engineered DLL3-binding peptide of about 5 mg / kg, per body weight of the subject.

[0139] In some embodiments, the engineered DLL3-binding peptide is administered to the subject once daily, twice daily, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, once every two weeks, once every month, once every two months, once every three months, once every six months, or once every year.

[0140] In some embodiments, the engineered DLL3-binding peptide is administered to the subject for at least about 1 day, about 1 week, about 1 month, about 3 months, about 6 months, about 1 year, or about 5 years.

[0141] In some embodiments, the engineered DLL3-binding peptide is administered to the subject for at least about 1 day, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 40 days, about 45 days, about 50 days, about 60 days, about 75 days, about 90 days, about 100 days, about 110 days, or about 120 days.EXAMPLES

[0142] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.Example 1: Engineered DLL3 -Binding Peptide Expression and Purification

[0143] Genes encoding protein variants were ordered as gblock gene fragments from IDT and cloned in pet29b in between Ndel / Xhol restriction sites with an N-term Avi-His-TEV tag (MGWSCIILFLVATATGVHSGLNDIFEAQKIEWHEGGSHHHHHHSGGENLYF QS / G; SEQ ID NO: 168), or directly ordered from IDT already cloned into pet29b with a stop coon before the C-term Histag. Alternatively, the constructs were synthesized with appropriate bacterial expression vector. All the mutant variants of the proteins were expressed in BL21(DE3*) using Studier autoinduction technique in standard shake flasks at 37 °C for 24 h. Cells were harvested and resuspended in 20 mM Tris, 250 mM NaCl, 20 mM Imidazole (lysis buffer). Cells were lysed using microfluidizer and cell debris was separated by centrifuging atWSGR Docket No. 70774-714.60124,000 g for 45 min. Soluble proteins were first purified using standard Ni-NTA affinity columns followed by size exclusion chromatography (S75 10 / 300 Increase) on a GE-Akta pure FPLC system. A peak corresponding to the monomeric protein was collected and further verified by mass spectrometry.Example 2: Binding Data

[0144] The binding affinity of several exemplary engineered DLL3 -binding peptides (SEQ ID NOs: 1-11, 18, 23, 24, 27, 29, 30, 32, 33, 37, and 41) to DLL3 was measured by 2:1 binding bio-layer interferometry (BLI) according to procedures known in the art. The BLI 2: 1 heterogeneous binding model may be used in BLI analysis to describe a specific type of molecular interaction. Specifically, this model assumes that the analyte, i.e., the engineered DLL3-binding peptide, can bind to two distinct binding sites on the immobilized ligand, i.e., DLL3. When there is heterogenous binding, this signifies that the two binding sites have different binding affinities. In other words, the analyte binds more strongly to one site compared to the other.

[0145] Additionally, two-state binding data for four exemplary engineered DLL3-binding peptides (SEQ ID NOs: 2, 7, 32, and 33) was obtained by surface plasmon resonance (SPR) according to procedures known in the art (FIGS. 3A and 3B). In SPR experiments, experiments, two-state binding refers to a model where the analyte, e.g., the engineered DLL3-binding peptide, can bind to the immobilized ligand, e.g., DLL3, in two distinct conformations or states via two distinct binding sites on the analyte. Additionally, the analyte may possess two binding sites that can each interact with the immobilized ligand. Each binding state exhibits its own set of association and dissociation rate constants, and the two binding events can occur sequentially (one binding site interacts first, followed by the second) or concurrently (both binding sites interact simultaneously). The KD values for the exemplary peptides determined by the BLI and SPR measurements are provided in Table 1.Table 1. Binding Affinity to DLL3WSGR Docket No. 70774-714.601ND: not determined

[0146] As shown above, several engineered DLL3-binding peptides (e.g., SEQ ID NOs: 1-11, 18, 23, 26, 27, 29, 32, 33, and 41) exhibited sub 1000 nM binding to DLL3 as measured by BLI and / or SPR. Further, SEQ ID NOs: 2, 5, 7, 10, 29, 32, and 33 exhibited sub 100 nM binding to DLL3 as measured by BLI and / or SPR.Example 3: Cell Surface Binding of Engineered DLL3-binding Peptides

[0147] The cell surface binding of exemplary engineered DLL3 -binding peptides (SEQ ID NOs: 2, 7, 32, and 33) on two DLL3(+) cancer cell lines (SHP77 and NCI-H82) and one DLL3(-) cancer cell line (A431) was measured by flow cytometer according to the following protocol. The cells were collected, washed with phosphate buffered saline (PBS), and then seeded with 7,000 cells per 100 mL to each well. Live / dead cell stain dye was added to each well and the cells were washed with a binding buffer twice. Biotinylated DLL3-binding peptides were prepared with streptavidin phycoerythrin (SAPE) tetramers at a final concentration of 1000 nM. Two aliquots of 50 mL tetramer were added to 50 mL of cells for final DLL3-binding peptide staining concentrations of 500 nM, 100 nM, 20 nM, 4 nM, and 0 nM. The cells were then incubated on ice for 30 minutes, after which time, the cells were washed with the binding buffer twice, and then resuspended in PBS and run on the flow cytometer (iQue® 3 from Sartorius) to determine cell surface binding. The results for each cancer cell line are shown in FIGS. 4A-4C against a SAPE only control.WSGR Docket No. 70774-714.601

[0148] As can be seen, SEQ ID NOs: 2, 7, 32, and 33 exhibited increased binding towards DLL3(+) cell lines SHP77 (FIG. 4A) and NCI-H82 (FIG. 4B) relative to the control, but comparable binding towards DLL3(-) cell line A431 (FIG. 4C) relative to the control. Therefore, FIGS. 4A-4C demonstrate selective binding of the engineered DLL3 -binding peptides to DLL3 expressed on the cell surface of cancer cells.Embodiments

[0149] Various embodiments of the present technology are set forth herein below:

[0150] Embodiment 1. An engineered delta like ligand 3-binding (DLL3 -binding) peptide comprising a sequence of Formula (I):X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30x31x32x33x34x35x36x37x38x39x40x41x42x43x44x45x46x47x48x49x50x51x52x53x54x55x56xX58X59X6OX61X62X5763X64 )wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T; X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y;X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y; X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y; X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V; X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y; X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, V, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, T, and V; XIIis selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V; X12is selected from the group consisting of A, D, E, G, I, K, L, N, P, R, S, T, and V; X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, P, R, T, V, and Y;X14is selected from the group consisting of A, D, E, F, G, I, K, L, P, Q, R, T, and V; X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y;WSGR Docket No. 70774-714.601X16is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y;X18is selected from the group consisting of A, C, D, E, F, L, M, P, Q, R, S, T, V, W, and Y;X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y;X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y;X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V;X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y; X25is selected from the group consisting of A, C, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y; X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, S, and V; X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V; X30is selected from the group consisting of A, C, D, E, H, I, F, K, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, P, Q, R, S, and V; X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y;X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, V, and Y; X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y; X37is selected from the group consisting of A, C, D, E, F, G, K, L, M, N, P, Q, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X38is selected from the group consisting of A, C, D, E, F, G, H, I, L, N, P, R, S, T, V, and Y;X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W;X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W; X42is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, V, W, and Y;X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, T, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y;X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V;X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, W, and Y;X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V;X49is selected from the group consisting of A, C, D, E, F, H, I, L, M, N, P, Q, R, S, T, V, and Y;X50is selected from the group consisting of A, C, E, F, G, I, L, Q, R, T, V, W, and Y; X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y;X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, S, T, and V;X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y;WSGR Docket No. 70774-714.601X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y; X57is absent or selected from the group consisting of A, C, E, L, Q, R, T, V, and Y; X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, E, F, K, L, P, R, and V;X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

[0151] Embodiment 2. The engineered DLL3-binding peptide of embodiment 1, comprising a sequence of Formula (IA):x1x2x3x4x5x6x7x8x9x10x11X12X13X14X15X16X17X18X19X20X21EX23X24X25X26X27X28X29X30wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, P, Q, R, S, and T; X2is selected from the group consisting of C E, F, I, L, P, Q, R, S, T, V, W, and Y; X3is selected from the group consisting of A, C, E, F, K, L, Q, R, T, V, and Y;X4is selected from the group consisting of A, C, E, L, R, T, and V;X5is selected from the group consisting of A, C, E, F, H, I, L, R, T, V and Y;X6is selected from the group consisting of A, C, E, H, I, L, R, S, T, and V;X7is selected from the group consisting of A, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, E, G, L, P, Q, S, T, and V;X9is selected from the group consisting of A, D, E, F, G, L, N, P, S, and T;X10is selected from the group consisting of C, D, E, G, L, Q, R, S, T;XIIis selected from the group consisting of A, D, E, G, L, N, P, Q, and R;X12is selected from the group consisting of A, D, E, G, I, K, P, R, S, T, and V;X13is selected from the group consisting of A, D, G, K, L, M, P, R, T, and V;X14is selected from the group consisting of E, F, G, I, L, Q, R, T, and V;X15is selected from the group consisting of A, E, F, G, I, R, S, T, V, and W;X16is selected from the group consisting of A, C, E, F, I, L, P, Q, R, S, T, V, W, and Y;WSGR Docket No. 70774-714.601X17is selected from the group consisting of A, C, E, F, H, K, L, Q, R, V, W, and Y; X18is selected from the group consisting of A, D, E, P, R, S, and T;X19is selected from the group consisting of A, D, E, F, L, N, P, Q, S, and T;X20is selected from the group consisting of A, C, E, G, I, K, L, M, R, T, V, and W; X21is selected from the group consisting of A, D, E, F, G, I, P, Q, S, T, V, and Y; X23is selected from the group consisting of A, C, D, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, I, L, K, P, R, S, and V;X25is selected from the group consisting of A, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, G, I, L, P, Q, R, and S;X27is selected from the group consisting of A, C, E, F, I, L, P, R, and V;X28is selected from the group consisting of A, D, E, G, K, M, N, Q, and R;X29is selected from the group consisting of A, D, E, K, N, Q, R, S, and V;X30is selected from the group consisting of A, C, D, E, H, R, S, T, V, and Y;X31is selected from the group consisting of A, C, F, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, and V;X33is selected from the group consisting of A, C, D, E, K, L, R, S, T, V, and W; X34is selected from the group consisting of A, D, E, G, K, H, L, N, Q, R, S, T, and Y; X35is selected from the group consisting of A, C, E, G, K, N, R, and V;X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V and Y; X37is selected from the group consisting of A, C, D, E, K, L, N, P, Q, R, S, T, V, andX38is selected from the group consisting of A, C, E, F, G, H, I, L, P, R, T, V, and Y; X39is selected from the group consisting of A, C, E, I, K, L, P, R, S, T, V, and W; X40is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, and V; X41is selected from the group consisting of A, D, E, F, G, L, Q, R, S, V, W, and Y; X42is selected from the group consisting of A, D, E, H, K, N, Q„ R, S, V, W, and Y; X43is selected from the group consisting of A, D, E, F, I, K, L, Q, R, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, Q, R, V, and Y; X45is selected from the group consisting of A, D, E, G, K, L, P, R, S, V, and W; X46is selected from the group consisting of A, C, D, E, G, I, K, N, Q, T, and V;X47is selected from the group consisting of A, C, E, F, G, K, L, N, Q, R, S, T, V, andX48is selected from the group consisting of A, C, D, E, I, L, N, P, S, T, and V;WSGR Docket No. 70774-714.601X49is selected from the group consisting of A, D, E, F, H, I, L, M, N, P, R, T, V, and Y;X50is selected from the group consisting of A, C, E, G, I, L, R, T, V, and W;X51is selected from the group consisting of A, C, D, E, F, H, K, L, Q, R, T, V, and Y; X52is selected from the group consisting of A, C, E, G, I, , L, P, Q, R, and V;X53is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, E, L, R, T, and V;X55is absent or selected from the group consisting of A, E, I, L, P, R, T, V, and Y; X56is absent or selected from the group consisting of A, E, H, P, R, and Y;X57is absent or selected from the group consisting of C, L, R, and V;X58is absent or selected from the group consisting of A, E, R, and V;X59is absent or selected from the group consisting of L, P, R, and V;X60is absent or selected from the group consisting of A, E, F, L, and T;X61is absent or selected from the group consisting of E, P, R, and V;X62is absent, E, or P;X63is absent or R; andX64is absent.

[0152] Embodiment 3. The engineered DLL3 -binding peptide of embodiment 1, comprising a sequence of Formula (IB):wherein:X1is selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T;X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y; X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y;X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y;X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V;X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y;X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y;WSGR Docket No. 70774-714.601X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, Q, R, S, T, and V;X11is selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V;X12is selected from the group consisting of A, D, E, G, K, L, P, R, S, T, and V;X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, N, P, R, S, T, and V; X14is selected from the group consisting of A, D, E, F, G, I, K, P, Q, R, T, and V;X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y; X16is selected from the group consisting of A, C, E, F, H, I, L, P, Q, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y; X18is selected from the group consisting of A, C, D, E, F, L, P, Q, R, S, T, V, W, and Y; X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y; X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y; X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y;X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V; X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y;X25is selected from the group consisting of A, C, D, E, K, G, L, P, Q, R, S, T, and V;X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y;X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y;X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, and S;X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V;X30is selected from the group consisting of A, C, D, E, F, K, H, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, Q, R, S, and V;X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y; X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, and V;X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y;X37is selected from the group consisting of A, C, D, E, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, E, F, G, H, I, L, N, P, R, S, T, V, and Y; X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W; X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;WSGR Docket No. 70774-714.601X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W;X42is selected from the group consisting of A, D, E, H, K, L, N, Q, R, S, T, V, W, and Y; X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, V, and W; X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y; X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W; X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V; X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, and Y; X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V; X49is selected from the group consisting of A, C, D, E, F, H, I, L, N, P, Q, R, S, T, V, and Y; X50is selected from the group consisting of A, C, E, F, G, I, L, R, T, V, W, and Y;X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y; X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, T, and V; X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y; X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y; X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y;X57is absent or selected from the group consisting of C, E, L, Q, R, T, V, and Y;X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, D, E, F, K, L, P, R, and V;X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

[0153] Embodiment 4. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X64are absent.

[0154] Embodiment 5. The engineered DLL3 -binding peptide of any one of embodiments 1-4, wherein:X1is M or P;X3is R or L;WSGR Docket No. 70774-714.601X9is G or P;X11is R or G;X19is D or S;X22is E;X25is E or A;X30is A or Y;X35is G or A;X42is E;X46is D;X48is V or L; andX52is C or V.

[0155] Embodiment 6. The engineered DLL3-binding peptide of any one of embodiments 1-5, wherein:X2is selected from L, V, and I;X4is selected from V, L, and C;X6is selected from V, I, and L;X10is selected from D, L, and G;X13is selected from V, G, and A;X14is selected from V, R, and I;X16is selected from E, Y, and L;X17is selected from A, F, and V;X18is selected from A, D, and P;X27is selected from A, L, and E;X29is selected from E, K, and R;X31is selected from C, A, and L;X32is selected from R, A, and E;X37is selected from E, T, and R;X38is selected from V, L, and I;X41is selected from L, E, and V; andX53is selected from R, A, and E.WSGR Docket No. 70774-714.601

[0156] Embodiment 7. The engineered DLL3-binding peptide of any one of embodiments 1-5, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-5.

[0157] Embodiment 8. The engineered DLL3 -binding peptide of any one of embodiments 1-3, wherein X54is present and X55-X64are absent.

[0158] Embodiment 9. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein the peptide comprises a sequence of SEQ ID NO: 6.

[0159] Embodiment 10. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54and X55are present and X56-X64are absent.

[0160] Embodiment 11. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 10, wherein:X2is selected from L, T, and E;X4is selected from V, Y, and T;X5is selected from R, V, and L;X9is N or T;X10is selected from G, S, and D;X11is selected from R, A, and L;X12is selected from E, T, and S;X14is selected from V, Q, and E;X15is selected from F, T, and E;X16is selected from P, Y, and A;X18is selected from P, V, and E;X22is selected from E, P, and A;X23is selected from G, I, and L;X25is selected from A, E, and D;X26is selected from R, F, and E;X28is selected from R, A, and E;X29is selected from A, H, and E;X30is selected from D, R, and E;X32is E or G;WSGR Docket No. 70774-714.601X33is A or W;X34is selected from L, E, and R;X35is A or V;X37is selected from A, D, and Y;X40is selected from C, V and L;X43is selected from A, E, and D;X44is selected from H, V, and G;X47is selected from G, D, and Y;X48is selected from D, Q, and I;X52is A or V;X53is selected from V, T, and R; andX55is selected from E, P and A.

[0161] Embodiment 12. The engineered DLL3-binding peptide of any one of embodiments 1-3, 10, and 11, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 7-12.

[0162] Embodiment 13. The engineered DLL3 -binding peptide of any one of embodiments 1-3 and 10-12, wherein:XIis E or T;X2is T or E;X4is V or T;X5is L;X6is S or T;X7is W or Y;X9is T;X10is D;XIIis A or L;X12is S;X14is E;X15is E;X16is A;X17is A or E;X18is E;WSGR Docket No. 70774-714.601X19is E or L;X20is A or G;X22is E or A;X23is I or L;X26is R or E;X27is I or L;X28is E;X29is A or E;X30is E;X32is G;X34is E or R;X37is A or Y;X38is H or T;X39is I or V;X40is V or L;X43is E or D;X44is G;X45is R or V;X46is R or T;X47is Y;X48is I;X50is V or I;X52is V; andX54is D or E.

[0163] Embodiment 14. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 10-13, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 9-12.

[0164] Embodiment 15. The engineered DLL3 -binding peptide of any one of embodiments 1-3 and 10, wherein X2, X3, X5, X6, and X7are each A.

[0165] Embodiment 16. The engineered DLL3-binding peptide of any one of embodiments 1-3, 10, and 15, wherein:WSGR Docket No. 70774-714.601X4is L;X8is Q;Xnis L;X15is V;X16is E;X17is A;X18is A;X19is L;X20is G;X21is V;X22is P;X23is V;X25is P;X26is A;X27is A;X28is V;X30is T;X33is E;X34is G;X38is A;X42is A;X44is V;X45is D;X46is G;X49is L;X51is F; andX52is S.

[0166] Embodiment 17. The engineered DLL3-binding peptide of any one of embodiments 1-3, 15, and 16, wherein the peptide comprises a sequence of SEQ ID NO: 13 or 14.

[0167] Embodiment 18. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X56are present and X57-X64are absent.WSGR Docket No. 70774-714.601

[0168] Embodiment 19. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X57are present and X58-X64are absent.

[0169] Embodiment 20. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 19, wherein:X2is V;X4is R;X5is Y;X6is A;X7is V;X9is S;X10is V;X12is A;X13is L;X15is A;X16is L;X17is L;X19is R;X21is A;X22is D;X23is V;X24is D;X25is P;X29is A;X30is A;X31is L;X33is A;X35is V;X36is A;X39is I;X40is A;X42is R;X43is R;WSGR Docket No. 70774-714.601X44is A;X45is A;X46is G;X47is E;X48is D;X50is W;X51is V;X52is E;X53is V;X56is R; andX57is L.

[0170] Embodiment 2E The engineered DLL3-binding peptide of any one of embodiments 1-3, 19, and 20, wherein the peptide comprises a sequence of SEQ ID NO: 18 or 19.

[0171] Embodiment 22. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X58are present and X59-X64are absent.

[0172] Embodiment 23. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X59are present and X60-X64are absent.

[0173] Embodiment 24. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 23, wherein the peptide comprises a of SEQ ID NO: 21.

[0174] Embodiment 25. The engineered DLL3 -binding peptide of any one of embodiments 1-3, wherein X54-X60are present and X61-X64are absent.

[0175] Embodiment 26. The engineered DLL3-binding peptide of any one of embodiments 1-3, and 25, wherein the peptide comprises a sequence of SEQ ID NO: 23.

[0176] Embodiment 27. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X61are present and X62-X64are absent.WSGR Docket No. 70774-714.601

[0177] Embodiment 28. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 27, wherein:X5is V;X7is I;X9is L;X14is G;X19is A;X31is R;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E; andX50is G.

[0178] Embodiment 29. The engineered DLL3-binding peptide of any one of embodiments 1-3, 27, and 28, wherein:X4is R or A;X10is T or R;X12is E or A;X16is V or E;X17is R or Q;X18is R or T;X20is E or T;X22is E or R;X26is P or S;X28is A or E;X30is A or V;X33is D or E;X34is G or A;X35is E or L;X37is V or L;WSGR Docket No. 70774-714.601X38is A or G;X43is A or R;X46is E or A;X49is T or D;X57is V or L;X58is R or E; andX61is R or E.

[0179] Embodiment 30. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 27-29, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 26-30.

[0180] Embodiment 31. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 27-30, wherein:X5is V;X7is I;X9is L;X14is G;X19is A;X31is R;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E; andX50is G.

[0181] Embodiment 32. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 27-31, wherein:X1is selected from P, A, and M;X4is R or V;X10is R or T;WSGR Docket No. 70774-714.601X13is selected from D, K, and E;X16is V or E;X17is R or Q;X18is T or R;X20is E or T;X22is E or R;X26is P or S;X28is A or E;X30is A or V;X32is selected from R, A, and V;X34is G or A;X35is E or L;X37is V or L;X39is selected from R, A, and E;X43is A or R;X49is D or T;X52is selected from R, A, and P;X53is selected from Y, V, and W;X54is selected from R, T, and E;X58is R or E;X59is selected from L, V, and F;X60is selected from F, T, and E; andX61is R or E.

[0182] Embodiment 33. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 27-32, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 26-30.

[0183] Embodiment 34. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X62are present and X63and X64are absent.

[0184] Embodiment 35. The engineered DLL3 -binding peptide of any one of embodiments 1-3 and 34, wherein:X1is selected from G, P, and M;WSGR Docket No. 70774-714.601X5is A or V;X7is R or L;X8is A or T;X14is selected from E, D, and F;X19is selected from Q, T, and E;X22is selected from V, E, and D;X23is G or A;X24is E or A;X25is selected from V, A, and L;X32is S or A;X34is selected from D, I, and E;X36is selected from R, G, and P;X39is selected from V, W, and R;X40is A or P;X43is V or E;X45is selected from K, L, and A;X49is T or E;X51is K or A;X52is selected from E, A, and V;X53is E or T;X54is selected from V, L, and A;X55is selected from R, L, and D;X56is selected from R, A, and H;X58is V or A;X59is selected from P, E, and A;X60is L or A; andX61is selected from R, P, and A.

[0185] Embodiment 36. The engineered DLL3-binding peptide of any one of embodiments 1-3, 34, and 35, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 32-35.

[0186] Embodiment 37. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X63are present and X64is absent.WSGR Docket No. 70774-714.601

[0187] Embodiment 38. The engineered DLL3 -binding peptide of any one of embodiments 1-3 and 34, wherein:X3is R;X4is L;X28is E;X46is A; andX60is A.

[0188] Embodiment 39. The engineered DLL3-binding peptide of any one of embodiments 1-3, 37, and 38, wherein the peptide comprises a sequence of SEQ ID NO: 37 or 38.

[0189] Embodiment 40. The engineered DLL3-binding peptide of any one of embodiments 1-3, wherein X54-X64are present.

[0190] Embodiment 41. The engineered DLL3-binding peptide of any one of embodiments 1-3 and 40, wherein the peptide comprises a sequence of SEQ ID NO: 41.

[0191] Embodiment 42. The engineered DLL3-binding peptide of any one of embodiments 1-32, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-14, 18, 19, 21, 23, 26-30, 32-35, 37, 38, and 41.

[0192] Embodiment 43. The engineered DLL3-binding peptide of embodiment 1 or 2, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 43-167.

[0193] Embodiment 44. The DLL3-binding peptide of any one of embodiments 1-43, wherein the peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to any one of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, or 43-167.WSGR Docket No. 70774-714.601

[0194] Embodiment 45. The engineered DLL3 -binding peptide of any one of embodiments 1-43, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, and 43-167.

[0195] Embodiment 46. The engineered DLL3-binding peptide of any one of embodiments 1-44, wherein the peptide binds DLL3 with a KD of less than about 100 nM.

[0196] Embodiment 47. The engineered DLL3-binding peptide of any one of embodiments 1-45, wherein the peptide binds DLL3 with a KD of about 1 nM to about 50 nM.

[0197] Embodiment 48. The engineered DLL3 -binding peptide of any one of embodiments 1-46, wherein the peptide binds DLL3 with a KD of about 20 nM to about 40 nM.

[0198] Embodiment 49. The engineered DLL3-binding peptide of any one of embodiments 1-48, wherein the peptide binds DLL3 with a KD of less than 1 nM.

[0199] Embodiment 50. The engineered DLL3-binding peptide of any one of embodiments 1-49, wherein the peptide binds DLL3 with a KD of between about IpM and about 1 nM.

[0200] Embodiment 51. The engineered DLL3-binding peptide of any one of embodiments 1-48, wherein the peptide binds DLL3 with a KD of less than 1 pM.

[0201] Embodiment 52. The engineered DLL3-binding peptide of any one of embodiments 1-51, wherein the peptide has a length of at least 53 residues, at least 54 residues, at least 55 residues, at least 56 residues, at least 57 residues, at least 58 residues, at least 59 residues, at least 60 residues, at least 61 residues, at least 62 residues, at least 63 residues, or at least 64 residues.

[0202] Embodiment 53. The engineered DLL3-binding peptide of any one of embodiments 1-51, wherein the peptide has a length of at most 53 residues, at most 54WSGR Docket No. 70774-714.601residues, at most 55 residues, at most 56 residues, at most 57 residues, at most 58 residues, at most 59 residues, at most 60 residues, at most 61 residues, at most 62 residues, at most 63 residues, or at most 64 residues.

[0203] Embodiment 54. The engineered DLL3-binding peptide of any one of embodiments 1-53, wherein the peptide binds to an extracellular domain of DLL3 expressed on a cell.

[0204] Embodiment 55. The engineered DLL3 -binding peptide of embodiment 54, wherein the peptide binds to an N-terminal domain, an EGF1 domain, or an EGF2 domain within the extracellular domain of DLL3.

[0205] Embodiment 56. The engineered DLL3-binding peptide of embodiment 54 or 55, wherein the peptide binds to the extracellular domain of DLL3 expressed by a cancer cell.

[0206] Embodiment 57. The engineered DLL3-binding peptide of embodiment 56, wherein cancer cell is selected from the group consisting of a small cell lung cancer cell, a prostate cancer cell, and a large cell neuroendocrine carcinoma cell.

[0207] Embodiment 58. The engineered DLL3 -binding peptide of any one of embodiments 55-57, wherein the peptide binds to the N-terminal domain.

[0208] Embodiment 59. The engineered DLL3-binding peptide of embodiment 58, wherein:X5is V;X9is L;X14is G;X19isA;X36is E;X40is L;X41is L;X42is A;X47is A;X48is E; andX50is G.WSGR Docket No. 70774-714.601

[0209] Embodiment 60. The engineered DLL3-binding peptide of any one of embodiments 58 or 59, wherein:X7is I;X20is E;X30is A;X31is R;X34is A;X45is L;X57is V; andX61is E.

[0210] Embodiment 6E The engineered DLL3-binding peptide of any one of embodiments 58-60, wherein:X5is V;X7is I;X9is L;X14is G;X19is A;X20is E;X30is A;X31is R;X34is A;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E;X50is G;X57is V; andX61is E.WSGR Docket No. 70774-714.601

[0211] Embodiment 62. The engineered DLL3-binding peptide of any one of embodiments 58-59, wherein:X4is R;X5is V;X7is I;X9is L;X14is G;X17is R;X19is A;X26is P;X31is R;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E; andX50is G.

[0212] Embodiment 63. The engineered DLL3-binding peptide of any one of embodiments 58-62, wherein:X3is V;X4is R;X5is V;X7is I;X9is L;X10is R;X14is G;X15isR;X17is R;X18isR;X19is A;X20is E;WSGR Docket No. 70774-714.601X26is P;X28is A;X30is A;X31is R;X32is A;X33is E;X34is A;X35is E;X36is E;X40is L;X41is L;X42is A;X43is A;X45is L;X47is A;X48is E;X50is G;X51isL;X57is V;X58is R;X59is L;X60is E; andX61is E.

[0213] Embodiment 64. The engineered DLL3-binding peptide of any one of embodiments 58-63, wherein:X3is V;X4is R;X5is V;X7is I;X9is L;X10is R;X14is G;X15isR;WSGR Docket No. 70774-714.601X17is R;X18is R;X19is A;X20is E;X22is E;X26is P;X28is A;X30is A;X31is R;X32is A;X33is E;X34is A;X35is E;X36is E;X40is L;X41is L;X42is A;X43is A;X45is L;X47is A;X48is E;X50is G;X51is L;X57is V;X58is R;X59is L;X60is E; andX61is E.

[0214] Embodiment 65. The engineered DLL3 -binding peptide of any one of embodiments 58-61, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166.WSGR Docket No. 70774-714.601

[0215] Embodiment 66. The engineered DLL3-binding peptide of embodiment 65, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166.

[0216] Embodiment 67. The engineered DLL3-binding peptide of embodiment 65, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 23, 26, 27, 29, 30 or 33.

[0217] Embodiment 68. The engineered DLL3 -binding peptide of embodiment 67, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 23, 26, 27, 29, 30 or 33.

[0218] Embodiment 69. The engineered DLL3-binding peptide of any one of embodiments 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of less than 1 nM.

[0219] Embodiment 70. The engineered DLL3-binding peptide of any one of embodiments 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of between about 1 pM to about 1 nM.

[0220] Embodiment 71. The engineered DLL3-binding peptide of any one of embodiments 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of less than 1 pM.

[0221] Embodiment 72. The engineered DLL3-binding peptide of any one of embodiments 55-57, wherein the peptide binds to the EGF1 domain.

[0222] Embodiment 73. The engineered DLL3-binding peptide of embodiment 72, wherein:X5is L;X14is E;WSGR Docket No. 70774-714.601X15is E;X32is G;X44is G;and X52is V.

[0223] Embodiment 74. The engineered DLL3-binding peptide of embodiment 72, wherein:X22is E;X23is L;X35is A;X43is E; andX52is V.

[0224] Embodiment 75. The engineered DLL3 -binding peptide of any one of embodiments 72-74, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ IDNOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164.

[0225] Embodiment 76. The engineered DLL3-binding peptide of embodiment 75, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164.

[0226] Embodiment 77. The engineered DLL3-binding peptide of embodiment 75, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37.

[0227] Embodiment 78. The engineered DLL3-binding peptide of embodiment 77, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37.WSGR Docket No. 70774-714.601

[0228] Embodiment 79. The engineered DLL3-binding peptide of any one of embodiments 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of less than 1 nM.

[0229] Embodiment 80. The engineered DLL3-binding peptide of any one of embodiments 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of between about 1 pM to about 1 nM.

[0230] Embodiment 81. The engineered DLL3-binding peptide of any one of embodiments 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of less than 1 pM.

[0231] Embodiment 82. The engineered DLL3-binding peptide of any one of embodiments 55-57, wherein the peptide binds to the EGF2 domain.

[0232] Embodiment 83. The engineered DLL3-binding peptide of embodiment 82, wherein:X11is G;X13is G; andX22is E.

[0233] Embodiment 84. The engineered DLL3-binding peptide of embodiment 82, wherein:X6is I;X8is G;X9is P;X17is F;X19is S;X20is L;X21is E;WSGR Docket No. 70774-714.601X26is A;X30is Y;X35is G;X38is L;X39is L;X45is G;X46is D; andX52is V.

[0234] Embodiment 85. The engineered DLL3-binding peptide of any one of embodiments 82-84, wherein:X6is I;X8is G;X9is P;X11is G;X13is G;X17isF;X19is S;X20is L;X21is E;X22is E;X26is A;X30is Y;X35is G;X38is L;X39is L;X45is G;X46is D; andX52is V.WSGR Docket No. 70774-714.601

[0235] Embodiment 86. The engineered DLL3-binding peptide of embodiment 82, wherein:X19is S;X22is E;X42is E; andX46is D.

[0236] Embodiment 87. The engineered DLL3-binding peptide of embodiment 82, wherein:X3is R;X9is P;X11is G;X13is G;X18is D;X25is A;X29is R;X35is G; andX48is V.

[0237] Embodiment 88. The engineered DLL3 -binding peptide of any one of embodiments 86-87, wherein:X3is R;X9is P;X11is G;X13is G;X18is D;X19is S;X22is E;X25is A;X29is R;X35is G;X42is E;X46is D;X48is V; andWSGR Docket No. 70774-714.601X52is V.

[0238] Embodiment 89. The engineered DLL3-binding peptide of any one of embodiments 82-88, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ IDNOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167.

[0239] Embodiment 90. The engineered DLL3-binding peptide of embodiment 89, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167.

[0240] Embodiment 91. The engineered DLL3-binding peptide of embodiment 89, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 2-6, or 41.

[0241] Embodiment 92. The engineered DLL3-binding peptide of embodiment 91, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, or 41.

[0242] Embodiment 93. The engineered DLL3-binding peptide of any one of embodiments 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of less than 1 nM.

[0243] Embodiment 94. The engineered DLL3-binding peptide of any one of embodiments 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of between about 1 pM to about 1 nM.WSGR Docket No. 70774-714.601

[0244] Embodiment 95. The engineered DLL3 -binding peptide of any one of embodiments 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of less than 1 pM.

[0245] From the foregoing, it will be appreciated that specific embodiments of the present technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the present technology. Accordingly, the present technology is not limited except as by the appended claims.

Claims

1. WSGR Docket No. 70774-714.601CLAIMSWhat is claimed is:

1. An engineered delta like ligand 3-binding (DLL3 -binding) peptide comprising a sequence of Formula (I):X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30x31x32x33x34x35x36x37x38x39x40x41x42x43x44x45x46x47x48x49x50x51x52x53x54x55x56x57X58X59X6OX61X62X63X64 )wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T; X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y;X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y; X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y; X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V; X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y; X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, V, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, T, and V; XIIis selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V; X12is selected from the group consisting of A, D, E, G, I, K, L, N, P, R, S, T, and V; X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, P, R, T, V, and Y;X14is selected from the group consisting of A, D, E, F, G, I, K, L, P, Q, R, T, and V; X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y;X16is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y;WSGR Docket No. 70774-714.601X18is selected from the group consisting of A, C, D, E, F, L, M, P, Q, R, S, T, V, W, and Y;X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y;X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y;X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V;X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y; X25is selected from the group consisting of A, C, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y; X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y; X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, S, and V; X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V; X30is selected from the group consisting of A, C, D, E, H, I, F, K, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, P, Q, R, S, and V; X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y;X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, V, and Y; X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y; X37is selected from the group consisting of A, C, D, E, F, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, D, E, F, G, H, I, L, N, P, R, S, T, V, and Y;X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W;WSGR Docket No. 70774-714.601X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y;X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W; X42is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, V, W, and Y;X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, T, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y;X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V;X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, W, and Y;X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V;X49is selected from the group consisting of A, C, D, E, F, H, I, L, M, N, P, Q, R, S, T, V, and Y;X50is selected from the group consisting of A, C, E, F, G, I, L, Q, R, T, V, W, and Y; X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y;X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, S, T, and V;X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y;X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y; X57is absent or selected from the group consisting of A, C, E, L, Q, R, T, V, and Y; X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, E, F, K, L, P, R, and V;WSGR Docket No. 70774-714.601X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

2. The engineered DLL3-binding peptide of claim 1, comprising a sequence of Formula (IA):x1x2x3x4x5x6x7x8x9x10x11X12X13X14X15X16X17X18X19X20X21EX23X24X25X26X27X28X29X30wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, P, Q, R, S, and T; X2is selected from the group consisting of C E, F, I, L, P, Q, R, S, T, V, W, and Y; X3is selected from the group consisting of A, C, E, F, K, L, Q, R, T, V, and Y;X4is selected from the group consisting of A, C, E, L, R, T, and V;X5is selected from the group consisting of A, C, E, F, H, I, L, R, T, V and Y;X6is selected from the group consisting of A, C, E, H, I, L, R, S, T, and V;X7is selected from the group consisting of A, E, F, G, I, K, L, R, S, T, V, W, and Y; X8is selected from the group consisting of A, E, G, L, P, Q, S, T, and V;X9is selected from the group consisting of A, D, E, F, G, L, N, P, S, and T;X10is selected from the group consisting of C, D, E, G, L, Q, R, S, T;XIIis selected from the group consisting of A, D, E, G, L, N, P, Q, and R;X12is selected from the group consisting of A, D, E, G, I, K, P, R, S, T, and V;X13is selected from the group consisting of A, D, G, K, L, M, P, R, T, and V;X14is selected from the group consisting of E, F, G, I, L, Q, R, T, and V;X15is selected from the group consisting of A, E, F, G, I, R, S, T, V, and W;X16is selected from the group consisting of A, C, E, F, I, L, P, Q, R, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, K, L, Q, R, V, W, and Y; X18is selected from the group consisting of A, D, E, P, R, S, and T;X19is selected from the group consisting of A, D, E, F, L, N, P, Q, S, and T;X20is selected from the group consisting of A, C, E, G, I, K, L, M, R, T, V, and W;WSGR Docket No. 70774-714.601X21is selected from the group consisting of A, D, E, F, G, I, P, Q, S, T, V, and Y; X23is selected from the group consisting of A, C, D, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, I, L, K, P, R, S, and V;X25is selected from the group consisting of A, D, E, G, K, L, P, Q, R, S, T, and V; X26is selected from the group consisting of A, D, E, G, I, L, P, Q, R, and S;X27is selected from the group consisting of A, C, E, F, I, L, P, R, and V;X28is selected from the group consisting of A, D, E, G, K, M, N, Q, and R;X29is selected from the group consisting of A, D, E, K, N, Q, R, S, and V;X30is selected from the group consisting of A, C, D, E, H, R, S, T, V, and Y;X31is selected from the group consisting of A, C, F, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, and V;X33is selected from the group consisting of A, C, D, E, K, L, R, S, T, V, and W; X34is selected from the group consisting of A, D, E, G, K, H, L, N, Q, R, S, T, and Y; X35is selected from the group consisting of A, C, E, G, K, N, R, and V;X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V and Y; X37is selected from the group consisting of A, C, D, E, K, L, N, P, Q, R, S, T, V, andX38is selected from the group consisting of A, C, E, F, G, H, I, L, P, R, T, V, and Y; X39is selected from the group consisting of A, C, E, I, K, L, P, R, S, T, V, and W; X40is selected from the group consisting of A, C, D, E, G, L, N, Q, R, S, and V; X41is selected from the group consisting of A, D, E, F, G, L, Q, R, S, V, W, and Y; X42is selected from the group consisting of A, D, E, H, K, N, Q„ R, S, V, W, and Y; X43is selected from the group consisting of A, D, E, F, I, K, L, Q, R, V, and W;X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, Q, R, V, and Y; X45is selected from the group consisting of A, D, E, G, K, L, P, R, S, V, and W; X46is selected from the group consisting of A, C, D, E, G, I, K, N, Q, T, and V;X47is selected from the group consisting of A, C, E, F, G, K, L, N, Q, R, S, T, V, andX48is selected from the group consisting of A, C, D, E, I, L, N, P, S, T, and V;X49is selected from the group consisting of A, D, E, F, H, I, L, M, N, P, R, T, V, andX50is selected from the group consisting of A, C, E, G, I, L, R, T, V, and W;X51is selected from the group consisting of A, C, D, E, F, H, K, L, Q, R, T, V, and Y; X52is selected from the group consisting of A, C, E, G, I, , L, P, Q, R, and V;WSGR Docket No. 70774-714.601X53is selected from the group consisting of A, D, E, G, I, K, L, Q, R, S, T, V, W, and Y;X54is absent or selected from the group consisting of A, C, E, L, R, T, and V;X55is absent or selected from the group consisting of A, E, I, L, P, R, T, V, and Y; X56is absent or selected from the group consisting of A, E, H, P, R, and Y;X57is absent or selected from the group consisting of C, L, R, and V;X58is absent or selected from the group consisting of A, E, R, and V;X59is absent or selected from the group consisting of L, P, R, and V;X60is absent or selected from the group consisting of A, E, F, L, and T;X61is absent or selected from the group consisting of E, P, R, and V;X62is absent, E, or P;X63is absent or R; andX64is absent.

3. The engineered DLL3-binding peptide of claim 1, comprising a sequence of Formula (IB):wherein:XIis selected from the group consisting of A, D, E, G, K, L, M, N, P, Q, R, S, and T;X2is selected from the group consisting of A, C, E, F, I, K, L, P, Q, R, S, T, V, W, and Y; X3is selected from the group consisting of A, C, E, F, K, L, P, Q, R, T, V, W, and Y;X4is selected from the group consisting of A, C, E, L, R, T, V, and Y;X5is selected from the group consisting of A, C, D, E, F, H, I, L, Q, R, S, T, V, and Y;X6is selected from the group consisting of A, C, E, G, H, I, L, M, R, S, T, and V;X7is selected from the group consisting of A, C, E, F, G, I, K, L, R, S, T, V, W, and Y;X8is selected from the group consisting of A, C, E, F, G, L, P, Q, R, S, T, V, and Y;X9is selected from the group consisting of A, C, D, E, F, G, L, N, P, R, S, T, W, and Y;X10is selected from the group consisting of A, C, D, E, G, L, Q, R, S, T, and V;XIIis selected from the group consisting of A, D, E, G, K, L, N, P, Q, R, S, and V;X12is selected from the group consisting of A, D, E, G, K, L, P, R, S, T, and V;X13is selected from the group consisting of A, D, E, F, G, I, K, L, M, N, P, R, S, T, and V;WSGR Docket No. 70774-714.601X14is selected from the group consisting of A, D, E, F, G, I, K, P, Q, R, T, and V;X15is selected from the group consisting of A, E, F, G, I, K, L, Q, R, S, T, V, W, and Y; X16is selected from the group consisting of A, C, E, F, H, I, L, P, Q, S, T, V, W, and Y;X17is selected from the group consisting of A, C, E, F, H, I, K, L, P, Q, R, V, W, and Y; X18is selected from the group consisting of A, C, D, E, F, L, P, Q, R, S, T, V, W, and Y; X19is selected from the group consisting of A, D, E, F, G, L, N, P, Q, R, S, T, V, and Y; X20is selected from the group consisting of A, C, E, F, G, I, K, L, M, N, R, T, V, W, and Y; X21is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y;X22is selected from the group consisting of A, C, D, E, F, G, K, L, N, P, Q, R, S, T, and V; X23is selected from the group consisting of A, C, D, E, G, I, L, Q, S, T, and V;X24is selected from the group consisting of A, C, D, E, G, I, K, L, P, R, S, V, and Y;X25is selected from the group consisting of A, C, D, E, K, G, L, P, Q, R, S, T, and V;X26is selected from the group consisting of A, D, E, F, G, I, L, P, Q, R, S, T, V, and Y;X27is selected from the group consisting of A, C, D, E, F, I, K, L, P, Q, R, V, and Y;X28is selected from the group consisting of A, C, D, E, G, K, M, N, Q, R, and S;X29is selected from the group consisting of A, D, E, F, H, K, L, N, Q, R, S, T, and V;X30is selected from the group consisting of A, C, D, E, F, K, H, M, R, S, T, V, and Y;X31is selected from the group consisting of A, C, D, E, F, G, I, K, L, R, S, T, V, and Y;X32is selected from the group consisting of A, C, D, E, F, G, I, K, L, Q, R, S, and V;X33is selected from the group consisting of A, C, D, E, H, K, L, P, Q, R, S, T, V, W, and Y; X34is selected from the group consisting of A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, and Y;X35is selected from the group consisting of A, C, E, G, K, L, M, N, R, S, and V;X36is selected from the group consisting of A, C, D, E, G, K, L, P, R, S, T, V, and Y;X37is selected from the group consisting of A, C, D, E, G, K, L, M, N, P, Q, R, S, T, V, and Y;X38is selected from the group consisting of A, C, E, F, G, H, I, L, N, P, R, S, T, V, and Y; X39is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, R, S, T, V, and W; X40is selected from the group consisting of A, C, D, E, G, K, L, N, P, Q, R, S, V, W, and Y; X41is selected from the group consisting of A, D, E, K, L, M, Q, R, S, T, V, and W;X42is selected from the group consisting of A, D, E, H, K, L, N, Q, R, S, T, V, W, and Y; X43is selected from the group consisting of A, C, D, E, F, G, I, K, L, N, Q, R, V, and W; X44is selected from the group consisting of A, D, E, F, G, H, I, K, L, N, Q, R, V, W, and Y; X45is selected from the group consisting of A, C, D, E, G, I, K, L, P, Q, R, S, V, and W;WSGR Docket No. 70774-714.601X46is selected from the group consisting of A, C, D, E, G, I, K, L, M, N, Q, R, T, and V; X47is selected from the group consisting of A, C, D, E, F, G, K, L, N, Q, R, S, T, V, and Y; X48is selected from the group consisting of A, C, D, E, I, L, M, N, P, Q, R, S, T, and V; X49is selected from the group consisting of A, C, D, E, F, H, I, L, N, P, Q, R, S, T, V, and Y; X50is selected from the group consisting of A, C, E, F, G, I, L, R, T, V, W, and Y;X51is selected from the group consisting of A, C, D, E, F, G, H, K, L, N, Q, R, S, T, V, and Y; X52is selected from the group consisting of A, C, D, E, G, I, K, L, N, P, Q, R, T, and V; X53is selected from the group consisting of A, C, D, E, G, I, K, L, Q, R, S, T, V, W, and Y; X54is absent or selected from the group consisting of A, C, D, E, F, K, L, P, Q, R, T, V, and Y;X55is absent or selected from the group consisting of A, D, E, G, H, I, L, P, R, T, V, and Y; X56is absent or selected from the group consisting of A, E, H, I, L, P, R, W, and Y;X57is absent or selected from the group consisting of C, E, L, Q, R, T, V, and Y;X58is absent or selected from the group consisting of A, D, E, G, L, R, and V;X59is absent or selected from the group consisting of A, D, E, F, K, L, P, R, and V;X60is absent or selected from the group consisting of A, C, E, F, L, S, T, and V;X61is absent or selected from the group consisting of A, E, I, L, P, R, and V;X62is absent or selected from the group consisting of A, E, L, and P;X63is absent or selected from the group consisting of L, P, Q, and R; andX64is absent or P.

4. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X64are absent.

5. The engineered DLL3-binding peptide of any one of claims 1-4, wherein: XIis M or P;X3is R or L;X9is G or P;XIIis R or G;X19is D or S;X22is E;X25is E or A;X30is A or Y;X35is G or A;WSGR Docket No. 70774-714.601X42is E;X46is D;X48is V or L; andX52is C or V.

6. The engineered DLL3-binding peptide of any one of claims 1-5, wherein: X2is selected from L, V, and I;X4is selected from V, L, and C;X6is selected from V, I, and L;X10is selected from D, L, and G;X13is selected from V, G, and A;X14is selected from V, R, and I;X16is selected from E, Y, and L;X17is selected from A, F, and V;X18is selected from A, D, and P;X27is selected from A, L, and E;X29is selected from E, K, and R;X31is selected from C, A, and L;X32is selected from R, A, and E;X37is selected from E, T, and R;X38is selected from V, L, and I;X41is selected from L, E, and V; andX53is selected from R, A, and E.

7. The engineered DLL3-binding peptide of any one of claims 1-5, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-5.

8. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54is present and X55-X64are absent.

9. The engineered DLL3-binding peptide of any one of claims 1-3, wherein the peptide comprises a sequence of SEQ ID NO: 6.WSGR Docket No. 70774-714.60110. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54and X55are present and X56-X64are absent.

11. The engineered DLL3 -binding peptide of any one of claims 1-3 and 10, wherein:X2is selected from L, T, and E;X4is selected from V, Y, and T;X5is selected from R, V, and L;X9is N or T;X10is selected from G, S, and D;X11is selected from R, A, and L;X12is selected from E, T, and S;X14is selected from V, Q, and E;X15is selected from F, T, and E;X16is selected from P, Y, and A;X18is selected from P, V, and E;X22is selected from E, P, and A;X23is selected from G, I, and L;X25is selected from A, E, and D;X26is selected from R, F, and E;X28is selected from R, A, and E;X29is selected from A, H, and E;X30is selected from D, R, and E;X32is E or G;X33is A or W;X34is selected from L, E, and R;X35is A or V;X37is selected from A, D, and Y;X40is selected from C, V and L;X43is selected from A, E, and D;X44is selected from H, V, and G;X47is selected from G, D, and Y;X48is selected from D, Q, and I;X52is A or V;WSGR Docket No. 70774-714.601X53is selected from V, T, and R; andX55is selected from E, P and A.

12. The engineered DLL3-binding peptide of any one of claims 1-3, 10, and 11, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 7-12.

13. The engineered DLL3-binding peptide of any one of claims 1-3 and 10-12, wherein:XIis E or T;X2is T or E;X4is V or T;X5is L;X6is S or T;X7is W or Y;X9is T;X10is D;XIIis A or L;X12is S;X14is E;X15is E;X16is A;X17is A or E;X18is E;X19is E or L;X20is A or G;X22is E or A;X23is I or L;X26is R or E;X27is I or L;X28is E;X29is A or E;X30is E;X32is G;WSGR Docket No. 70774-714.601X34is E or R;X37is A or Y;X38is H or T;X39is I or V;X40is V or L;X43is E or D;X44is G;X45is R or V;X46is R or T;X47is Y;X48is I;X50is V or I;X52is V; andX54is D or E.

14. The engineered DLL3-binding peptide of any one of claims 1-3 and 10-13, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 9-12.

15. The engineered DLL3 -binding peptide of any one of claims 1-3 and 10, wherein X2, X3, X5, X6, and X7are each A.

16. The engineered DLL3-binding peptide of any one of claims 1-3, 10, and 15, wherein:X4is L;X8is Q;Xnis L;X15is V;X16is E;X17is A;X18is A;X19is L;X20is G;X21is V;WSGR Docket No. 70774-714.601X22is P;X23is V;X25is P;X26is A;X27is A;X28is V;X30is T;X33is E;X34is G;X38is A;X42is A;X44is V;X45is D;X46is G;X49is L;X51is F; andX52is S.

17. The engineered DLL3-binding peptide of any one of claims 1-3, 15, and 16, wherein the peptide comprises a sequence of SEQ ID NO: 13 or 14.

18. The engineered DLL3 -binding peptide of any one of claims 1-3, wherein X54- X56are present and X57-X64are absent.

19. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X57are present and X58-X64are absent.

20. The engineered DLL3-binding peptide of any one of claims 1-3 and 19, wherein:X2is V;X4is R;X5is Y;X6is A;X7is V;WSGR Docket No. 70774-714.601X9is S;X10is V;X12is A;X13is L;X15is A;X16is L;X17is L;X19is R;X21is A;X22is D;X23is V;X24is D;X25is P;X29is A;X30is A;X31is L;X33is A;X35is V;X36is A;X39is I;X40is A;X42is R;X43is R;X44is A;X45is A;X46is G;X47is E;X48is D;X50is W; X51is V;X52is E;X53is V;X56is R; and X57is L.WSGR Docket No. 70774-714.60121. The engineered DLL3-binding peptide of any one of claims 1-3, 19, and 20, wherein the peptide comprises a sequence of SEQ ID NO: 18 or 19.

22. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X58are present and X59-X64are absent.

23. The engineered DLL3 -binding peptide of any one of claims 1-3, wherein X54- X59are present and X60-X64are absent.

24. The engineered DLL3-binding peptide of any one of claims 1-3 and 23, wherein the peptide comprises a of SEQ ID NO: 21.

25. The engineered DLL3 -binding peptide of any one of claims 1-3, wherein X54- X60are present and X61-X64are absent.

26. The engineered DLL3-binding peptide of any one of claims 1-3, and 25, wherein the peptide comprises a sequence of SEQ ID NO: 23.

27. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X61are present and X62-X64are absent.

28. The engineered DLL3 -binding peptide of any one of claims 1-3 and 27, wherein:X5is V;X7is I;X9is L;X14is G;X19is A;X31is R;X36is E;X40is L;X41is L;X42is A;WSGR Docket No. 70774-714.601X45is L;X47is A;X48is E; andX50is G.

29. The engineered DLL3-binding peptide of any one of claims 1-3, 27, and 28, wherein:X4is R or A;X10is T or R;X12is E or A;X16is V or E;X17is R or Q;X18is R or T;X20is E or T;X22is E or R;X26is P or S;X28is A or E;X30is A or V;X33is D or E;X34is G or A;X35is E or L;X37is V or L;X38is A or G;X43is A or R;X46is E or A;X49is T or D;X57is V or L;X58is R or E; andX61is R or E.

30. The engineered DLL3-binding peptide of any one of claims 1-3 and 27-29, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 26-30.WSGR Docket No. 70774-714.60131. The engineered DLL3-binding peptide of any one of claims 1-3 and 27-30, wherein:X5is V;X7is I;X9is L;X14is G;X19is A;X31is R;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E; andX50is G.

32. The engineered DLL3-binding peptide of any one of claims 1-3 and 27-31, wherein:X1is selected from P, A, and M;X4is R or V;X10is R or T;X13is selected from D, K, and E;X16is V or E;X17is R or Q;X18is T or R;X20is E or T;X22is E or R;X26is P or S;X28is A or E;X30is A or V;X32is selected from R, A, and V;X34is G or A;X35is E or L;WSGR Docket No. 70774-714.601X37is V or L;X39is selected from R, A, and E;X43is A or R;X49is D or T;X52is selected from R, A, and P;X53is selected from Y, V, and W;X54is selected from R, T, and E;X58is R or E;X59is selected from L, V, and F;X60is selected from F, T, and E; andX61is R or E.

33. The engineered DLL3-binding peptide of any one of claims 1-3 and 27-32, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 26-30.

34. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X62are present and X63and X64are absent.

35. The engineered DLL3-binding peptide of any one of claims 1-3 and 34, wherein:X1is selected from G, P, and M;X5is A or V;X7is R or L;X8is A or T;X14is selected from E, D, and F;X19is selected from Q, T, and E;X22is selected from V, E, and D;X23is G or A;X24is E or A;X25is selected from V, A, and L;X32is S or A;X34is selected from D, I, and E;X36is selected from R, G, and P;WSGR Docket No. 70774-714.601X39is selected from V, W, and R;X40is A or P;X43is V or E;X45is selected from K, L, and A;X49is T or E;X51is K or A;X52is selected from E, A, and V;X53is E or T;X54is selected from V, L, and A;X55is selected from R, L, and D;X56is selected from R, A, and H;X58is V or A;X59is selected from P, E, and A;X60is L or A; andX61is selected from R, P, and A.

36. The engineered DLL3-binding peptide of any one of claims 1-3, 34, and 35, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 32-35.

37. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X63are present and X64is absent.

38. The engineered DLL3-binding peptide of any one of claims 1-3 and 34, wherein:X3is R;X4is L;X28is E;X46is A; andX60is A.

39. The engineered DLL3-binding peptide of any one of claims 1-3, 37, and 38, wherein the peptide comprises a sequence of SEQ ID NO: 37 or 38.WSGR Docket No. 70774-714.60140. The engineered DLL3-binding peptide of any one of claims 1-3, wherein X54- X64are present.

41. The engineered DLL3 -binding peptide of any one of claims 1-3 and 40, wherein the peptide comprises a sequence of SEQ ID NO: 41.

42. The engineered DLL3-binding peptide of any one of claims 1-32, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-14, 18, 19, 21, 23, 26-30, 32-35, 37, 38, and 41.

43. The engineered DLL3-binding peptide of claim 1 or 2, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 43- 167.

44. The DLL3-binding peptide of any one of claims 1-43, wherein the peptide comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% to any one of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, or 43-167.

45. The engineered DLL3 -binding peptide of any one of claims 1-43, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-21, 23, 26-30, 32-35, 37, 38, 41, and 43-167.

46. The engineered DLL3-binding peptide of any one of claims 1-44, wherein the peptide binds DLL3 with a KD of less than about 100 nM.

47. The engineered DLL3-binding peptide of any one of claims 1-45, wherein the peptide binds DLL3 with a KD of about 1 nM to about 50 nM.

48. The engineered DLL3 -binding peptide of any one of claims 1-46, wherein the peptide binds DLL3 with a KD of about 20 nM to about 40 nM.WSGR Docket No. 70774-714.60149. The engineered DLL3-binding peptide of any one of claims 1-48, wherein the peptide binds DLL3 with a KD of less than 1 nM.

50. The engineered DLL3-binding peptide of any one of claims 1-49, wherein the peptide binds DLL3 with a KD of between about IpM and about 1 nM.

51. The engineered DLL3-binding peptide of any one of claims 1-48, wherein the peptide binds DLL3 with a KD of less than 1 pM.

52. The engineered DLL3-binding peptide of any one of claims 1-51, wherein the peptide has a length of at least 53 residues, at least 54 residues, at least 55 residues, at least 56 residues, at least 57 residues, at least 58 residues, at least 59 residues, at least 60 residues, at least 61 residues, at least 62 residues, at least 63 residues, or at least 64 residues.

53. The engineered DLL3-binding peptide of any one of claims 1-51, wherein the peptide has a length of at most 53 residues, at most 54 residues, at most 55 residues, at most 56 residues, at most 57 residues, at most 58 residues, at most 59 residues, at most 60 residues, at most 61 residues, at most 62 residues, at most 63 residues, or at most 64 residues.

54. The engineered DLL3-binding peptide of any one of claims 1-53, wherein the peptide binds to an extracellular domain of DLL3 expressed on a cell.

55. The engineered DLL3 -binding peptide of claim 54, wherein the peptide binds to an N-terminal domain, an EGF1 domain, or an EGF2 domain within the extracellular domain of DLL3.

56. The engineered DLL3-binding peptide of claim 54 or 55, wherein the peptide binds to the extracellular domain of DLL3 expressed by a cancer cell.

57. The engineered DLL3-binding peptide of claim 56, wherein cancer cell is selected from the group consisting of a small cell lung cancer cell, a prostate cancer cell, and a large cell neuroendocrine carcinoma cell.WSGR Docket No. 70774-714.60158. The engineered DLL3-binding peptide of any one of claims 55-57, wherein the peptide binds to the N-terminal domain.

59. The engineered DLL3-binding peptide of claim 58, wherein:X5is V;X9is L;X14is G;X19isA;X36is E;X40is L;X41is L;X42is A;X47is A;X48is E; andX50is G.

60. The engineered DLL3-binding peptide of any one of claims 58 or 59, wherein: X7is I;X20is E;X30is A;X31is R;X34is A;X45is L;X57is V; andX61is E.

61. The engineered DLL3-binding peptide of any one of claims 58-60, wherein: X5is V;X7is I;X9is L;X14is G;X19is A;X20is E;X30is A;X31is R;WSGR Docket No. 70774-714.601X34is A;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E;X50is G;X57is V; andX61is E.

62. The engineered DLL3-binding peptide of any one of claims 58-59, wherein: X4is R;X5is V;X7is I;X9is L;X14is G;X17is R;X19is A;X26is P;X31is R;X36is E;X40is L;X41is L;X42is A;X45is L;X47is A;X48is E; andX50is G.

63. The engineered DLL3-binding peptide of any one of claims 58-62, wherein: X3is V;X4is R;WSGR Docket No. 70774-714.601X5is V;X7is I;X9is L;X10is R;X14is G;X15is R;X17is R;X18is R;X19is A;X20is E;X26is P;X28is A;X30is A;X31is R;X32is A;X33is E;X34is A;X35is E;X36is E;X40is L;X41is L;X42is A;X43is A;X45is L;X47is A;X48is E;X50is G;X51is L;X57is V;X58is R;X59is L;X60is E; and X61is E.WSGR Docket No. 70774-714.60164. The engineered DLL3-binding peptide of any one of claims 58-63, wherein: X3is V;X4is R;X5is V;X7is I;X9is L;X10is R;X14is G;X15isR;X17is R;X18isR;X19is A;X20is E;X22is E;X26is P;X28is A;X30is A;X31is R;X32is A;X33is E;X34is A;X35is E;X36is E;X40is L;X41is L;X42is A;X43is A;X45is L;X47is A;X48is E;X50is G;X51isL;X57is V;X58is R;WSGR Docket No. 70774-714.601X59is L;X60is E; andX61is E.

65. The engineered DLL3 -binding peptide of any one of claims 58-61, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166.

66. The engineered DLL3-binding peptide of claim 65, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 1, 21, 23, 26-30, 33, 34, 38, 61, 65, 73, 77, 95, 100, 110, 116, 155, or 166.

67. The engineered DLL3-binding peptide of claim 65, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 23, 26, 27, 29, 30 or 33.

68. The engineered DLL3 -binding peptide of claim 67, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 23, 26, 27, 29, 30 or 33.

69. The engineered DLL3-binding peptide of any one of claims 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of less than 1 nM.

70. The engineered DLL3-binding peptide of any one of claims 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of between about 1 pM to about 1 nM.

71. The engineered DLL3-binding peptide of any one of claims 58-68, wherein the peptide binds the N-terminal domain of DLL3 with a KD of less than 1 pM.

72. The engineered DLL3-binding peptide of any one of claims 55-57, wherein the peptide binds to the EGF1 domain.WSGR Docket No. 70774-714.60173. The engineered DLL3-binding peptide of claim 72, wherein:X5is L;X14is E;X15is E;X32is G;X44is G;and X52is V.

74. The engineered DLL3-binding peptide of claim 72, wherein:X22is E;X23is L;X35is A;X43is E; andX52is V.

75. The engineered DLL3 -binding peptide of any one of claims 72-74, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164.

76. The engineered DLL3-binding peptide of claim 75, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 7-14, 18, 19, 32, 35, 37, 44, 45, 49, 51, 53, 59, 60, 64, 70, 72, 74, 76, 78, 79, 81, 82, 84, 85, 92, 98, 101, 102, 104, 105, 107, 108, 112-115, 121, 123, 125, 128, 129, 132, 136, 137, 139, 141, 143, 145, 150, 151, 153, 161 or 164.

77. The engineered DLL3-binding peptide of claim 75, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37.WSGR Docket No. 70774-714.60178. The engineered DLL3-binding peptide of claim 77, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 7, 8, 10, 11, 18, 19, 32, or 37.

79. The engineered DLL3-binding peptide of any one of claims 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of less than 1 nM.

80. The engineered DLL3-binding peptide of any one of claims 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of between about 1 pM to about 1 nM.

81. The engineered DLL3-binding peptide of any one of claims 72-78, wherein the peptide binds the EGF1 domain of DLL3 with a KD of less than 1 pM.

82. The engineered DLL3-binding peptide of any one of claims 55-57, wherein the peptide binds to the EGF2 domain.

83. The engineered DLL3-binding peptide of claim 82, wherein:X11is G;X13is G; andX22is E.

84. The engineered DLL3-binding peptide of claim 82, wherein:X6is I;X8is G;X9is P;X17is F;X19is S;X20is L;X21is E;X26is A;WSGR Docket No. 70774-714.601X30is Y;X35is G;X38is L;X39is L;X45is G;X46is D; andX52is V.

85. The engineered DLL3-binding peptide of any one of claims 82-84, wherein: X6is I;X8is G;X9is P;X11is G;X13is G;X17isF;X19is S;X20is L;X21is E;X22is E;X26is A;X30is Y;X35is G;X38is L;X39is L;X45is G;X46is D; andX52is V.

86. The engineered DLL3-binding peptide of claim 82, wherein:X19is S;X22is E;WSGR Docket No. 70774-714.601X42is E; andX46is D.

87. The engineered DLL3-binding peptide of claim 82, wherein:X3is R;X9is P;X11is G;X13is G;X18is D;X25is A;X29is R;X35is G; andX48is V.

88. The engineered DLL3-binding peptide of any one of claims 86-87, wherein: X3is R;X9is P;X11is G;X13is G;X18is D;X19is S;X22is E;X25is A;X29is R;X35is G;X42is E;X46is D;X48is V; andX52is V.

89. The engineered DLL3-binding peptide of any one of claims 82-88, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one ofWSGR Docket No. 70774-714.601SEQ ID NOs: 2-6, 41, 43, 44-48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167.

90. The engineered DLL3-binding peptide of claim 89, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, 41, 43, 44- 48, 50, 52, 53, 55-58, 62, 63, 66-69, 71, 75, 80, 83, 86-91, 93, 94, 96, 97, 99, 103, 106, 109, 111, 117-120, 122, 124, 126, 127, 130, 131, 133-135, 138, 140, 142, 144, 146, 147, 148, 149, 152, 154, 156-160, 162, 163, 165, or 167.

91. The engineered DLL3-binding peptide of claim 89, wherein the peptide comprises a sequence having at least 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 2-6, or 41.

92. The engineered DLL3-binding peptide of claim 91, wherein the peptide comprises a sequence selected from any one of SEQ ID NOs: 2-6, or 41.

93. The engineered DLL3-binding peptide of any one of claims 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of less than 1 nM.

94. The engineered DLL3-binding peptide of any one of claims 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of between about 1 pM to about 1 nM.

95. The engineered DLL3 -binding peptide of any one of claims 82-92, wherein the peptide binds the EGF2 domain of DLL3 with a KD of less than 1 pM.

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