Bispecific binding construct capable of binding to ACKR4, compositions comprising a bispecific binding construct capable of binding to ACKR4, and methods of using bispecific binding construct capable of binding to ACKR4

Abstract

Provided herein are bispecific binding constructs with binding specificity for ACKR4 and another antigen. In particular, heteromultimeric antibodies e.g., full length antibodies or antigen binding fragments thereof, that specifically bind to ACKR4 and another antigen, such as HER2, TNF-α, or HLA-G, are provided. Compositions comprising such antibodies, methods for producing and purifying such antibodies, and their use in diagnostics and therapeutics are also provided.

Description

1107368.00143 BISPECIFIC BINDING CONSTRUCT CAPABLE OF BINDING TO ACKR4, COMPOSITIONS COMPRISING A BISPECIFIC BINDING CONSTRUCT CAPABLE OF BINDING TO ACKR4, AND METHODS OF USING BISPECIFIC BINDING CONSTRUCT CAPABLE OF BINDING TO ACKR4 RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application number 63 / 536,627, filed September 5, 2023 and U.S. provisional application number 63 / 568,951, filed March 22, 2024, each of which are incorporated by reference herein in their entirety. FIELD

[0002] Provided herein are bispecific antigen binding constructs with binding specificity for ACKR4 and an additional antigen, including pharmaceutical compositions, diagnostic compositions, and kits. SEQUENCE LISTING

[0003] The application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on March 15, 2024, is named “1107368.00143.xml” and is 776,710 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND

[0004] Atypical chemokine recepetor 4 (ACKR4), formerly known as CCRL1 and CCX- CKR, is a protein that in humans is encoded by the ACKR4 gene. ACKR4 is a cell surface receptor with seven transmembrane domains structurally similar to G protein-coupled receptor proteins. ACKR4 is a receptor for C-C type chemokines and has been shown to bind to dendritic cell and T cell-activated chemokines including CCL19, CCL21, and CCL25.

[0005] ACKR4 has been found to regulate the availability of chemokines. Specifically, unlike other G-protein coupled receptors, ACKR4 functions as a “scavenger,” internalizing chemokines and sorting them for lysosomal degradation to limit local and systemic chemokine1107368.00143 concentrations.

[0006] Recent studies have shown the advantages of targeted degradation of endogenous proteins over inhibition. ACKR4’s ability to internalize and degrade chemokines may be potentially useful in degradation of target proteins, such as through the use of a bispecific antigen binding construct.

[0007] A bispecific antigen binding construct is a protein that can bind to two different antigens. Bispecific antigen binding constructs are usually fusion proteins consisting of two different antibodies or amino acid sequences, such as, for example, two different single-chain variable fragments (scFvs). One of the scFvs binds to a first target while one of the scFvs binds to a second target.

[0008] A bispecific binding construct that binds to ACKR4 and to a second target would be particularly useful. SUMMARY

[0009] A first aspect provides a bispecific antigen binding construct comprising a binding domain capable of binding to ACKR4 and an additional binding domain capable of binding to a second target. In some embodiments, ACKR4 comprises or consists of an amino acid sequence set forth in SEQ ID NO: 147. In some embodiments, the additional binding domain capable of binding to a second target is capable of to HER2, TNF-α, or HLA-G.

[0010] In some embodiments, the binding domain capable of binding to ACKR4 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in SEQ ID NOS: 1-5 or SEQ ID NOS: 12-16, b) a VHCDR2 having the sequence set forth in SEQ ID NOS: 23-25 or SEQ ID NOS: 34-36, c) a VHCDR3 having the sequence set forth in SEQ ID NOS: 45-48, d) a VLCDR1 having the sequence set forth in SEQ ID NOS: 55-59, e) a VLCDR2 having the sequence set forth in SEQ ID NOS: 67-70, and f) a VLCDR3 having the sequence set forth in SEQ ID NOS: 77-81.

[0011] In some embodiments, the second target comprises or consists of HER2. In some embodiments, HER2 comprises or consists of an amino acid sequence set forth in SEQ ID NO: 231.

[0012] In some embodiments, the additional binding domain capable of binding to HER21107368.00143 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 155-156 or SEQ ID NOS: 160-161, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 165-167 or SEQ ID NOS: 171-174, c) a VHCDR3 having the sequence set forth in SEQ ID NOS: 178-179, d) a VLCDR1 having the sequence set forth in SEQ ID NOS: 183-184, e) a VLCDR2 having the sequence set forth in SEQ ID NOS: 188-190, and f) a VLCDR3 having the sequence set forth in SEQ ID NOS: 194-195.

[0013] In some embodiments, the second target comprises or consists of HLA-G. In some embodiments, HLA-G comprises or consists of an amino acid sequence set forth in SEQ ID NO: 575.

[0014] In some embodiments, the additional binding domain capable of binding to HLA- G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: the additional binding domain capable of binding to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 234-247 or SEQ ID NOS: 251-267, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 271-283 or SEQ ID NOS: 287-304, c) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 309-334, d) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 338-357, e) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 361-378, and f) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 382-399.

[0015] In some embodiments, the second target comprises or consists of TNF-α. In some embodiments, TNF-α comprises or consists of an amino acid sequence set forth in SEQ ID NO: 650.

[0016] In some embodiments, the additional binding domain capable of binding to TNF-α comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 579-582 or SEQ ID NOS: 585-588, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 591-594 or SEQ ID NOS: 597-600, c) a VHCDR3 having the sequence set forth in SEQ ID NOS: 603-606, d) a VLCDR1 having the sequence set forth SEQ ID NOS: 609-612, e) a VLCDR2 having the sequence set forth in SEQ ID1107368.00143 NOS: 615-618, and f) a VLCDR3 having the sequence set forth in SEQ ID NOS: 621-624.

[0017] In some embodiments, the binding domain capable of binding to ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89- 94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a HER2 epitope comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 199-202 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 206-209.

[0018] In some embodiments, the binding domain capable of binding to ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89- 94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a HLA-G epitope comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 403-433 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 437-461.

[0019] In some embodiments, the binding domain capable of binding to ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89- 94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a TNF-α epitope comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 627-630 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 633-636.

[0020] In some embodiments, the bispecific binding construct capable of binding to ACKR4 and a second target comprises 1, 2, 3, 4, 5, or 6 of the following: a binding construct capable of binding to ACKR4 comprising a HC linked on a C-terminus to an N-terminus of a scFv1107368.00143 capable of binding to the second target, wherein the HC comprises a sequence selected from SEQ ID NOS: 113-120; a binding construct capable of binding to the second target comprising a HC linked on a C-terminus to an N-terminus of a scFv capable of binding to ACKR4, wherein the scFv capable of binding to ACKR4 comprises a sequence selected from SEQ ID NOS: 89-94 and SEQ ID NOS: 101-106; a scFv capable of binding to the second target linked on a C-terminus to an N- terminus of a binding construct capable of binding to ACKR4 comprising a LC, wherein the LC comprises a sequence selected from SEQ ID NOS: 128-133; a scFv capable of binding to the second target linked on a C-terminus to an N-terminus of a binding construct capable of binding to ACKR4 comprising a HC, wherein the HC comprises a sequence selected from SEQ ID NOS: 113-120; a binding construct capable of binding to ACKR4 comprising a LC linked on a C- terminus to an N-terminus of a scFv capable of binding to the second target wherein the LC comprises a sequence selected from SEQ ID NOS: 128-133; or a binding construct capable of binding to ACKR4 comprising a VH linked to a hIgG1 AAA containing a ‘hole’ mutation in the CH3 domain and a scFv capable of binding to the second target linked to a hIgG1 AAA containing a ‘knob’ mutation in the CH3 domain, wherein the VH comprises a sequence selected from SEQ ID NOS: 89-94.

[0021] A second aspect provides a pharmaceutical composition comprising or consisting of a bispecific antigen binding construct provided herein.

[0022] A third aspect provides one or more nucleic acids encoding the bispecific antigen binding constructs provided herein. In some embodiments, the one or more nucleic acids comprise one or more vectors. Some embodiments provide a host transformed with the one or more vectors.

[0023] A fourth aspect provide a method for the production of one or more bispecific antigen binding constructs comprising the steps of expressing any of the one or more nucleic acids provided herein in a prokaryotic or eukaryotic host cell and recovering the one or more bispecific antigen binding construct from the cell or the cell culture supernatant.

[0024] A fifth aspect provides a method for treating a subject with cancer comprising administering any of the bispecific antigen binding constructs or pharmaceutical compositions provided herein to the subject in a therapeutically effective amount. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 provides a table showing schematics of the nine HACKR format types engaging ACKR4 via antibody.1107368.00143

[0026] FIG.2 provides a table showing cellular ACKR4 binding and target binding of the 38 HACKR constructs and controls representing the nine HACKR format types engaging ACKR4 via antibody and the target of interest.

[0027] FIG. 3A shows CHO-hACKR4 binding by representative antibody-based constructs. FIG. 3B shows CHO-hACKR4 binding by antibody-based constructs detected by soluble DL650-HLA-G to indicate HACKR construct co-binding of cellular ACKR4 and soluble target. FIG. 3C shows sensorgram of soluble HER2 binding by representative antibody-based constructs.

[0028] FIG. 4 shows 48 h ACKR4-specific internalization by representative 10 nM antibody-based constructs in CHO cells.

[0029] FIG.5A shows time-dependent ACKR4-specific degradation of 2 nM HER2 by 2 nM antibody construct in MC38 cells. FIG.5B shows 24 h degradation of 10 nM HER2 by 10 nM antibody-based constructs in MC38-hACKR4 and MC38-parental cells. FIG.5C shows ACKR4- specific degradation of 10 nM HER2 by 10 nM antibody constructs in CHO cells.

[0030] FIG. 6A shows 100 nM DL650-HLA-G cellular uptake mediated by 100 nM antibody construct in CHO-hACKR4 and CHO-parental cells. FIG.6B shows amount of DL650 signal from supernatant in CHO-hACKR4 and CHO-parental cells after 24 h. FIG.6C shows 100 nM pHrodo Red-HLA-G lysosomal uptake mediated by 100 nM antibody-based constructs in CHO-hACKR4 cells. FIG.6D shows 48 h ACKR4-specific degradation of 10 nM HLA-G by 10 nM antibody-based constructs in CHO cells.

[0031] FIG.7A shows 50 nM DL650-TNF-α cellular uptake mediated by 50 nM antibody- based constructs in CHO-hACKR4 cells. FIG. 7B shows amount of DL650 signal from supernatant in CHO-hACKR4 and CHO-parental cells after 1 h. FIG. 7C shows 20 nM pHrodo Red-TNF-α lysosomal uptake mediated by 100 nM antibody construct in CHO-hACKR4 and CHO-parental cells. FIG.7D shows 24 hACKR4-specific degradation of 10 nM TNF-α by 50 nM antibody-based constructs in CHO cells.

[0032] FIG.8A shows time-dependent membrane HER2 degradation by 100 nM antibody construct in SUIT2 WT cells. FIG.8B shows dose-dependent membrane HER2 degradation by an antibody construct at 69 h in SUIT2 WT cells. FIG.8C shows 24 h membrane HER2 degradation by 10 nM antibody-based constructs in SUIT2 WT cells. FIG. 8D shows representative flow cytometry histogram in AsPC-1 WT cells.1107368.00143

[0033] FIGS. 9A-9D show in vivo detection of 50 ug of antibody constructs in mouse serum of huACKR4 KI / muACKR4 KO mice (HO) and muACKR4 wild type mice (WT) after 14 days.

[0034] FIG.10 shows in vivo degradation of 20 ug (1413.2 nM) soluble HER2 by 100 ug (2534.2 nM) antibody construct in huACKR4 KI / muACKR4 KO mice (HO) and muACKR4 wild type mice (WT) after four days.

[0035] FIG. 11A shows percentage of DL650 signal remaining in serum of huACKR4 KI / muACKR4 KO mice (HO) relative to muACKR4 wild type mice (WT) after three days. FIG. 11B shows staining of DL650-HACKR or DL650-HER2 in ACKR4 expressing tissues (lymph node, spleen, small intestine, and colon) in HO mice three days after intravenous delivery. White arrows indicate areas of positive signal for DL650.

[0036] FIG. 12 shows in vivo detection of 100 ug (2537.2 nM) of antibody construct in mouse serum of huACKR4 KI / muACKR4 KO mice (HO) and muACKR4 wild type mice (WT) after eight days.

[0037] FIG. 13A shows 24 h degradation of 10 nM HER2 by 10 nM antibody-based constructs in MC38-hACKR4 and MC38-parental cells. FIG.13B shows in vivo degradation of 20 ug (1413.2 nM) soluble HER2 by 100 ug (2537.2 nM) antibody construct in huACKR4 KI / muACKR4 KO mice (HO) and muACKR4 wild type mice (WT) after eight days. DETAILED DESCRIPTION

[0038] Provided herein are bispecific binding constructs with binding specificity for ACKR4 and another antigen. In particular, heteromultimeric antibodies e.g., full length antibodies or antigen binding fragments thereof, that specifically bind to ACKR4 and another antigen, such as HER2, TNF-α, or HLA-G, are provided. Compositions comprising such antibodies, methods for producing and purifying such antibodies, and their use in diagnostics and therapeutics are also provided. 1. Definitions

[0039] Unless otherwise defined, all terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference and the inclusion of such1107368.00143 definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0040] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0041] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value.

[0042] The term “combinations thereof” includes every possible combination of elements to which the term refers.

[0043] The term “Atypical chemokine receptor 4” or “ACKR4” means a receptor for C-C type chemokines having the amino acid sequence set forth an amino acid in SEQ ID NO: 147.

[0044] Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human ACKR4 that are naturally expressed by cells, or that are expressed by cells transfected with an ACKR4 gene.

[0045] The terms “HLA-G,” “MHC-G,” and “major histocompatibility complex, class I, G” as well as any terms known to one skilled in the art are used interchangeably herein, means a protein having amino acid sequence set forth in SEQ ID NO: 575. HLA-G belongs to the HLA class I heavy chain paralogues. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human HLA-G that are naturally expressed by cells, or that are expressed by cells transfected with an HLA-G gene.

[0046] As used herein, “human epidermal growth factor receptor 2” or “HER2” is an 185kDa transmembrane glycoprotein that is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinase receptors having the amino acid sequence set forth an amino1107368.00143 acid in SEQ ID NO: 231. HER2 is protein encoded by the ERBB2 gene. Amplification or overexpression of HER2 has been shown to play an important role in the development of certain breast cancer.

[0047] Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human HER2 that are naturally expressed by cells, or that are expressed by cells transfected with an HER2 gene.

[0048] As used herein, “tumor necrosis factor alpha” or TNF-α is a 17 kDa protein consisting of 157 amino acids having the amino acid sequence set forth in SEQ ID NO: 650. TNF-α is a cytokine within the tumor necrosis factor superfamily. TNF-α is secreted by activated macrophages and monocytes and regulates growth and differentiation of tumor and normal cells.

[0049] Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human TNF-α that are naturally expressed by cells, or that are expressed by cells transfected with a TNF-α gene.

[0050] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, CH1, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0051] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments and antigen binding proteins. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VLdimer. For example, an “ACKR4 antibody,” “anti-ACKR4 antibody,” “ACKR4 Ab,” “ACKR4-specific antibody,” or “anti-ACKR4 Ab” is an antibody, as1107368.00143 described herein, which binds specifically to the antigen ACKR4.

[0052] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0053] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0054] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and µ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0055] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0056] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0057] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat / Chothia numbering scheme. Where the residues encompassed1107368.00143 by these two numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia. Table 1. Residues in CDRs according to Kabat and Chothia numbering schemes. CDR Kabat Chothia L1 L24-L34 L24-L34 L2 L50-L56 L50-L56 L3 L89-L97 L89-L97 H1 (Kabat Numbering)H31-H35BH26-H32 or H34*H1 (Chothia Numbering) H31-H35 H26-H32 H2 H50-H65 H52-H56 H3 H95-H102 H95-H102 * The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0058] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0059] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab′)2fragments, Fab′ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0060] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0061] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full-length antibody.

[0062] “F(ab′)2” fragments contain two Fab′ fragments joined, near the hinge region, by disulfide bonds. F(ab′)2fragments may be generated, for example, by pepsin digestion of an intact antibody. The F(ab′) fragments can be dissociated, for example, by treatment with ß- mercaptoethanol.1107368.00143

[0063] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp.269-315). Springer- Verlag, New York, incorporated by reference in its entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VHor VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used.

[0064] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0065] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0066] The term “bispecific antigen binding construct” or “bispecific antibody” or any related term known or used by one skilled in the art describes a type of immunoglobulin that can bind at least two different antigens.

[0067] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The1107368.00143 donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0068] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0069] An “isolated antibody” is one that has been separated and / or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody's natural environment is not present. In some embodiments, an isolated antibody is prepared by at least one purification step.

[0070] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight of an antibody, the remainder of the weight comprising the weight of other solutes dissolved in the solvent.

[0071] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an1107368.00143 antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore®instrument, or using bio-layer interferometry technology, such as an Octet®instrument.

[0072] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0073] The term “kd” (sec−1), as used herein, refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the koff value.

[0074] The term “ka” (M−1×sec−1), as used herein, refers to the association rate constant of a particular antibody-antigen interaction. This value is also referred to as the konvalue.

[0075] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD= kd / ka.

[0076] The term “KA” (M−1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0077] An “affinity matured” antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s). In one embodiment, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in the art. For example,1107368.00143 Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and / or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is incorporated by reference in its entirety.

[0078] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to an antigen (e.g., ACKR4). In one exemplary assay, ACKR4 is coated on a plate and allowed to bind a first antibody, after which a second, labeled antibody is added. If the presence of the first antibody reduces binding of the second antibody, then the antibodies compete. The term “competes with” also includes combinations of antibodies where one antibody reduces binding of another antibody, but where no competition is observed when the antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit binding of each other, regardless of the order in which they are added. In some embodiments, one antibody reduces binding of another antibody to its antigen by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0079] The term “epitope” means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to ACKR4 variants with different point-mutations.

[0080] Percent “identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes1107368.00143 of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0081] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of one or more amino acids with one or more chemically or functionally similar amino acids. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” By way of example, the following groups of amino acids are considered conservative substitutions for one another. Acidic Residues D and E Basic Residues K, R, and H Hydrophilic Uncharged Residues S, T, N, and Q Aliphatic Uncharged Residues G, A, V, L, and I Non-polar Uncharged Residues C, M, and P Aromatic Residues F, Y, and W Alcohol Group-Containing Residues S and T Aliphatic Residues I, L, V, and M Cycloalkenyl-associated Residues F, H, W, and Y Hydrophobic Residues A, C, F, G, H, I, L, M, V, W, and Y Negatively Charged Residues D and E Polar Residues C, D, E, H, K, N, Q, R, S, and T Positively Charged Residues H, K, and R Small Residues A, C, D, G, N, P, S, T, and V Very Small Residues A, G, and S Residues Involved in Turn Formation A, C, D, E, G, H, K, N, Q, R, S, P, and T Flexible Residues Q, T, K, S, G, P, D, E, and R Group 1 A, S, and T1107368.00143 Group A A and G Group B D and EStructures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.”

[0082] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0083] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.

[0084] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder.

[0085] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses,1107368.00143 camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and / or an infection that can be treated with an antibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and / or an acute infection and chronic infection.

[0086] A first aspect provides a bispecific antigen binding construct comprising a binding domain capable of binding to ACKR4 and an additional binding domain capable of binding to a second target. ACKR4 has been shown to bind dendritic cell and T cell-activated chemokines including CXCL13, CCL19, CCL20, CCL21, CCL22, and CCL25. ACKR4 has also been shown to act as a chemokine “scavenger”, regulating the concentration of chemokines by internalizing and degrading bound chemokines through lysosomal degradation.

[0087] In some embodiments, the binding domain capable of binding to ACKR4 comprises a light chain. In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain.

[0088] In some embodiments, the binding domain capable of binding to ACKR4 comprises a heavy chain. In some embodiments, the heavy chain is an IgA. In some embodiments, the heavy chain is an IgD. In some embodiments, the heavy chain is an IgE. In some embodiments, the heavy chain is an IgG. In some embodiments, the heavy chain is an IgM. In some embodiments, the heavy chain is an IgG1. In some embodiments, the heavy chain is an IgG2. In some embodiments, the heavy chain is an IgG3. In some embodiments, the heavy chain is an IgG4. In some embodiments, the heavy chain is an IgA1. In some embodiments, the heavy chain is an IgA2.

[0089] In some embodiments, the binding domain is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is a F(ab')2 fragment.

[0090] In some embodiments, the antibody fragment is a Fab' fragment. In some embodiments, the antibody fragment is an scFv (sFv) fragment. In some embodiments, the antibody fragment is an scFv-Fc fragment. In some embodiments, the antibody fragment is a minibody. In some embodiments, the antibody fragment is a single domain antibody.

[0091] In some embodiments, the binding domain is a chimeric antibody. In some1107368.00143 embodiments, the binding domain is a humanized antibody. In some embodiments, the binding domain is a human antibody.

[0092] In some embodiments, the binding domain is an affinity matured antibody. In some embodiments, the binding domain is an affinity matured antibody derived from an illustrative sequence provided in this disclosure. 2. Binding Domains Capable of Binding to ACKR4

[0093] In some embodiments, ACKR4 comprises or consists of a protein having an amino acid sequence set forth in SEQ ID NO: 147. VHSequences Comprising Illustrative CDRs

[0094] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof. VHSequences Comprising Illustrative Kabat CDRs

[0095] In some embodiments, the binding domain capable of binding to an ACKR4 comprises a VHsequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof. Kabat CDR-H3

[0096] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 47. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 48.1107368.00143

[0097] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. Kabat CDR-H2

[0098] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23-25. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 23. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 24. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 25. Kabat CDR-H1

[0099] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-5. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 1. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 2. In some embodiments, the binding domain capable of binding to an ACKR4 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 3. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting1107368.00143 of, or consisting essentially of SEQ ID NO: 4. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 5. Kabat CDR-H3+Kabat CDR-H2

[0100] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23- 25. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-94. Kabat CDR-H3+Kabat CDR-H1

[0101] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48 and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1- 5. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative VHsequence selected from SEQ ID NOS: 89-94. Kabat CDR-H1+Kabat CDR-H2

[0102] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-5 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23- 25. In some embodiments, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 89-94. Kabat CDR-H1+Kabat CDR-H2+Kabat CDR-H31107368.00143

[0103] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 1-5, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 23-25, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48. In some embodiments, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1, Kabat CDR- H2, and Kabat CDR-H3 are all from a single illustrative VHsequence selected from SEQ ID NOS: 89-94.

[0104] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR- H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a Kabat CDR- H2 sequence comprising SEQ ID NO: 24, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 46. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR- H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 47. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR- H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR- H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR- H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45. Variants of VHSequences Comprising Illustrative Kabat CDRs

[0105] In some embodiments, the VH sequences provided herein comprise a variant of an1107368.00143 illustrative Kabat CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0106] In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0107] In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0108] In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H1 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VHSequences Comprising Illustrative Chothia CDRs

[0109] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof. Chothia CDR-H31107368.00143

[0110] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 46. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 47. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 48. Chothia CDR-H2

[0111] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34-36. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 34. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 35. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 36. Chothia CDR-H1

[0112] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-16. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 12. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of1107368.00143 SEQ ID NO: 13. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 14. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 15. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 16. Chothia CDR-H3+Chothia CDR-H2

[0113] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34- 36. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-94. Chothia CDR-H3+Chothia CDR-H1

[0114] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48 and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12- 16. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-94. Chothia CDR-H1+Chothia CDR-H2

[0115] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-16 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34- 36. In some embodiments, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are1107368.00143 both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 89-94. Chothia CDR-H1+Chothia CDR-H2+Chothia CDR-H3

[0116] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 12-16, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 34- 36, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 45-48. In some embodiments, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VHsequence selected from SEQ ID NOS: 89-94.

[0117] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 35, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 46. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 47. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 15, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia1107368.00143 CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45. Variants of VHSequences Comprising Illustrative Chothia CDRs

[0118] In some embodiments, the VH sequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0119] In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0120] In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0121] In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid1107368.00143 substitutions. VHSequences

[0122] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 89-94. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 91. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 92. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 93. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 94. Variants of VHSequences

[0123] In some embodiments, the VHsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in this disclosure.

[0124] In some embodiments, the VHsequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VH sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VHsequences provided in this disclosure.

[0125] In some embodiments, the VH sequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences Comprising Illustrative CDRs

[0126] In some embodiments, the binding domain capable of binding to ACKR4 comprises1107368.00143 a VL sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof. CDR-L3

[0127] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-81. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 77. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 78. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 79. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 80. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81. CDR-L2

[0128] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-70. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 67. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 68. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 69. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 70.1107368.00143 CDR-L1

[0129] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 55-59. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 55. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 56. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 57. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 58. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 59. CDR-L3+CDR-L2

[0130] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-81 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-70. In some embodiments, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L2 are both from a single illustrative VLsequence selected from SEQ ID NOS: 101-106. CDR-L3+CDR-L1

[0131] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-81 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 55-59. In some embodiments, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L1 are both from a single illustrative VL sequence selected from SEQ ID NOS: 101-106.1107368.00143 CDR-L1+CDR-L2

[0132] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 55-59 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-70. In some embodiments, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L1 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 101-106. CDR-L1+CDR-L2+CDR-L3

[0133] In some embodiments, the binding domain capable of binding to ACKR4 comprises SEQ ID NOS: 55-59, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 67-70, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 77-81. In some embodiments, the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L1, CDR- L2, and CDR-L3 are all from a single illustrative VLsequence selected from SEQ ID NOS: 101- 106.

[0134] In some embodiments, the binding domain capable of binding to an ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR- L2 sequence comprising SEQ ID NO: 67, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68, and a CDR-L3 sequence SEQ ID NO: 78. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence SEQ ID NO: 79. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 58, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 80. In some embodiments, the binding1107368.00143 domain capable of binding to ACKR4 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 81. Variants of VLSequences Comprising Illustrative CDR-Ls

[0135] In some embodiments, the VL sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and / or CDR-L1 sequence provided in this disclosure.

[0136] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0137] In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0138] In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences1107368.00143

[0139] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 101-106. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 102. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 103. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 104. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 105. In some embodiments, the binding domain capable of binding to ACKR4 comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 106. Variants of VLSequences

[0140] In some embodiments, the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VLsequence provided in this disclosure.

[0141] In some embodiments, the VLsequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0142] In some embodiments, the VL sequence comprises, consists of, or consists essentially of any of the illustrative VLsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. Pairs CDR-H3-CDR-L3 Pairs

[0143] In some embodiments, the binding domain capable of binding to ACKR4 comprises1107368.00143 a CDR-H3 sequence and a CDR-L3 sequence. In some embodiments, the CDR-H3 sequence is part of a VH and the CDR-L3 sequence is part of a VL.

[0144] In some embodiments, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 45-48, and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 77-81.

[0145] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 45 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-82. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 79. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 80. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 81.

[0146] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 46 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-82. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 79. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 80. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 81.

[0147] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 47 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-82. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 79. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 80. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 81.

[0148] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 48 and the CDR-L3 sequence is selected from SEQ ID NOS: 77-82. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 77. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 78. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 79. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 80. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 81. Variants of CDR-H3-CDR-L3 Pairs

[0149] In some embodiments, the CDR-H3 – CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and / or CDR-L1 sequence provided in this disclosure.

[0150] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence1107368.00143 having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0151] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VH-VLPairs

[0152] In some embodiments, the binding domain capable of binding to ACKR4 comprises a VHsequence and / or a VLsequence.

[0153] In some embodiments, the VH sequence is a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 89-94 and the VL sequence is a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 101-106.

[0154] In some embodiments, the VHsequence is SEQ ID NO: 89 and the VLsequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102. In some embodiments, the VL sequence is SEQ ID NO: 103. In some embodiments, the VLsequence is SEQ ID NO: 104. In some embodiments, the VL sequence is SEQ ID NO: 105. In some embodiments, the VL sequence is SEQ ID NO: 106.

[0155] In some embodiments, the VHsequence is SEQ ID NO: 90 and the VLsequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102. In some embodiments, the VL sequence is SEQ ID NO: 103. In some embodiments, the VLsequence is SEQ ID NO: 104. In some embodiments, the VLsequence is SEQ ID NO: 105. In some embodiments, the VLsequence is SEQ ID NO: 106.1107368.00143

[0156] In some embodiments, the VH sequence is SEQ ID NO: 91 and the VL sequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VLsequence is SEQ ID NO: 102. In some embodiments, the VLsequence is SEQ ID NO: 103. In some embodiments, the VL sequence is SEQ ID NO: 104. In some embodiments, the VL sequence is SEQ ID NO: 105. In some embodiments, the VL sequence is SEQ ID NO: 106.

[0157] In some embodiments, the VHsequence is SEQ ID NO: 92 and the VLsequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VLsequence is SEQ ID NO: 102. In some embodiments, the VLsequence is SEQ ID NO: 103. In some embodiments, the VLsequence is SEQ ID NO: 104. In some embodiments, the VL sequence is SEQ ID NO: 105. In some embodiments, the VL sequence is SEQ ID NO: 106.

[0158] In some embodiments, the VHsequence is SEQ ID NO: 93 and the VLsequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VL sequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102. In some embodiments, the VL sequence is SEQ ID NO: 103. In some embodiments, the VLsequence is SEQ ID NO: 104. In some embodiments, the VLsequence is SEQ ID NO: 105. In some embodiments, the VLsequence is SEQ ID NO: 106.

[0159] In some embodiments, the VHsequence is SEQ ID NO: 94 and the VLsequence is selected from SEQ ID NOS: 101-106. In some embodiments, the VLsequence is SEQ ID NO: 101. In some embodiments, the VL sequence is SEQ ID NO: 102. In some embodiments, the VL sequence is SEQ ID NO: 103. In some embodiments, the VLsequence is SEQ ID NO: 104. In some embodiments, the VLsequence is SEQ ID NO: 105. In some embodiments, the VLsequence is SEQ ID NO: 106. CDR-H1+CDR-H2+CDR-H3+CDR-L1+CDR-L2+CDR-L3

[0160] In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 1, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 67, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 2, a1107368.00143 Kabat CDR-H2 sequence comprising SEQ ID NO: 24, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 46 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68, and a CDR-L3 sequence SEQ ID NO: 78. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 47 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence SEQ ID NO: 79. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence SEQ ID NO: 79. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR- H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 58, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 80. In some embodiments, the antibody comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 81. In some embodiments, the antibody comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 4, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 81.

[0161] In some embodiments, the antibody comprises a VH sequence comprising a Chothia1107368.00143 CDR-H1 sequence comprising SEQ ID NO: 12, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR-L2 sequence comprising SEQ ID NO: 67, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 13, a Chothia CDR-H2 sequence comprising SEQ ID NO: 35, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 46 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 56, a CDR-L2 sequence comprising SEQ ID NO: 68, and a CDR-L3 sequence SEQ ID NO: 78. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR- H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 47 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence SEQ ID NO: 79. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 15, a Chothia CDR- H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 55, a CDR- L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 77. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48 and a VL sequence comprising a CDR- L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence SEQ ID NO: 79. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 15, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 58, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 80. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR- L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 81. In some embodiments, the antibody comprises a VH sequence1107368.00143 comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence SEQ ID NO: 81. Variants of VH-VLPairs

[0162] In some embodiments, the VH– VLpairs provided herein comprise a variant of an illustrative VHand / or VLsequence provided in this disclosure.

[0163] In some embodiments, the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VHsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.1% identity with any of the illustrative VH sequences provided in this disclosure.

[0164] In some embodiments, the VHsequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0165] In some embodiments, the VLsequence comprises, consists of, or consists essentially of a variant of an illustrative VLsequence provided in this disclosure. In some embodiments, the VL sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0166] In some embodiments, the VL sequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. HC + LC

[0167] In some embodiments, the binding domain capable of binding to ACKR4 comprises1107368.00143 or consists of one or more heavy chains consisting of an HC sequence and one or more light chains consisting of an LC sequence. In some embodiments, the binding domain capable of binding to ACKR4 comprises or consists of two identical heavy chains consisting of an HC sequence and two identical light chains consisting of an LC sequence.

[0168] In some embodiments, the HC sequence is an HC sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 113-120 and the LC sequence is an LC sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 128-133. In some embodiments, the HC sequence is an HC sequence consisting of a sequence selected from SEQ ID NOS: 113-120 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-133.

[0169] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 113 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-133. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0170] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 114 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0171] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 115 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.1107368.00143

[0172] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 116 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0173] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 117 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0174] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 118 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0175] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 119 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0176] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 120 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 128-134. In some embodiments, the LC sequence is SEQ ID NO: 128. In some1107368.00143 embodiments, the LC sequence is SEQ ID NO: 129. In some embodiments, the LC sequence is SEQ ID NO: 130. In some embodiments, the LC sequence is SEQ ID NO: 131. In some embodiments, the LC sequence is SEQ ID NO: 132. In some embodiments, the LC sequence is SEQ ID NO: 133.

[0177] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 113 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 128. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 114 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 129. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 115 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 130. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 116 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 131. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 117 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 130. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 118 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 132. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 119 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 133. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 124 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 133. 3. Binding Domains Capable of Binding to a Target Protein

[0178] In some embodiments, the additional binding domain is capable of binding to a second target. In some embodiments, the additional binding domain is capable of binding to a cytokine such as an interferon, an interleukin, a lymphokine, an MIP, a growth factor, a hormone, a complement factor, a neuropeptide, a capsid, a soluble receptor, an enzyme, or a tumor necrosis factor.

[0179] In some embodiments, the additional binding domain is capable of binding to an interferon. In some embodiments, the interferon comprises or consists of IFN-a and / or IFN-g.

[0180] In some embodiments, the additional binding domain is capable of binding to an interleukin. In some embodiments, the interleukin comprises or consists of IL1A, IL1B, IL2, IL4, IL5, IL6, IL8, IL9, IL10, IL12, IL13, IL15, IL17A, IL17C, IL17F, IL18, IL18BP, IL20, IL22,1107368.00143 IL23, such as IL23p19 or IL23p40, such as IL12p40, IL31, IL33, and / or IL36.

[0181] In some embodiments, the additional binding domain is capable of binding to a growth factor. In some embodiments, the growth factor comprises or consists of ANGPT1, ANGPT2, ANDPTL3, BDNF, EGF, EGFL7, FGF2, FGF23, GDF11, HBEGF, HGF, IGF1, IGF2, INHBA, INHBB, MSTN, NGF, NTF3, NTF4, PDGFB, PDGFD, PGF, TGFB1, TGFB2, TGFB3, VEGFA, VEGFB, VEGFC, VEGFD, CTGF, REG4, soluble FGL2, and / or CSF1.

[0182] In some embodiments, the additional binding domain is capable of binding to a soluble receptor. In some embodiments, the soluble receptor comprises or consists of IL6R, EGFR, TNFR1, TNFR2, ILT2, CD24, CD28, DC-HIL, LOX-1, DLL3, BCMA, MSLN, PSMA, EpCAM, OX40, IL13R, IL1RAP, VLA4, Toll-like receptors, TRPA1, LPAM-1, and / or T-cell receptor.

[0183] In some embodiments, the additional binding domain is capable of binding to a neuropeptide. In some embodiments, the neuropeptide comprises or consists of ADM, AGT, CALCA_B, GAST and / or INS.

[0184] In some embodiments, the additional binding domain is capable of binding to an enzyme. In some embodiments, the enzyme comprises or consists of CD39, CD73, PCSK9 and / or Cathepsin S.

[0185] In some embodiments, the additional binding domain is capable of binding to a signaling molecule. In some embodiments, the signaling molecule comprises or consists of APOB, CGB3, DLL4, HAMP, HTT, RSPO3, sCLU, SEMA4D, SOST, and / or VWF.

[0186] In some embodiments, the additional binding domain is capable of binding to a tumor necrosis factor. In some embodiments, the tumor necrosis factor comprises or consists of FASLG, LTA, LTB, TNF, TNFSF11, TNFSF13, TNFSF13B, TNFSF14, TNFS4, TL1A, and / or VEGI.

[0187] In some embodiments, the additional binding domain is capable of binding to a IgE Fc-region, a deamidated gliadin peptide, a tissue transglutaminase, C1q, C3, C4b, C5, CTHRC1, an immune complex, an autoantibody, antimiR-103, antimiR-107, antimiR-122, antimiR-155, antimiR-21, antimiR-92a, CSF2, MIF, S1P, and / or TSLP.

[0188] In some embodiments, the additional binding domain is capable of binding to one or more of the following:1107368.00143 Target Type EGFR Membrane receptor TNFR1 Membrane receptor ILT2 Membrane receptor CD24 Membrane receptor DC-HIL Membrane receptor LOX-1 Membrane receptor DLL3 Membrane receptor BCMA Membrane receptor MSLN Membrane receptor PSMA Membrane receptor EpCAM Membrane receptor OX40 Membrane receptor CD28 Membrane receptor IL13R Membrane receptor VLA4 Membrane receptor TNFR2 Membrane receptor Toll-like receptors Membrane receptor IL1RAP Membrane receptor TRPA1 Membrane receptor Specific TCRs Membrane receptor IL6R Membrane receptor Integrin a4b7 Membrane receptor ADM Neuropeptides AGT Neuropeptides CALCA_B Neuropeptides INS Neuropeptides GAST Neuropeptides CALCA_B Neuropeptides GNRH1 Neuropeptides1107368.00143 ANGPT1 Growth factors ANGPT2 Growth factors ANGPTL3 Growth factors BDNF Growth factors CTGF Growth factors EGF Growth factors EGFL7 Growth factors FGF2 Growth factors FGF23 Growth factors GDF11 Growth factors HBEGF Growth factors HGF Growth factors IGF1 Growth factors IGF2 Growth factors INHBA Growth factors INHBB Growth factors MSTN Growth factors NGF Growth factors NTF3 Growth factors NTF4 Growth factors PDGFB Growth factors PDGFD Growth factors PGF Growth factors TGFB1 Growth factors TGFB2 Growth factors TGFB3 Growth factors VEGFA Growth factors VEGFB Growth factors VEGFC Growth factors VEGFD Growth factors1107368.00143 REG4 Growth factors Soluble FGL2 Growth factors CSF1 Cytokine CSF2 Cytokine FASLG Cytokine IFN-a Cytokine (Interferons) IFN-g Cytokine (Interferons) IL10 Cytokine (Interleukins) IL13 Cytokine (Interleukins) IL15 Cytokine (Interleukins) IL17A Cytokine (Interleukins) IL17C Cytokine (Interleukins) IL17F Cytokine (Interleukins) IL18 Cytokine (Interleukins) IL18BP Cytokine (Interleukins) IL1A Cytokine (Interleukins) IL1B Cytokine (Interleukins) IL20 Cytokine (Interleukins) IL22 Cytokine (Interleukins) IL23p19 Cytokine (Interleukins) IL31 Cytokine (Interleukins) IL33 Cytokine (Interleukins) IL2 Cytokine (Interleukins) IL4 Cytokine (Interleukins) IL5 Cytokine (Interleukins) IL6 Cytokine (Interleukins) IL8 Cytokine (Interleukins) IL9 Cytokine (Interleukins) IL36 Cytokine (Interleukins) IL1B Cytokine (Interleukins)1107368.00143 p40 subunit of both IL12 + IL23 Cytokine (Interleukins) LTA Cytokine LTB Cytokine MIF Cytokine TNF Cytokine TNFSF11 Cytokine TNFSF13 Cytokine TNFSF13B Cytokine TNFSF14 Cytokine TNFSF4 Cytokine TSLP Cytokine VEGI Cytokine TL1A Cytokine C1q Inflammatory mediator C3 Inflammatory mediator C4b Inflammatory mediator C5 Inflammatory mediator APOB Signalling CGB3 Signalling DLL4 Signalling HAMP Signalling HTT Signalling RSPO3 Signalling sCLU Signalling SEMA4D Signalling SOST Signalling VWF Signalling AntimiR-103 / AntimiR-107 Other AntimiR-122 Other AntimiR-155 Other1107368.00143 AntimiR-21 Other AntimiR-92a Other IgE Fc-region Other S1P Other Autoantibodies Other Deamidated gliadin peptides Other Tissue transglutaminase Other PCSK9 Other CTHRC1 Other Immune complexes Other Cathepsin S Other CD73 Other CD39 Other

[0189] Table 2: List of Second Binding Targets

[0190] In some embodiments, the additional binding domain is capable of binding to a HER2 polypeptide. In some embodiments, the additional binding domain is capable of binding to an HLA-G polypeptide. In some embodiments, the additional binding domain is capable of binding to a TNF-α polypeptide. Binding Domains Capable of Binding to HER2

[0191] In some embodiments, the second target comprises a HER2 polypeptide. In some embodiments, the HER2 comprises or consists of an amino acid sequence set forth in SEQ ID NO: 231.

[0192] HER2 is a 185kDa transmembrane glycoprotein that is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinase receptors. HER2 is protein encoded by the ERBB2 gene. Amplification or overexpression of HER2 has been shown to play an important role in the development of certain breast cancer. HER2 Sequences VHSequences Comprising Illustrative CDRs

[0193] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure,1107368.00143 and variants thereof. VHSequences Comprising Illustrative Kabat CDRs

[0194] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof. Kabat CDR-H3

[0195] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 179. Kabat CDR-H2

[0196] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 171-174. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 171. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 172. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 173. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR- H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 174. Kabat CDR-H1

[0197] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or1107368.00143 consisting essentially of a sequence selected from SEQ ID NOS: 160-161. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 160. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 161. Kabat CDR-H3+Kabat CDR-H2

[0198] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179, and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 171-174. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 199-202. Kabat CDR-H3+Kabat CDR-H1

[0199] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179 and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 160-161. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 199-202. Kabat CDR-H1+Kabat CDR-H2

[0200] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 160-161 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 171-174. In some embodiments, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example,1107368.00143 in some embodiments, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 199-202. Kabat CDR-H1+Kabat CDR-H2+Kabat CDR-H3

[0201] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 160-161, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 171-174, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179. In some embodiments, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOS: 199-202.

[0202] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding toHER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 161, a Kabat CDR-H2 sequence comprising SEQ ID NO: 173, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 179. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR- H1 sequence comprising SEQ ID NO: 161, a Kabat CDR-H2 sequence comprising SEQ ID NO: 174, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 179. Variants of VHSequences Comprising Illustrative Kabat CDRs

[0203] In some embodiments, the VH sequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0204] In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this1107368.00143 disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0205] In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0206] In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H1 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VHSequences Comprising Illustrative Chothia CDRs

[0207] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof. Chothia CDR-H3

[0208] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179. In some embodiments,1107368.00143 the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding toHER2 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 179. Chothia CDR-H2

[0209] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 165-167. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 165. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 166. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 167. Chothia CDR-H1

[0210] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 155-156. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 155. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 156. Chothia CDR-H3+Chothia CDR-H2

[0211] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179, and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 165-167. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H21107368.00143 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 199-202. Chothia CDR-H3+Chothia CDR-H1

[0212] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179 and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 155-156. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 199-202. Chothia CDR-H1+Chothia CDR-H2

[0213] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 155-156 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 165-167. In some embodiments, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1 and Chothia CDR-H2 are both from a single illustrative VH sequence selected from SEQ ID NOS: 199-202. Chothia CDR-H1+Chothia CDR-H2+Chothia CDR-H3

[0214] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 155-156, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 165-167, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 178-179. In some embodiments, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative1107368.00143 VH sequence selected from SEQ ID NOS: 199-202.

[0215] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 178. In some embodiments, the additional binding domain capable of binding toHER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 156, a Chothia CDR-H2 sequence comprising SEQ ID NO: 167, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 179. Variants of VHSequences Comprising Illustrative Chothia CDRs

[0216] In some embodiments, the VHsequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0217] In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0218] In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid1107368.00143 substitutions.

[0219] In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VHSequences

[0220] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 199-202. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 199. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 200. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 201. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 202.

[0221] In some embodiments, the binding domain capable of binding to HER2 comprises three heavy chain CDRs each comprising, consisting of, or consisting essentially of a CDR sequence of a VH having the sequence set forth in one of SEQ ID NOS: 199-202. Variants of VHSequences

[0222] In some embodiments, the VHsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VHsequence provided in this disclosure.

[0223] In some embodiments, the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VHsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative1107368.00143 VH sequences provided in this disclosure.

[0224] In some embodiments, the VH sequence comprises, consists of, or consists essentially of any of the illustrative VHsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences Comprising Illustrative CDRs

[0225] In some embodiments, the additional binding domain capable of binding toHER2 comprises a VLsequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof. CDR-L3

[0226] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 194-195. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 194. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 195. CDR-L2

[0227] In some embodiments, the additional binding domain capable of binding toHER2 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 188-190. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 188. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 189. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or1107368.00143 consisting essentially of SEQ ID NO: 190. CDR-L1

[0228] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 183-184. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 183. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 184. CDR-L3+CDR-L2

[0229] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 194-195 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 188- 190. In some embodiments, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 206-209. CDR-L3+CDR-L1

[0230] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 194-195 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 183- 184. In some embodiments, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative VLsequence provided in this disclosure. For example, in some embodiments, the CDR-L3 and CDR-L1 are both from a single illustrative VLsequence selected from SEQ ID NOS: 206-209. CDR-L1+CDR-L2

[0231] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting1107368.00143 essentially of a sequence selected from SEQ ID NOS: 183-184 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 188- 190. In some embodiments, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L1 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 206-209. CDR-L1+CDR-L2+CDR-L3

[0232] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 183-184, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 188-190, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 194-195. In some embodiments, the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VLsequence selected from SEQ ID NOS: 206-209.

[0233] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR- L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 189, and a CDR-L3 sequence SEQ ID NO: 195. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 190, and a CDR-L3 sequence SEQ ID NO: 195. Variants of VLSequences Comprising Illustrative CDR-Ls

[0234] In some embodiments, the VLsequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and / or CDR-L1 sequence provided in this disclosure.

[0235] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence1107368.00143 having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0236] In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0237] In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences

[0238] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 206-209. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 206. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 207. In some embodiments, the additional binding domain capable of binding to HER2 comprises a VLsequence comprising, consisting of, or consisting essentially of SEQ ID NO: 208. In some embodiments, the additional binding domain capable of binding to HER21107368.00143 comprises a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 209.

[0239] In some embodiments, the binding domain capable of binding to HER2 comprises three light chain CDRs, each comprising, consisting of, or consisting essentially of a CDR sequence of a VL having the sequence set forth in one of SEQ ID NO: 206-209. Variants of VLSequences

[0240] In some embodiments, the VLsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VLsequence provided in this disclosure.

[0241] In some embodiments, the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VLsequence provided in this disclosure. In some embodiments, the VLsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0242] In some embodiments, the VLsequence comprises, consists of, or consists essentially of any of the illustrative VL sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. Pairs CDR-H3-CDR-L3 Pairs

[0243] In some embodiments, the additional binding domain capable of binding to HER2 comprises a CDR-H3 sequence and a CDR-L3 sequence. In some embodiments, the CDR-H3 sequence is part of a VHand the CDR-L3 sequence is part of a VL.

[0244] In some embodiments, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 178-179, and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 194-195.

[0245] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 178 and the CDR-L3 sequence is selected from SEQ ID NOS: 194-195. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 194. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 195.

[0246] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 179 and the CDR-L3 sequence is selected from SEQ ID NOS: 194-195. In some embodiments, the CDR-L3 sequence1107368.00143 is SEQ ID NO: 194. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 195. Variants of CDR-H3-CDR-L3 Pairs

[0247] In some embodiments, the CDR-H3-CDR-L3 pairs provided herein comprise a variant of an illustrative CDR-H3 and / or CDR-L1 sequence provided in this disclosure.

[0248] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0249] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VH-VLPairs

[0250] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence and a VLsequence.

[0251] In some embodiments, the VH sequence is a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 199-202 and the VL sequence is a VL sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 206-209.

[0252] In some embodiments, the VH sequence is SEQ ID NO: 199 and the VL sequence is selected from SEQ ID NOS: 206-209. In some embodiments, the VL sequence is SEQ ID NO: 206. In some embodiments, the VLsequence is SEQ ID NO: 207. In some embodiments, the VLsequence is SEQ ID NO: 208. In some embodiments, the VLsequence is SEQ ID NO: 209.

[0253] In some embodiments, the VH sequence is SEQ ID NO: 200 and the VL sequence1107368.00143 is selected from SEQ ID NOS: 206-209. In some embodiments, the VL sequence is SEQ ID NO: 206. In some embodiments, the VL sequence is SEQ ID NO: 207. In some embodiments, the VLsequence is SEQ ID NO: 208. In some embodiments, the VLsequence is SEQ ID NO: 209.

[0254] In some embodiments, the VH sequence is SEQ ID NO: 201 and the VL sequence is selected from SEQ ID NOS: 206-209. In some embodiments, the VL sequence is SEQ ID NO: 206. In some embodiments, the VLsequence is SEQ ID NO: 207. In some embodiments, the VLsequence is SEQ ID NO: 208. In some embodiments, the VLsequence is SEQ ID NO: 209.

[0255] In some embodiments, the VH sequence is SEQ ID NO: 202 and the VL sequence is selected from SEQ ID NOS: 206-209. In some embodiments, the VLsequence is SEQ ID NO: 206. In some embodiments, the VLsequence is SEQ ID NO: 207. In some embodiments, the VL sequence is SEQ ID NO: 208. In some embodiments, the VL sequence is SEQ ID NO: 209. CDR-H1+CDR-H2+CDR-H3+CDR-L1+CDR-L2+CDR-L3

[0256] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194.

[0257] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194.

[0258] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 161, a Kabat CDR-H2 sequence comprising SEQ ID NO: 173, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 179 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 189, and a CDR-L3 sequence SEQ ID NO: 195.1107368.00143

[0259] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 161, a Kabat CDR-H2 sequence comprising SEQ ID NO: 174, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 179 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 190, and a CDR-L3 sequence SEQ ID NO: 195.

[0260] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194.

[0261] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194.

[0262] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 156, a Chothia CDR-H2 sequence comprising SEQ ID NO: 167, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 179 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 189, and a CDR-L3 sequence SEQ ID NO: 195.

[0263] In some embodiments, the additional binding domain capable of binding to HER2 comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 156, a Chothia CDR-H2 sequence comprising SEQ ID NO: 167, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 179 and a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 184, a CDR-L2 sequence comprising SEQ ID NO: 190, and a CDR-L3 sequence SEQ ID NO: 195. Variants of VH-VLPairs1107368.00143

[0264] In some embodiments, the VH-VL pairs provided herein comprise a variant of an illustrative VH and / or VL sequence provided in this disclosure.

[0265] In some embodiments, the VHsequence comprises, consists of, or consists essentially of a variant of an illustrative VH sequence provided in this disclosure. In some embodiments, the VH sequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.1% identity with any of the illustrative VHsequences provided in this disclosure.

[0266] In some embodiments, the VH sequence comprises, consists of, or consists essentially of any of the illustrative VHsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0267] In some embodiments, the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VLsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0268] In some embodiments, the VL sequence comprises, consists of, or consists essentially of any of the illustrative VLsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. HC + LC

[0269] In some embodiments, the binding domain capable of binding to HER2 comprises or consists of one or more heavy chains consisting of an HC sequence and one or more light chains consisting of an LC sequence. In some embodiments, the binding domain capable of binding to an HER2 comprises or consists of two identical heavy chains consisting of an HC sequence and two identical light chains consisting of an LC sequence.1107368.00143

[0270] In some embodiments, the HC sequence is an HC sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 213-217 and the LC sequence is an LC sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 221-224 In some embodiments, the HC sequence is an HC sequence consisting of a sequence selected from SEQ ID NOS: 213-217 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224.

[0271] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 213 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224. In some embodiments, the LC sequence is SEQ ID NO: 221. In some embodiments, the LC sequence is SEQ ID NO: 222. In some embodiments, the LC sequence is SEQ ID NO: 223. In some embodiments, the LC sequence is SEQ ID NO: 224.

[0272] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 214 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224. In some embodiments, the LC sequence is SEQ ID NO: 221. In some embodiments, the LC sequence is SEQ ID NO: 222. In some embodiments, the LC sequence is SEQ ID NO: 223. In some embodiments, the LC sequence is SEQ ID NO: 224.

[0273] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 215 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224. In some embodiments, the LC sequence is SEQ ID NO: 221. In some embodiments, the LC sequence is SEQ ID NO: 222. In some embodiments, the LC sequence is SEQ ID NO: 223. In some embodiments, the LC sequence is SEQ ID NO: 224.

[0274] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224. In some embodiments, the LC sequence is SEQ ID NO: 221. In some embodiments, the LC sequence is SEQ ID NO: 222. In some embodiments, the LC sequence is SEQ ID NO: 223. In some embodiments, the LC sequence is SEQ ID NO: 224.

[0275] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 217 and the LC sequence is an LC sequence consisting of a sequence selected from SEQ ID NOS: 221-224. In some embodiments, the LC sequence is SEQ ID NO: 221. In some embodiments, the LC sequence is SEQ ID NO: 222. In some embodiments, the LC sequence is SEQ ID NO: 223. In some embodiments, the LC sequence is SEQ ID NO: 224.1107368.00143

[0276] In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 213 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 221. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 214 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 221. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 215 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 222. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 216 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 223. In some embodiments, the HC sequence is an HC sequence consisting of SEQ ID NO: 217 and the LC sequence is an LC sequence consisting of sequence SEQ ID NO: 224. Bispecific Binding Constructs Capable of Binding to ACKR4 and HER2

[0277] In some embodiments, the bispecific binding construct comprises an anti-ACKR4 HC sequence linked on its C-terminus to the N-terminus of an anti-HER2 scFv sequence and an anti-ACKR4 LC, where the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 659-663, 668-669 and the anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 671-675.

[0278] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 659 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0279] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 660 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0280] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises1107368.00143 or consists of SEQ ID NO: 661 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0281] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 662 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0282] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 663 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0283] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 668 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0284] In some embodiments, the anti-ACKR4 HC-anti-HER2 scFv sequence comprises or consists of SEQ ID NO: 669 and the anti-ACKR4 LC comprises or consists of a sequence selected from SEQ ID NOS: 671-675. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 671. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 672. In1107368.00143 some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 673. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 674. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 675.

[0285] In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, the anti- HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, the anti-1107368.00143 HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0286] In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR- H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti- ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81. In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, , and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a1107368.00143 CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0287] In some embodiments, the bispecific binding construct comprises an anti-HER2 HC sequence linked on its C-terminus to the N-terminus of an anti-ACKR4 scFv sequence and an anti-HER2 LC, where the anti-HER2 HC-anti-ACKR4 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 677-678 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 682.

[0288] In some embodiments, the anti-HER2 HC-anti-ACKR4 scFv sequence comprises or consists of SEQ ID NO: 677 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 682.

[0289] In some embodiments, the anti-HER2 HC-anti-ACKR4 scFv sequence comprises or consists of SEQ ID NO: 678 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 682.

[0290] In some embodiments, the anti-HER2 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, the anti-ACKR4 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti-HER2 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-1107368.00143 H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, the anti-ACKR4 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79, and the anti- HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0291] In some embodiments, the anti-HER2 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti-HER2 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, the anti-ACKR4 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0292] In some embodiments, the bispecific binding construct comprises an anti-HER2 HC sequence linked on its C-terminus to the N-terminus of a stabilized anti-ACKR4 scFv sequence and an anti-HER2 LC, where the anti-HER2 HC-stabilized anti-ACKR4 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 686-687 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 691.

[0293] In some embodiments, the anti-HER2 HC-stabilized anti-ACKR4 scFv sequence1107368.00143 comprises or consists of SEQ ID NO: 686 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 691.

[0294] In some embodiments, the anti-HER2 HC-stabilized anti-ACKR4 scFv sequence comprises or consists of SEQ ID NO: 687 and the anti-HER2 LC sequence comprises or consists of SEQ ID NO: 691.

[0295] In some embodiments, the anti-HER2 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, the stabilized anti-ACKR4 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti-HER2 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR- H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, the stabilized anti-ACKR4 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, a Kabat CDR- H3 sequence comprising SEQ ID NO: 48, a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0296] In some embodiments, the anti-HER2 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, the stabilized anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence1107368.00143 comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti-HER2 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 178, the stabilized anti-ACKR4 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79, and the anti-HER2 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0297] In some embodiments, the bispecific binding construct comprises or consists of an anti-ACKR4 VH sequence linked to a hIgG1 AAA Fc containing a ‘hole’ mutation in the CH3 domain, an anti-HER2 scFv sequence linked to a hIgG1 AAA Fc containing a ‘knob’ mutation in the CH3 domain, and an anti-ACKR4 LC sequence. In some embodiments, the anti-ACKR4 VH sequence linked to a hIgG1 AAA Fc containing a ‘hole’ mutation in the CH3 domain comprises or consists of SEQ ID NO: 697. In some embodiments, anti-HER2 scFv sequence linked to a hIgG1 AAA Fc containing a ‘knob’ mutation in the CH3 domain comprises or consists of SEQ ID NO: 696. In some embodiments, the anti-ACKR4 LC sequence comprises or consists of SEQ ID NO: 701.

[0298] In some embodiments, the anti-ACKR4 VH comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, a Kabat CDR- H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv sequence comprises a Kabat CDR- H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0299] In some embodiments, the anti-ACKR4 VH comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv sequence1107368.00143 comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0300] In some embodiments, the bispecific binding construct comprises an anti-ACKR4 HC sequence and an anti-HER2 scFv sequence linked on its C-terminus to the N-terminus of an anti-ACKR4 LC sequence, where the anti-ACKR4 HC sequence comprises or consists of a sequence selected from SEQ ID NOS: 705-708 and the anti-HER2 scFv-anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 712-715.

[0301] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 705 and the anti-HER2 scFv-anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 712-715. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 712. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 713. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 714. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 715.

[0302] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 706 and the anti-HER2 scFv-anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 712-715. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 712. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 713. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 714. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 715.

[0303] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 707 and the anti-HER2 scFv-anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 712-715. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 712. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 713. In some embodiments, the anti-HER2 scFv-anti- ACKR4 LC sequence is SEQ ID NO: 714. In some embodiments, the anti-HER2 scFv-anti-1107368.00143 ACKR4 LC sequence is SEQ ID NO: 715.

[0304] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 708 the anti-HER2 scFv-anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 712-715. In some embodiments, the anti-HER2 scFv-anti-ACKR4 LC sequence is SEQ ID NO: 712. In some embodiments, the anti-HER2 scFv-anti-ACKR4 LC sequence is SEQ ID NO: 713. In some embodiments, the anti-HER2 scFv-anti-ACKR4 LC sequence is SEQ ID NO: 714. In some embodiments, the anti-HER2 scFv-anti-ACKR4 LC sequence is SEQ ID NO: 715.

[0305] In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence1107368.00143 comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, the anti- HER2 scFv comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR- H2 sequence comprising SEQ ID NO: 171, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0306] In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR- H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, the anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti- ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81. In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, the1107368.00143 anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti- ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0307] In some embodiments, the bispecific binding construct comprises an anti-HER2 scFv sequence linked on its C-terminus to the N-terminus of an anti-ACKR4 HC sequence and an anti-ACKR4 LC sequence, where the anti-HER2 scFv-anti-ACKR4 HC sequence comprises or consists of a sequence selected from SEQ ID NOS: 719-720 and the anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 724-725.

[0308] In some embodiments, the anti-HER2 scFv-anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 719 and the anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 724-725. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 724. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 724.

[0309] In some embodiments, the anti-HER2 scFv-anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 720 and the anti-ACKR4 LC sequence comprises or consists of a sequence selected from SEQ ID NOS: 724-725. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 724. In some embodiments, the anti-ACKR4 LC sequence is SEQ ID NO: 724.

[0310] In some embodiments, the anti-HER2 scFv sequence comprises a Kabat CDR-H11107368.00143 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0311] In some embodiments, the anti-HER2 scFv sequence comprises a Chothia CDR- H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, the anti-ACKR4 HC sequence comprises a Chothia CDR- H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79. In some embodiments, the anti-HER2 scFv sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, the anti-ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H31107368.00143 sequence comprising SEQ ID NO: 45, and the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81.

[0312] In some embodiments, the bispecific binding construct comprises an anti-ACKR4 HC sequence and an anti-ACKR4 LC linked on its C-terminus to the N-terminus of an anti-HER2 scFv, where the anti-ACKR4 HC comprises or consists of a sequence selected from SEQ ID NOS: 729-730 and the anti-ACKR4 LC-anti-HER2 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 734-735.

[0313] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 729 and the anti-ACKR4 LC-anti-HER2 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 734-735. In some embodiments, the anti-ACKR4 LC-anti- HER2 scFv sequence is SEQ ID NO: 734. In some embodiments, the anti-ACKR4 LC-anti-HER2 scFv sequence is SEQ ID NO: 735.

[0314] In some embodiments, the anti-ACKR4 HC sequence comprises or consists of SEQ ID NO: 730 and the anti-ACKR4 LC-anti-HER2 scFv sequence comprises or consists of a sequence selected from SEQ ID NOS: 734-735. In some embodiments, the anti-ACKR4 LC-anti- HER2 scFv sequence is SEQ ID NO: 734. In some embodiments, the anti-ACKR4 LC-anti-HER2 scFv sequence is SEQ ID NO: 735.

[0315] In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 3, a Kabat CDR-H2 sequence comprising SEQ ID NO: 25, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 48, the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 comprising sequence SEQ ID NO: 79, and the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR- L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti-ACKR4 HC sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45, the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO:1107368.00143 81, and the anti-HER2 scFv sequence comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 172, a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0316] In some embodiments, the anti-ACKR4 HC sequence comprises a Chothia CDR- H1 sequence comprising SEQ ID NO: 14, a Chothia CDR-H2 sequence comprising SEQ ID NO: 36, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 48, the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 57, a CDR-L2 sequence comprising SEQ ID NO: 69, and a CDR-L3 sequence comprising SEQ ID NO: 79, and the anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194. In some embodiments, the anti- ACKR4 HC sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45, the anti-ACKR4 LC sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, and the anti-HER2 scFv comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 166, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194.

[0317] In some embodiments, the bispecific binding construct comprises or consists of an anti-ACKR4 VL sequence linked on its C-terminus to the N-terminus of an anti-HER2 VH sequence and an anti-HER2 VL sequence linked on its C-terminus to the N-terminus of anti- ACKR4 VH sequence, where the anti-ACKR4 VL-anti-HER2 VH sequence comprises or consists of a SEQ ID NO: 751 and the anti-HER2 VL-anti-ACKR4 VH sequence comprises or consists of SEQ ID NO: 743.

[0318] In some embodiments the anti-ACKR4 VL sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, the anti-HER2 VH sequence comprises a Kabat1107368.00143 CDR-H1 sequence comprising SEQ ID NO: 160, a Kabat CDR-H2 sequence comprising SEQ ID NO: 171, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 178, the anti-HER2 VL comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 VH comprises a Kabat CDR-H1 sequence comprising SEQ ID NO: 5, a Kabat CDR-H2 sequence comprising SEQ ID NO: 23, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 45.

[0319] In some embodiments the anti-ACKR4 VL sequence comprises a CDR-L1 sequence comprising SEQ ID NO: 59, a CDR-L2 sequence comprising SEQ ID NO: 70, and a CDR-L3 sequence comprising SEQ ID NO: 81, the anti-HER2 VH sequence comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 155, a Chothia CDR-H2 sequence comprising SEQ ID NO: 165, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 178, the anti-HER2 VL comprises a CDR-L1 sequence comprising SEQ ID NO: 183, a CDR-L2 sequence comprising SEQ ID NO: 188, and a CDR-L3 sequence comprising SEQ ID NO: 194, and the anti-ACKR4 VH comprises a Chothia CDR-H1 sequence comprising SEQ ID NO: 16, a Chothia CDR-H2 sequence comprising SEQ ID NO: 34, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 45. Binding Domains Capable of Binding to HLA-G

[0320] In some embodiments, the second target comprises a HLA-G polypeptide. In some embodiments, the HLA-G comprises or consists of an amino acid sequence set forth in SEQ ID NO: 575.

[0321] The class I HLA-G molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alphal and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.

[0322] HLA-G has been shown to be immune-suppressive. By binding receptors expressed on various myeloid and lymphoid cells, HLA-G may directly inhibit the functions of NK cells, cytotoxic T-lymphocytes, B cells, neutrophils, monocytes, macrophages, and dendritic cells. HLA- G also inhibits T and NK cell proliferation and cytolytic activities. HLA-G suppresses phagocytosis and induces the generation or expansion of regulatory T cells.1107368.00143

[0323] HLA-G expression is upregulated on a broad spectrum of tumors and is associated with poor prognosis and disease progression. Serum HLA-G levels are elevated in, for example, without limitation, breast, lung, colorectal cancer (CRC), gastric, esophageal, neuroblastoma, cervical, and hematological cancers. HLA-G has also been found to be correlated with clinical parameters in advanced disease, such as tumor metastasis, poor prognosis, immune escape, and tumor invasiveness. HLA-G Sequences VHSequences Comprising Illustrative CDRs

[0324] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising one or more CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-H sequences provided in this disclosure, and variants thereof. VHSequences Comprising Illustrative Kabat CDRs

[0325] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising one or more Kabat CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Kabat CDR-H sequences provided in this disclosure, and variants thereof. Kabat CDR-H3

[0326] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 310. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 311. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 312. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence1107368.00143 comprising, consisting of, or consisting essentially of SEQ ID NO: 313. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 315. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 316. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 317. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 318. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 319. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 320. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 321. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 322. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 323. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 324. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 325. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 326. In some embodiments, the binding domain capable of binding to1107368.00143 HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 327. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 328. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 329. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 330. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 331. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 332. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 333. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 334.

[0327] In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-H3 sequence provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-H3 sequences provided in this disclosure. In some embodiments, the CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. Kabat CDR-H2

[0328] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 287-304. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 287. In some1107368.00143 embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 288. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 289. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 290. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 291. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 292. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 293. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 294. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 295. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 296. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 297. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 298. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 299. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 300. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence1107368.00143 comprising, consisting of, or consisting essentially of SEQ ID NO: 301. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 302. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 303. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 304. Kabat CDR-H1

[0329] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 251-267. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 251. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 252. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 253. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 254. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 255. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 256. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 257. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 258. In some embodiments, the binding domain capable of binding to1107368.00143 HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 259. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 260. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 261. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 262. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 263. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 264. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 265. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 266. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 267. Kabat CDR-H3+Kabat CDR-H2

[0330] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 287- 304. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 403-433. Kabat CDR-H3+Kabat CDR-H1

[0331] In some embodiments, the binding domain capable of binding to HLA-G comprises1107368.00143 a VH sequence comprising a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334 and a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 251- 267. In some embodiments, the Kabat CDR-H3 sequence and the Kabat CDR-H1 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H3 and Kabat CDR-H1 are both from a single illustrative VHsequence selected from SEQ ID NOS: 403-433. Kabat CDR-H1+Kabat CDR-H2

[0332] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 251-267 and a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 287- 304. In some embodiments, the Kabat CDR-H1 sequence and the Kabat CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1 and Kabat CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 403-433. Kabat CDR-H1+Kabat CDR-H2+Kabat CDR-H3

[0333] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 251-267, a Kabat CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 287- 304, and a Kabat CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334. In some embodiments, the Kabat CDR-H1 sequence, Kabat CDR-H2 sequence, and Kabat CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Kabat CDR-H1, Kabat CDR-H2, and Kabat CDR-H3 are all from a single illustrative VHsequence selected from SEQ ID NOS: 403-433.

[0334] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 251, a Kabat CDR-H2 sequence comprising SEQ ID NO: 287, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises1107368.00143 a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 252, a Kabat CDR-H2 sequence comprising SEQ ID NO: 288, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 310. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 253, a Kabat CDR-H2 sequence comprising SEQ ID NO: 289, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 311. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 254, a Kabat CDR-H2 sequence comprising SEQ ID NO: 290, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 312. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 255, a Kabat CDR-H2 sequence comprising SEQ ID NO: 291, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 313. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 254, a Kabat CDR-H2 sequence comprising SEQ ID NO: 290, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 256, a Kabat CDR-H2 sequence comprising SEQ ID NO: 292, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 256, a Kabat CDR-H2 sequence comprising SEQ ID NO: 293, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 256, a Kabat CDR-H2 sequence comprising SEQ ID NO: 292, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 315. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 256, a Kabat CDR-H2 sequence comprising SEQ ID NO: 292, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 256, a Kabat CDR-H2 sequence comprising SEQ ID NO: 292, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 254, a Kabat1107368.00143 CDR-H2 sequence comprising SEQ ID NO: 290, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 316. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 254, a Kabat CDR-H2 sequence comprising SEQ ID NO: 290, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 317. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 257, a Kabat CDR-H2 sequence comprising SEQ ID NO: 294, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 318. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 257, a Kabat CDR-H2 sequence comprising SEQ ID NO: 294, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 319. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 258, a Kabat CDR-H2 sequence comprising SEQ ID NO: 295, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 320. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 259, a Kabat CDR-H2 sequence comprising SEQ ID NO: 296, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 321. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 259, a Kabat CDR-H2 sequence comprising SEQ ID NO: 296, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 322. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 258, a Kabat CDR-H2 sequence comprising SEQ ID NO: 296, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 323. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 260, a Kabat CDR-H2 sequence comprising SEQ ID NO: 297, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 323. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 261, a Kabat CDR-H2 sequence comprising SEQ ID NO: 295, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 324. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 262, a Kabat CDR-H2 sequence comprising SEQ ID NO: 297, and a Kabat CDR-H3 sequence comprising SEQ1107368.00143 ID NO: 325. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 258, a Kabat CDR-H2 sequence comprising SEQ ID NO: 298, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 326. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 263, a Kabat CDR-H2 sequence comprising SEQ ID NO: 299, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 327. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 264, a Kabat CDR-H2 sequence comprising SEQ ID NO: 300, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 328. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 265, a Kabat CDR-H2 sequence comprising SEQ ID NO: 301, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 329. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 266, a Kabat CDR-H2 sequence comprising SEQ ID NO: 302, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 330. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 267, a Kabat CDR-H2 sequence comprising SEQ ID NO: 303, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 331. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 251, a Kabat CDR-H2 sequence comprising SEQ ID NO: 287, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 332. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 264, a Kabat CDR-H2 sequence comprising SEQ ID NO: 304, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 333. In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Kabat CDR-H1 sequence comprising SEQ ID NO: 257, a Kabat CDR-H2 sequence comprising SEQ ID NO: 294, and a Kabat CDR-H3 sequence comprising SEQ ID NO: 334. Variants of VHSequences Comprising Illustrative Kabat CDRs

[0335] In some embodiments, the VHsequences provided herein comprise a variant of an illustrative Kabat CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.1107368.00143

[0336] In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H3 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H3 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0337] In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H2 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H2 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0338] In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Kabat CDR-H1 sequence provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Kabat CDR-H1 sequences provided in this disclosure. In some embodiments, the Kabat CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Kabat CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VHSequences Comprising Illustrative Chothia CDRs

[0339] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising one or more Chothia CDR-H sequences comprising, consisting of, or consisting essentially of one or more illustrative Chothia CDR-H sequences provided in this disclosure, and variants thereof. Chothia CDR-H3

[0340] In some embodiments, the binding domain capable of binding to HLA-G comprises1107368.00143 a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334.

[0341] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 310. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 311. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 312. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 313. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 315. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 316. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 317. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 318. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 319. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 320. In some embodiments, the binding domain capable of binding to HLA-G1107368.00143 comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 321. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 322. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 323. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 324. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 325. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 326. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 327. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 328. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 329. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 330. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 331. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 332. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 333. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence1107368.00143 comprising, consisting of, or consisting essentially of SEQ ID NO: 334. Chothia CDR-H2

[0342] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 271-283.

[0343] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 271. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 272. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 273. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 274. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 275. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 276. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 277. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 278. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 279. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 280. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 281. In1107368.00143 some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 282. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 283. Chothia CDR-H1

[0344] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 234-247.

[0345] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 234. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 235. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 236. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 237. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 238. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 239. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 240. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 241. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 242. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence1107368.00143 comprising, consisting of, or consisting essentially of SEQ ID NO: 243. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 244. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 245. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 246. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 247. Chothia CDR-H3+Chothia CDR-H2

[0346] In some embodiments, the binding domain capable of binding to HLA-G comprises a VHsequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 271- 283. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 403-443. Chothia CDR-H3+Chothia CDR-H1

[0347] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334, and a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 234- 247. In some embodiments, the Chothia CDR-H3 sequence and the Chothia CDR-H1 sequence are both from a single illustrative VHsequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H3 and Chothia CDR-H1 are both from a single illustrative VH sequence selected from SEQ ID NOS: 403-443. Chothia CDR-H1+Chothia CDR-H2

[0348] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting1107368.00143 essentially of a sequence selected from SEQ ID NOS: 234-247 and a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 271- 283. In some embodiments, the Chothia CDR-H1 sequence and the Chothia CDR-H2 sequence are both from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1 and Chothia CDR-H2 are both from a single illustrative VHsequence selected from SEQ ID NOS: 403-443. Chothia CDR-H1+Chothia CDR-H2+Chothia CDR-H3

[0349] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 234-247, a Chothia CDR-H2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 271- 283, and a Chothia CDR-H3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 309-334. In some embodiments, the Chothia CDR-H1 sequence, Chothia CDR-H2 sequence, and Chothia CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the Chothia CDR-H1, Chothia CDR-H2, and Chothia CDR-H3 are all from a single illustrative VH sequence selected from SEQ ID NOS: 403-433.

[0350] In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 234, a Chothia CDR-H2 sequence comprising SEQ ID NO: 271, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 272, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 310. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 273, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 311. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 236, a Chothia CDR-H2 sequence comprising SEQ ID NO: 274, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 312. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising1107368.00143 SEQ ID NO: 237, a Chothia CDR-H2 sequence comprising SEQ ID NO: 274, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 313. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 236, a Chothia CDR-H2 sequence comprising SEQ ID NO: 274, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 275, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 276, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 275, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 315. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 238, a Chothia CDR-H2 sequence comprising SEQ ID NO: 275, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 309. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 235, a Chothia CDR-H2 sequence comprising SEQ ID NO: 275, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 314. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 236, a Chothia CDR-H2 sequence comprising SEQ ID NO: 274, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 316. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 236, a Chothia CDR-H2 sequence comprising SEQ ID NO: 274, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 317. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 239, a Chothia CDR-H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 318. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 239, a Chothia CDR-H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR-1107368.00143 H3 sequence comprising SEQ ID NO: 319. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 240, a Chothia CDR-H2 sequence comprising SEQ ID NO: 278, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 320. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 241, a Chothia CDR-H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 321. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 241, a Chothia CDR-H2 sequence comprising SEQ ID NO: 278, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 322. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 240, a Chothia CDR-H2 sequence comprising SEQ ID NO: 278, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 323. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 239, a Chothia CDR-H2 sequence comprising SEQ ID NO: 278, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 324. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 241, a Chothia CDR-H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 325. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 240, a Chothia CDR-H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 326. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 243, a Chothia CDR-H2 sequence comprising SEQ ID NO: 279, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 327. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 244, a Chothia CDR-H2 sequence comprising SEQ ID NO: 280, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 328. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 245, a Chothia CDR-H2 sequence comprising SEQ ID NO: 281, and a Chothia CDR- H3 sequence comprising SEQ ID NO: 329. In some embodiments, the antibody comprises a VH1107368.00143 sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 246, a Chothia CDR- H2 sequence comprising SEQ ID NO: 277, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 330. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 247, a Chothia CDR-H2 sequence comprising SEQ ID NO: 282, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 331. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 234, a Chothia CDR-H2 sequence comprising SEQ ID NO: 271, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 332. In some embodiments, the antibody comprises a VHsequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 244, a Chothia CDR-H2 sequence comprising SEQ ID NO: 283, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 333. In some embodiments, the antibody comprises a VH sequence comprising a Chothia CDR-H1 sequence comprising SEQ ID NO: 239, a Chothia CDR-H2 sequence comprising SEQ ID NO: 377, and a Chothia CDR-H3 sequence comprising SEQ ID NO: 334. Variants of VHSequences Comprising Illustrative Chothia CDRs

[0351] In some embodiments, the VHsequences provided herein comprise a variant of an illustrative Chothia CDR-H3, CDR-H2, and / or CDR-H1 sequence provided in this disclosure.

[0352] In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H3 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H3 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H3 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0353] In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H2 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H2 sequences provided in this disclosure. In some1107368.00143 embodiments, the Chothia CDR-H2 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0354] In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a variant of an illustrative Chothia CDR-H1 sequence provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative Chothia CDR-H1 sequences provided in this disclosure. In some embodiments, the Chothia CDR-H1 sequence comprises, consists of, or consists essentially of any of the illustrative Chothia CDR-H1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VHSequences In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 403- 433. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 403. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 404. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 405. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 406. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 407. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 408. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 409. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting1107368.00143 of, or consisting essentially of SEQ ID NO: 410. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 411. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 412. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 413. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 414. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 415. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 416. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 417. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 418. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 419. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 420. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 421. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 422. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 423. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 424. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 425. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 426. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID1107368.00143 NO: 427. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 428. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 429. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 430. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 431. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 432. In some embodiments, the binding domain capable of binding to HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 433. Variants of VHSequences

[0355] In some embodiments, the VHsequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VH sequence provided in this disclosure.

[0356] In some embodiments, the VH sequence comprises, consists of, or consists essentially of a variant of an illustrative VHsequence provided in this disclosure. In some embodiments, the VHsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with any of the illustrative VHsequences provided in this disclosure.

[0357] In some embodiments, the VHsequence comprises, consists of, or consists essentially of any of the illustrative VH sequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences Comprising Illustrative CDRs

[0358] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising one or more CDR-L sequences comprising, consisting of, or consisting essentially of one or more illustrative CDR-L sequences provided in this disclosure, and variants thereof. CDR-L31107368.00143

[0359] In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 382-399. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 382. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 383. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 385. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 386. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 387. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 388. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 389. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 390. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 391. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 392. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 393. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 394. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 395. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 396. In some embodiments, the binding domain capable of binding to HLA-G comprises1107368.00143 a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 397. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 398. In some embodiments, the binding domain capable of binding to HLA-G comprises a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 399. CDR-L2

[0360] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 361-378. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 361. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 362. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 363. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 364. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 365. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 366. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 367. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 368. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 369. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 370. In some embodiments, the binding domain capable of binding to HLA-G comprises a1107368.00143 VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 371. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 372. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 373. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 374. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 375. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 376. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 377. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L2 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 378. CDR-L1

[0361] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 338-357. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 338. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 339. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 340. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 341. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting1107368.00143 essentially of SEQ ID NO: 342. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 343. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 344. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 345. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 346. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 347. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 348. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 349. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 350. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 351. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 352. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR- L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 353. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 354. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 355. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 356. In some embodiments, the binding domain capable of binding to1107368.00143 HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 357. CDR-L3+CDR-L2

[0362] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 382-399 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 361-378. In some embodiments, the CDR-L3 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR- L3 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 437- 461. CDR-L3+CDR-L1

[0363] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 382-399 and a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 338-357. In some embodiments, the CDR-L3 sequence and the CDR-L1 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR- L3 and CDR-L1 are both from a single illustrative VL sequence selected from SEQ ID NOS: 437- 461. CDR-L1+CDR-L2

[0364] In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 338-357 and a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 361-378. In some embodiments, the CDR-L1 sequence and the CDR-L2 sequence are both from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR- L1 and CDR-L2 are both from a single illustrative VL sequence selected from SEQ ID NOS: 437- 461. CDR-L1+CDR-L2+CDR-L3

[0365] In some embodiments, the binding domain capable of binding to HLA-G comprises1107368.00143 a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 338-357, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 361-378, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a sequence selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence selected from SEQ ID NOS: 437-461.

[0366] In some embodiments, the binding domain capable of binding to an HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 338, a CDR- L2 sequence comprising SEQ ID NO: 361, and a CDR-L3 sequence SEQ ID NO: 382. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 339, a CDR-L2 sequence comprising SEQ ID NO: 362, and a CDR-L3 sequence SEQ ID NO: 383. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 340, a CDR-L2 sequence comprising SEQ ID NO: 361, and a CDR-L3 sequence SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 341, a CDR- L2 sequence comprising SEQ ID NO: 363, and a CDR-L3 sequence SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 342, a CDR-L2 sequence comprising SEQ ID NO: 264, and a CDR-L3 sequence SEQ ID NO: 385. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 340, a CDR-L2 sequence comprising SEQ ID NO: 365, and a CDR-L3 sequence SEQ ID NO: 386. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 343, a CDR- L2 sequence comprising SEQ ID NO: 365, and a CDR-L3 sequence SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 344, a CDR-L2 sequence comprising SEQ ID NO: 266, and a CDR-L3 sequence SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence1107368.00143 comprising SEQ ID NO: 338, a CDR-L2 sequence comprising SEQ ID NO: 361, and a CDR-L3 sequence SEQ ID NO: 384. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 345, a CDR- L2 sequence comprising SEQ ID NO: 367, and a CDR-L3 sequence SEQ ID NO: 388. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 346, a CDR-L2 sequence comprising SEQ ID NO: 368, and a CDR-L3 sequence SEQ ID NO: 389. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 347, a CDR-L2 sequence comprising SEQ ID NO: 369, and a CDR-L3 sequence SEQ ID NO: 390. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 348, a CDR- L2 sequence comprising SEQ ID NO: 368, and a CDR-L3 sequence SEQ ID NO: 390. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 349, a CDR-L2 sequence comprising SEQ ID NO: 261, and a CDR-L3 sequence SEQ ID NO: 388. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 350, a CDR-L2 sequence comprising SEQ ID NO: 370, and a CDR-L3 sequence SEQ ID NO: 388. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 351, a CDR- L2 sequence comprising SEQ ID NO: 370, and a CDR-L3 sequence SEQ ID NO: 391. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 351, a CDR-L2 sequence comprising SEQ ID NO: 371, and a CDR-L3 sequence SEQ ID NO: 388. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 352, a CDR-L2 sequence comprising SEQ ID NO: 372, and a CDR-L3 sequence SEQ ID NO: 392. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 353, a CDR- L2 sequence comprising SEQ ID NO: 373, and a CDR-L3 sequence SEQ ID NO: 393. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 354, a CDR-L2 sequence comprising SEQ ID NO: 374, and a CDR-L3 sequence SEQ ID NO: 394. In some embodiments, the binding1107368.00143 domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 355, a CDR-L2 sequence comprising SEQ ID NO: 375, and a CDR-L3 sequence SEQ ID NO: 395. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 338, a CDR- L2 sequence comprising SEQ ID NO: 376, and a CDR-L3 sequence SEQ ID NO: 396. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 338, a CDR-L2 sequence comprising SEQ ID NO: 376, and a CDR-L3 sequence SEQ ID NO: 397. In some embodiments, the binding domain capable of binding to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 356, a CDR-L2 sequence comprising SEQ ID NO: 377, and a CDR-L3 sequence SEQ ID NO: 398. In some embodiments, the binding domain capable of binding to HLA- G comprises a VL sequence comprising a CDR-L1 sequence comprising SEQ ID NO: 357, a CDR- L2 sequence comprising SEQ ID NO: 378, and a CDR-L3 sequence SEQ ID NO: 399. Variants of VLSequences Comprising Illustrative CDR-Ls

[0367] In some embodiments, the VL sequences provided herein comprise a variant of an illustrative CDR-L3, CDR-L2, and / or CDR-L1 sequence provided in this disclosure.

[0368] In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L3 sequence provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L3 sequences provided in this disclosure. In some embodiments, the CDR-L3 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L3 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions.

[0369] In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L2 sequence provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L2 sequences provided in this disclosure. In some embodiments, the CDR-L2 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L2 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid1107368.00143 substitutions are conservative amino acid substitutions.

[0370] In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a variant of an illustrative CDR-L1 sequence provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of a sequence having at least 70%, 75%, 80%, 85%, 90%, or 95% identity with any of the illustrative CDR-L1 sequences provided in this disclosure. In some embodiments, the CDR-L1 sequence comprises, consists of, or consists essentially of any of the illustrative CDR-L1 sequences provided in this disclosure, with 1, 2, or 3 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. VLSequences Variants of VLSequences

[0371] In some embodiments, the VL sequences provided herein comprise, consist of, or consist essentially of a variant of an illustrative VLsequence provided in this disclosure.

[0372] In some embodiments, the VL sequence comprises, consists of, or consists essentially of a variant of an illustrative VL sequence provided in this disclosure. In some embodiments, the VLsequence comprises, consists of, or consists essentially of a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.05% identity with any of the illustrative VL sequences provided in this disclosure.

[0373] In some embodiments, the VLsequence comprises, consists of, or consists essentially of any of the illustrative VLsequences provided in this disclosure, 20 or fewer, 19 or fewer, 18 or fewer, 17 or fewer, 16 or fewer, 15 or fewer, 14 or fewer, 13 or fewer, 12 or fewer, 11 or fewer, 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer, or 1 or fewer amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. Pairs CDR-H3-CDR-L3 Pairs

[0374] In some embodiments, the CDR-H3 sequence is a CDR-H3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 309-334, and the CDR-L3 sequence is a CDR-L3 sequence comprising, consisting of, or consisting essentially of SEQ ID NOS: 382-399.

[0375] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 309 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L31107368.00143 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0376] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 310 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0377] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 311 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383.1107368.00143 In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399

[0378] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 312 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0379] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 313 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L31107368.00143 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0380] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 314 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0381] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 315 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID1107368.00143 NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0382] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 316 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0383] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 317 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments,1107368.00143 the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0384] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 318 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0385] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 319 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ1107368.00143 ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0386] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 320 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0387] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 321 and the CDR- L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some1107368.00143 embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0388] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 322 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0389] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 323 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ1107368.00143 ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0390] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 324 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0391] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 325 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some1107368.00143 embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0392] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 326 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 395. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 396. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 397. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 398. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 399.

[0393] In some embodiments, the CDR-H3 sequence is SEQ ID NO: 327 and the CDR-L3 sequence is selected from SEQ ID NOS: 382-399. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 382. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 383. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 384. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 385. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 386. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 387. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 388. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 389. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 390. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 391. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 392. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 393. In some embodiments, the CDR-L3 sequence is SEQ ID NO: 394. In some embodiments, the CDR-L31107368.001...

Claims

1107368.00143 WHAT IS CLAIMED IS:

1. A bispecific antigen binding construct comprising a binding domain capable of binding to an ACKR4 and an additional binding domain capable of binding to a second target.

2. The bispecific antigen binding construct according to claim 1, wherein the ACKR4 comprises or consists of an amino acid sequence set forth in SEQ ID NO:

147.

3. The bispecific antigen binding construct according to any of claims 1-2, wherein the binding domain capable of binding to the ACKR4 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in SEQ ID NOS: 1-5 or SEQ ID NOS: 12-16, b) a VHCDR2 having the sequence set forth in SEQ ID NOS: 23-25 or SEQ ID NOS: 34-36, c) a VHCDR3 having the sequence set forth in SEQ ID NOS: 45-48, d) a VLCDR1 having the sequence set forth in SEQ ID NOS: 55-59, e) a VLCDR2 having the sequence set forth in SEQ ID NOS: 67-70, and f) a VLCDR3 having the sequence set forth in SEQ ID NOS: 77-81.

4. The bispecific antigen binding construct according to claim 1, wherein the second target comprises a HER2.

5. The bispecific antigen binding construct according to claim 4, wherein the HER2 comprises or consists of an amino acid sequence set forth in SEQ ID NO:

231.

6. The bispecific antigen binding construct according to any one of claims 4-5, wherein the additional binding domain capable of binding to the HER2 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 155-156 or SEQ ID NOS: 160-161, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 165-167 or SEQ ID NOS: 171-174, c) a VHCDR3 having the sequence set forth in SEQ ID NO: 178-179, d) a VLCDR1 having the sequence set forth in SEQ ID NO: 183-184, e) a VLCDR2 having the sequence set forth in SEQ ID NO: 188-190, and f) a VLCDR3 having the sequence set forth in SEQ ID NO: 194-195.1107368.00143 7. The bispecific antigen binding construct according to claim 1, wherein the second target comprises a HLA-G.

8. The bispecific antigen binding construct according to claim 7, wherein the HLA-G comprises or consists of an amino acid sequence set forth in SEQ ID NO:

575.

9. The bispecific antigen binding construct according to any one of claims 7-8, wherein the additional binding domain capable of binding to a HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 234-247 or SEQ ID NOS: 251-267, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 271-283 or SEQ ID NOS: 287-304, c) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 309-334, d) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 338-357, e) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 361-378, and f) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 382-399.

10. The bispecific antigen binding construct according to claim 1, wherein the second target comprises a TNF-α.

11. The bispecific antigen binding construct according to claim 10, wherein the TNF- α comprises or consists of an amino acid sequence set forth in SEQ ID NO:

650.

12. The bispecific antigen binding construct according to any one of claims 10-11, wherein the additional binding domain capable of binding to a TNF-α comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising 1, 2, 3, 4, 5, or 6 of the following: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 579-582 or SEQ ID NOS: 585-588, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 591-594 and SEQ ID NOS: 597-600, c) a VHCDR3 having the sequence set forth in SEQ ID NO: 603-606, d) a VLCDR1 having the sequence set forth SEQ ID1107368.00143 NO: 609-612, e) a VLCDR2 having the sequence set forth in SEQ ID NO: 615-618, and f) a VLCDR3 having the sequence set forth in SEQ ID NO: 621-624.

13. The bispecific antigen binding construct according to any of claims 1-6, wherein the binding domain capable of binding to an ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89-94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a HER2 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 199- 202 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 206-209.

14. The bispecific antigen binding construct according to any of claims 1-3 or 7-9, wherein the binding domain capable of binding to an ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89-94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a HLA-G comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 403-433 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 437-461.

15. The bispecific antigen binding construct according to any of claims 1-3 or 10-12, wherein the binding domain capable of binding to an ACKR4 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 89-94 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS: 101-106, and the additional binding domain capable of binding to a TNF-α epitope1107368.00143 comprises a heavy chain variable region (VH) and a light chain variable region (VL), with VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NOS: 627-630 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NOS 633-636.

16. A bispecific binding construct capable of binding to ACKR4 and a second target, wherein the bispecific binding construct comprises 1, 2, 3, 4, 5, or 6 of the following: a) a binding construct capable of binding to ACKR4 comprising a HC linked on a C-terminus to an N-terminus of a scFv capable of binding to the second target, wherein the HC comprises a sequence selected from SEQ ID NOS: 113-120; b) a binding construct capable of binding to the second target comprising a HC linked on a C-terminus to an N-terminus of a scFv capable of binding to ACKR4, wherein the scFv capable of binding to ACKR4 comprises a sequence selected from SEQ ID NOS: 89-94 and SEQ ID NOS: 101-106; c) a scFv capable of binding to the second target linked on a C-terminus to an N-terminus of a binding construct capable of binding to ACKR4 comprising a LC, wherein the LC comprises a sequence selected from SEQ ID NOS: 128-133; d) a scFv capable of binding to the second target linked on a C-terminus to an N-terminus of a binding construct capable of binding to ACKR4 comprising a HC, wherein the HC comprises a sequence selected from SEQ ID NOS: 113-120; e) a binding construct capable of binding to ACKR4 comprising a LC linked on a C-terminus to an N-terminus of a scFv capable of binding to the second target wherein the LC comprises a sequence selected from SEQ ID NOS: 128-133; or f) a binding construct capable of binding to ACKR4 comprising a VH linked to a hIgG1 AAA containing a ‘hole’ mutation in the CH3 domain and a scFv capable of binding to the second target linked to a hIgG1 AAA containing a ‘knob;’ mutation in the CH3 domain, wherein the VH comprises a sequence selected from SEQ ID NOS: 89-94.

17. A pharmaceutical composition comprising or consisting of a bispecific antigen binding construct according to claims 1-16.1107368.00143 18. The pharmaceutical composition according to claim 17, further comprising an effective amount of one or more of: a) an anti-PD-Ll antibody or small molecule inhibitor; b) an anti -PD- 1 antibody or small molecule inhibitor; c) an anti-CD38 antibody or small molecule inhibitor; d) an anti-CD39 antibody or small molecule inhibitor; e) an anti-CD73 antibody or small molecule inhibitor; f) an anti-A2A receptor antibody or small molecule inhibitor; g) an anti-A2B receptor antibody or small molecule inhibitor; h) an anti-A2A / A2B dual receptor antibody or small molecule inhibitor; i) an anti-CD47 antibody or small molecule inhibitor; j) an anti-CTLA-4 antibody or small molecule inhibitor; k) an anti-LAG-3 antibody or small molecule inhibitor; l) an anti-TIM-3 antibody or small molecule inhibitor; m) an anti-TIGIT antibody or small molecule inhibitor; n) an anti-VISTA antibody or small molecule inhibitor; o) an anti-CD94 antibody or small molecule inhibitor; p) a small molecule inhibitor; q) an oncolytic virus; a chemotherapy; s) an adoptive cell therapy; and / or t) ADCC capable therapies using effector competent antibodies such as anti-CD 19, anti-CD20, anti-EGFR, anti-HER2, anti-SLAMF7, anti-CD52, anti- BCMA, anti-GD2, and / or anti-CCR4.

19. The pharmaceutical composition according to claim 17 or claim 18, further comprising one or both of: a) an antibody to an immune inhibitory receptor or ligand and / or b) an antibody to an immune stimulatory receptor or ligand.

20. One or more nucleic acids encoding the bispecific antigen binding constructs according to any one of claims 1-19.

21. One or more vectors comprising the one or more nucleic acids according to claim 16.

22. A host transformed with a vector according to claim 21.

23. A method for the production of one or more bispecific antigen binding construct comprising the steps of expressing one or more nucleic acids according to any of claims 20-22 in a prokaryotic or eukaryotic host cell and recovering the one or more bispecific antigen binding construct from the cell or the cell culture supernatant.

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