Anti-NKP46 antibodies and methods of use

Abstract

Provided are antibodies that specifically bind NKp46 and cross-react with human and mouse NKp46. Also provided are nucleic acids, cells and methods of making the antibodies of the present disclosure. Compositions comprising the antibodies and methods of using the antibodies, e.g., to activate NK cells in a subject in need thereof, are also provided. In some instances, provided are methods of increasing NK cell cytotoxicity in a subject in need thereof.

Description

[0001]Atty. Docket: STAN-2131WO (S23-217) ANTI-NKP46 ANTIBODIES AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No.63 / 553,972, filed February 15, 2024, which application is incorporated herein by reference in its entirety. INTRODUCTION Natural killer (NK) cells are an important component of the innate immune system, with the ability to recognize virally infected, non-self and tumorigenic cells1–3. NK cells are a vital component of tumor control through direct clearance of neoplastic and metastasizing cells and secretion of proinflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα)4–6. NK cells use a suite of cell surface receptors to recognize their targets, including NKG2D, the natural cytotoxicity receptors (NCRs), and the killer immunoglobulin-like receptors (KIRs)7,8. Notably, they utilize the FcγRIIIa receptor (CD16a) to recognize antibody- opsonized targets via the antibody Fc domain, resulting in target cell apoptosis via antibody- dependent cellular cytotoxicity (ADCC), which is an essential mechanism of action for many anticancer therapeutic antibodies9. NK cells have also been the target of cancer immunotherapy development, from cellular engineering efforts of off-the-shelf chimeric antigen receptor-NK cells to novel protein biologics for harnessing NK cell cytotoxicity10. For the latter, focus has as of late been on the construction of novel bispecific antibodies and within these, NK cell engagers (NKCEs)11. Bispecific antibodies are a broad class of molecules that can harness bespoke temporal and spatial binding characteristics12. NKCEs, like bispecific and trispecific killer cell engagers (BiKEs and TriKEs, respectively), focus on leveraging protein engineering approaches to enhance NK cell antitumor responses, which have shown promising results and are in clinical trials13. Considering the underlying ADCC mechanism of wild-type antibodies and the success of T cell engagers, these approaches center on better bridging effector cells to tumor cells14. Increasing the affinity of the Fc domain to CD16a through mutation or glycoengineering has resulted in improved therapies, and many multispecific NKCEs alternatively utilize a non-Fc CD16a binding domain11,15,16. However, given that CD16a is often cleaved from the NK cell surface after activation, parallel or substitute targeting of alternative NK cell receptors are also being studied. Under consideration are the remainder of the activating NK cell receptors, with recent work on NK cell surface proteins NKp30 and NKG2D17,18. Co-engagement of NKp46 in particular has been the target of ongoing study, with promising results reported19,20. NKp46, also known as natural cytotoxicity receptor 1 (NCR1) or CD335, is a member of the NCR family alongside NKp30 and NKp4421. It is a two-domain 40 kDa glycosylated cell surface receptor that is broadly expressed on NK cells and whose expression is restricted to NK cells, with the exception of a minor subset of ILC3s and T cells22–25. NKp46 is considered to be Atty. Docket: STAN-2131WO (S23-217) an early marker during the NK cell maturation process and signals through an arginine residue in the transmembrane domain and its intracellular ITAM domain, which recruits CD3ζ and FcεR1γ26–28. Though a canonical primary ligand is yet to be identified, a number of putative ligands have been characterized from both viral and host sources, including viral hemagglutinins and calreticulin29–31. NKp46 has also been found to be minimally downregulated on tumor-infiltrating NK cells as compared to other activating NK cell receptors19. Although an exact tumor-associated ligand is yet to be identified, NKp46 is an important component of the antitumor response, with NKp46 responsible for tumor control in both humans and mice32–35and expression associated with improved overall survival31,36. Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies. Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) and thereby are essential in modulating adaptive immune responses. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated. NK cells express several activating receptors that can be targeted to induce NK-cell-mediated anti-tumor immunity, including NKp46, cluster of differentiation 16 (CD16, also known as FcγRIIIA), natural killer group 2D (NKG2D), signaling lymphocyte activation molecule (SLAM)-family members, and the natural cytotoxicity receptors (NCRs) NKp30, and NKp44. NKp46 is expressed by resting and activated NK cells, innate lymphoid cell (ILC) 1, a small population of T lymphocytes, and a subset of ILC3 (NCR+ILC3) in mucosa. NKp46 plays a role in the NK-cell lysis of autologous, allogeneic, or xenogeneic cells. NKp46 triggering mediates signaling via its association with the immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules CD3ζ and FcRγ that, upon receptor-engagement, become tyrosine phosphorylated. NKp46 mAb-mediated cross-linking triggers not only NK-cell cytotoxic activity but also cytokine release. SUMMARY Provided are antibodies that specifically bind NKp46 and cross-react with human and mouse NKp46. Also provided are nucleic acids, cells and methods of making the antibodies of the present disclosure. Compositions comprising the antibodies and methods of using the antibodies, e.g., to activate NK cells in a subject in need thereof, are also provided. In some instances, provided are methods of increasing NK cell cytotoxicity in a subject in need thereof. Atty. Docket: STAN-2131WO (S23-217) BRIEFDESCRIPTION OF THEFIGURESFIG. 1: Engineering of a cross-reactive anti-NKp46 antibody. (a) Antibody discovery scheme. A phage library was alternately panned against hNKp46 and mNKp46. The enriched library was transformed into S. cerevisiae and the resulting library was sorted using FACS. (b) Binding of the top clone from the first library to hNKp46 and mNKp46. Binding to his-tagged ligands is shown as a fraction of maximum binding. Mean + / - SD is shown, n=3. (c) Diversification of the CDRH3 of the clone shown in (b) using NNT primers and FACS sorting of CDRH3-mutated variant library against decreasing concentrations of mNKp46. CDRH3 loop sequence is underlined (Kabat numbering) with mutated residues (blue). (d) Binding of RLN131 (also referred to herein as “RL_7”) to hNKp46 and mNKp46. Binding to his-tagged ligands is shown as a fraction of maximum binding. Mean + / - SD is shown, n=3. (e) BLI affinity measurement of RLN131 in IgG1 format to hNKp46, mNKp46, and cNKp46. his-tagged hNKp46, mNKp46, and cNKp46 were loaded on Octet NTA biosensors for 150 seconds. The biosensors were rinsed in the same buffer and two-fold dilutions of RLN131 were associated for 350 seconds, followed by dissociation for 1800 seconds, starting at 6.25nM (600s, 1600s, and 5nM, respectively, for cNKp46). Affinity was calculated with Octet data analysis software. (f) BLI affinity measurement of RLN131 Fab (hIgG1 isotype) to hNKp46 and mNKp46. His-tagged hNKp46 and mNKp46 were loaded on Octet NTA biosensors for 150 s. Following rinse of the biosensors, two-fold dilutions of RLN131 were associated for 600 s, followed by dissociation for 1200 s, starting at 40 nM Fab. The RLN131 Fab bound with an affinity (KDvalue) of 1.25 + / - 0.02 nM (hNKp46) and 3.51 + / - 0.07 nM (mNKp46). Affinity was calculated with Octet data analysis software. FIG. 2: Epitope mapping of RLN131. (a) BLI sensograms of competition binding of RLN131 and various hNKp46 antibodies. hNKp46 was immobilized on the sensor tip, followed by association of 100nM RLN131 for 350s. After washing, various hNKp46 antibodies at 100nM were associated for another 350s. (b) Binding of RLN131 to hNKp46 K41S / E42A and Y121A D121A expressed on the surface of Expi293 cells. Data represents the binding of RLN131 to hNKp46 mutants as a fraction of binding to wild-type hNKp46 expressed on the surface of Expi293 cells. Mean + / - SD is shown, n=3. (c) Alanine scan of hNKp46 and mNKp46. Binding of 1nM RLN131 to hNKp46 (top) and mNKp46 (bottom) with single alanine mutations is shown. Residues that constitute the binding epitope are highlighted (green). Mean + / - SD is shown, n=3. MFI, mean fluorescence intensity. (d) Binding epitope of RLN131 mapped to the three- dimensional structure of hNKp46 (PDB 6IAP) and mNKp46 (structure predicted with Alphafold 2.0) as seen from a side-view perspective. Residues that constitute the binding epitope as determined from (c) are labeled (green), and residues that were tested but are not part of the binding epitope are labeled (yellow). The N- and C-termini of the respective proteins are shown. FIG.3: NK cell activation with RLN131. (a) Binding of RLN131 to primary human NK cells and mouse NK cells. Binding is shown as the fraction of receptors bound. Mean + / - SD is shown. Data for human NK cell binding was collected from NK cells from 3 separate donors (n=3). Atty. Docket: STAN-2131WO (S23-217) Binding of mouse NK cells was collected from NK cells purified from the splenocytes of one C57BL / 6 mouse, n=3. (b) NK cell activation with RLN131. Primary human NK cells were thawed in RPMI overnight. NK cells were then incubated in RLN131- or isotype control antibody-coated wells for 4 hours. Cells were then fixed, stained, and analyzed with flow cytometry. Data is representative of two donors. (c) Redirected lysis assay of tumor cells using primary NK cells. Cytotoxicity of primary human NK cells toward THP-1 cells was measured using a calcein release assay. NK cells and THP-1 cells were cocultured for 4 hours at various E:T ratios in the presence of increasing concentrations of RLN131 (mIgG1 isotype). Mean + / - SD from one donor is shown, n=3. Data is representative of 3 separate donors. (d) Proliferation of primary human NK cells treated with RLN131. Primary human NK cells were purified from donor blood, labeled with CFSE and incubated on RLN131-coated plates for 11 days in the presence of various combinations of activating cytokines. NK cells were analyzed with flow cytometry. % of the NK cell sample that proliferated (left) and change in mean CFSE fluorescence from nonproliferating controls (right) is shown. Three donors are shown. (e) Binding of RLN131 (hIgG1 LALA-PG isotype) to primary human NK cells, as measured by flow cytometry. Data was collected from NK cells from 2 separate donors (n=1 per donor). FIG.4: Cytotoxicity of NKp46-engaging NKCEs incorporating RLN131. NKCE mediated cytotoxicity was measured via calcein release from CD20-expressing Raji cells cocultured with primary human NK cells and NKCEs. In all figures, an example of the construct tested is shown (RLN131, green; anti-CD20, purple). Comparison to an unmodified anti-CD20 antibody (black, identical across all panels) is shown. NK cells were thawed overnight in RPMI+10% FBS + 1% Pen / strep and incubated with Raji cells and antibodies at an E:T ratio of 2:1 for 4 hours. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. (a) Cytotoxicity of NKCE1 and NKCE1Fc-, N-terminal heavy chain fusions of RLN131 to an anti-CD20 antibody. NKCE1Fc-contains LALA-PG mutations to eliminate Fc effector function. (b) Cytotoxicity of NKCE2 and NKCE2Fc-, N-terminal light chain fusions of RLN131 to an anti-CD20 antibody. NKCE2Fc-contains LALA-PG mutations. (c) Cytotoxicity of NKCE3 and NKCE3Fc-, C-terminal heavy chain fusions of RLN131 to an anti-CD20 antibody. NKCE3Fc-contains LALA-PG mutations. (d) Cytotoxicity of NKCE4 and NKCE4Fc-, C-terminal light chain fusions of RLN131 to an anti-CD20 antibody. NKCE4Fc-contains LALA-PG mutations. (e) Cytotoxicity of NKCE5 and NKCE5Fc-, bispecific antibodies constructed using knobs-into-holes mutations and Crossmab engineering. NKCE5Fc-contains LALA-PG mutations. (f) Cytotoxicity of NKCE6, a bispecific killer cell engager (BiKE) consisting of the fusion of an anti-CD20 scFv to RLN131 scFv. FIG. 5: Further characterization of NKCE1 and NKCE1Fc-. (a) NKCE1 mediated cytotoxicity of primary human NK cells toward CD20-expressing Raji cells as a function of linker length. NKCE format NKCE1 was expressed with 0 aa, 5aa, 10aa, and 17aa (G4S)n linkers between RLN131 and the anti-CD20 antibody. Comparison to an unmodified anti-CD20 antibody (black) is shown. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. Atty. Docket: STAN-2131WO (S23-217) (b) NKCE1 and NKCE1Fc-mediated cytotoxicity of primary human PBMCs toward CD20- expressing Raji cells. PBMCs were thawed overnight in RPMI+10% FBS + 1% Pen / strep and incubated with Raji cells and NKCEs at an E:T ratio of 10:1 for 4 hours. Comparison to an unmodified anti-CD20 antibody (black) and an anti-CD20 antibody with the LALA-PG mutations (black, dotted) is shown. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. (c) NKCE1 and NKCE1Fc-mediated cytotoxicity of mouse splenocytes toward CD20- expressing Raji cells. Splenocytes were harvested from the spleen of a C57BL / 6 mouse and incubated in RPMI+10% FBS + 1% Pen / strep + 1000U / mL hIL-2 for seven days and incubated with Raji cells and NKCEs at an E:T ratio of 50:1 for 4 hours. Comparison to an unmodified anti- CD20 antibody (black) and an anti-CD20 antibody with the LALA-PG mutations (black, dotted) is shown. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. (d) NKCE1 and NKCE1Fc-mediated activation of primary human NK cells after coculture with CD20- expressing Raji cells. Primary human NK cells were thawed in RPMI, 10% FBS, 1% pen / strep, 1% 2-mercaptoethanol, 1% HEPES, 1% Nonessential Amino Acids, 1% sodium pyruvate, 10ng / mL hIL-15 overnight and incubated with 0.01nM NKCE and Raji cells at an E:T ratio of 1:1 for 4 hours. Cells were then fixed, stained, and analyzed with flow cytometry. (e) Primary NK cell activation against tumor cells. NKCE1 and NKCE1Fc-mediated activation of primary human NK cells during coculture with CD20-expressing Raji cells. Primary human NK cells were incubated with 0.01 nM NKCE and Raji cells at an E:T ratio of 1:1 for 4 h. Cells were then fixed, stained, and analyzed with flow cytometry. Comparison to an unmodified anti-CD20 antibody (black) is shown. FIG.6: Engineering of RLN131 with a second-generation scFv library. (a) Sort scheme of wild-type phage library. Three rounds of phage panning against hNKp46 or mNKp46 were performed. The enriched library was then transformed into yeast and sorted twice with FACS. (b) FACS plot of yeast surface display library to hNKp46-his after three rounds of phage panning. (c) FACS sort plots of yeast surface display library to decreasing concentrations of mNKp46 after three rounds of phage sorting. (d) Amino acid distribution in the four positions mutated using saturation mutagenesis after two rounds of FACS sorting. Sequencing data from ten clones is shown. Plot generated using WebLogo 3.7.4. (e) Binding of RLN131 to hNKp46 and mNKp46 compared to parent clone. Mean + / - SD is shown. N=3. (f) Binding of RLN131 in hIgG1 format to HEK293T cells expressing hNKp46 or mNKp46. Mean + / - SD is shown. N=3. FIG.7: Epitope mapping of anti-NKp46 antibodies. (a) Binding of yeast surface displayed RLN131 to native and denatured hNKp46 and mNKp46. hNKp46 and mNKp46 were denatured by incubation at elevated temperature in the presence of DTT. (b) Binding epitopes of D1, D2, and D1-2. The structure of the hNKp46, D1, and D1-2 complex is from PDB 6IAP. The structure and binding site of D2 is estimated from previous reports. (c) Competition binding of RLN131 to D1, D2, and D1-2 using yeast surface display. D1, D2, and D1-2 in scFv format were displayed on the surface of yeast. Binding to 3nM hNKp46-his complexed to varying concentrations of Atty. Docket: STAN-2131WO (S23-217) RLN131 in Fab format was measured. Mean + / - SD is shown, n=3. (d) BLI sensograms of competition binding of Mab1850 and 9E2 to RLN131. hNKp46 was immobilized on the sensor tip, followed by association of 100nM RLN131 for 300s. After washing, the indicated hNKp46 antibodies at 100nM were associated for another 300s.(e) BLI sensograms of competition binding of D1, D2, and D1-2 to 9E2. hNKp46 was immobilized on the sensor tip, followed by association of 100nM 9E2 for 300s. After washing, the indicated hNKp46 antibodies at 100nM were associated for another 300s. (f) BLI sensograms of competition binding of D1, D2, D1-2, and 9E2 to Mab1850. hNKp46 was immobilized on the sensor tip, followed by association of 100nM Mab1850 for 300s. After washing, the indicated hNKp46 antibodies at 100nM were associated for another 300s. (g) BLI sensograms of competition binding of 29A1.4 to RLN131. mNKp46 was immobilized on the sensor tip, followed by association of 100nM RLN131 for 300s. After washing, 29A1.4 antibody at 100nM were associated for another 300s. (h) Binding of control antibodies to hNKp46 and mNKp46 alanine mutants. 1nM of D1 (in IgG format) to hNKp46 (left) 1nM of a control mNKp46 antibody (right) were incubated with Expi293 cells for 30 minutes at 4C, washed, and stained with anti-human-AF647. Mean + / - SD is shown, n=3. FIG.8: NK cell activation with RLN131. NK cell activation using RLN131. NK cells were thawed in RPMI overnight without activating cytokines. The following day, they were incubated for four hours in either RLN131-coated plates (wells were coated with 5ug / mL RLN131 in PBS overnight) or with soluble RLN131 (5ug / mL). IL-15 was added to the indicated samples. CD107a and IFNg expression is shown. Data is representative of 2 donors. FIG.9: NKCEs expressed for cytotoxicity experiments in this study. RLN131 (green) was used as the NKp46-binding domain and an anti-CD20 (purple) antibody was used as the tumor antigen-binding domain. All antibodies were expressed with hIgG1 constant regions where applicable. Dashed lines denote that the antibody or NKCE was expressed with the LALA-PG mutations to ablate Fc effector function. The unmodified anti-CD20 antibodies are not shown. FIG. 10: (a) Binding of antibodies and NKCEs to hNKp46 and CD20. Antibodies and NKCEs were incubated at 10nM with hNKp46-expressing HEK293T cells or CD20-expressing Raji cells. Cells were stained with anti-human-AF647 antibody except for NKCE6, which was stained with anti-6His-AF647 antibody. (b) NKCE mediated NK cell fratricide of primary human NK cells. NK cells were labeled with calcein blue and incubated with Raji cells and NKCE molecules for four hours. Comparison to an unmodified anti-CD20 antibody (black) is shown. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. (c) Anti-CD20 (black) and anti-CD20Fc-(dashed) cytotoxicity of primary human NK cells toward CD20- expressing Raji cells. NK cells were thawed overnight in RPMI+10% FBS + 1% Pen / strep and incubated with Raji cells and antibodies at an E:T ratio of 2:1 for 4 hours. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. FIG. 11: (a) NKCE3 mediated cytotoxicity of primary human NK cells toward CD20- expressing Raji cells as a function of linker length. NKCE format NKCE5 was expressed with 0 Atty. Docket: STAN-2131WO (S23-217) aa, 5aa, 10aa, and 18aa (G4S)nlinkers between RLN131 and the anti-CD20 antibody. Comparison to an unmodified anti-CD20 antibody (black) is shown. Mean + / - SD from one donor is shown, n=3. Data is representative of 3 donors. (b) NKCE1 and NKCE1Fc-mediated activation of primary human NK cells after coculture with CD20-expressing Raji cells. Primary human NK cells were thawed in RPMI, 10% FBS, 1% pen / strep, 1% 2-mercaptoethanol, 1% HEPES, 1% Nonessential Amino Acids, 1% sodium pyruvate, 10ng / mL hIL-15 overnight and incubated with 0.01nM NKCE and Raji cells at an E:T ratio of 1:1 for 4 hours. Afterwards, cells were fixed, stained, and run on flow cytometry. DETAILED DESCRIPTION Before the antibodies and methods of the present disclosure are described in greater detail, it is to be understood that the antibodies and methods are not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the antibodies and methods will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the antibodies and methods. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the antibodies and methods, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the antibodies and methods. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the antibodies and methods belong. Although any antibodies and methods similar or equivalent to those described herein can also be used in the practice or testing of the antibodies and methods, representative illustrative antibodies and methods are now described. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be Atty. Docket: STAN-2131WO (S23-217) incorporated by reference and are incorporated herein by reference to disclose and describe the materials and / or methods in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present antibodies and methods are not entitled to antedate such publication, as the date of publication provided may be different from the actual publication date which may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. It is appreciated that certain features of the antibodies and methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the antibodies and methods, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace operable processes and / or compositions. In addition, all sub-combinations listed in the embodiments describing such variables are also specifically embraced by the present antibodies and methods and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present methods. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. ANTI-NKP46 ANTIBODIES The present disclosure provides antibodies that specifically bind NKp46 and cross-react with human and mouse NKp46. In some instances, the antibodies further cross-react with cynomolgus monkey NKp46 (cNKp46). According to some embodiments, the antibodies bind to human NKp46 and mouse NKp46 (and optionally cNKp46) with subnanomolar affinities. The antibodies find use in a variety of applications, a non-limiting example of which is increasing NK cell cytotoxicity in subjects in need thereof. Because the antibodies of the present disclosure cross-react with human and mouse NKp46, the antibodies are advantageous as compared to antibodies specific for human NKp46, e.g., by permitting testing in mice without changing the Atty. Docket: STAN-2131WO (S23-217) NKp46 binding sequence to one that binds mouse NKp46. Details regarding the antibodies of the present disclosure will now be provided. The amino acid sequences of the VH polypeptides and VL polypeptides of exemplary antibodies of the present disclosure are provided in Table 1 below. CDR sequences defined according to IMGT and Kabat are provided in separate rows. Antibody RL_7 is also referred to herein as RLN131. Table 1 – Amino Acid Sequences of Example Anti-NKp46 Antibodies RL_1 VH EVQLLESGGGLVQPGGSLRLSCAASGFTYSNYAMSWVRQAPGKGLEWVSVISAG SEQ ID NO:1 GGSTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCARDVQRGVGAFDI W TLVTV S Atty. Docket: STAN-2131WO (S23-217) RL_1 VL CDR3 QQSYSIPTWT SEQ ID NO:14 K b t S L G S L Atty. Docket: STAN-2131WO (S23-217) SEQ ID NO:30 IMGT RL 3 V CDR2 VSGSGAST S S L Atty. Docket: STAN-2131WO (S23-217) RL_4 VH CDR1 SYIMS SEQ ID NO:47 K b t G S L Atty. Docket: STAN-2131WO (S23-217) SEQ ID NO:63 Kabat RL 5 V DI MT SPSSLSASVGDRVTITCRAS SIHSYLNWY KPGKAPKLLIYGASTLLSG S L Atty. Docket: STAN-2131WO (S23-217) SEQ ID NO:80 IMGT RL 6 V CDR3 SYSTPSYT S L Atty. Docket: STAN-2131WO (S23-217) RL_7 VL CDR2 RASRLQS SEQ ID NO:97 K b t S Q Atty. Docket: STAN-2131WO (S23-217) RL_9 VH EVQLLESGGGLVQPGGSLRLSCAASGFRFGNYAMSWVRQAPGKGLEWVSSISGS SEQ ID GGSTYQADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSSGFIDSWGQ NO113 GTLVTVSS G By “antibody” is meant an antibody or immunoglobulin of any isotype (e.g., IgG (e.g., IgG1, IgG2, IgG3, or IgG4), IgE, IgD, IgA, IgM, etc.), whole antibodies (e.g., antibodies composed of a tetramer which in turn is composed of two dimers of a heavy and light chain polypeptide); single chain antibodies (e.g., scFv); fragments of antibodies (e.g., fragments of whole or single chain antibodies) which retain specific binding to the target molecule (e.g., a cell surface molecule Atty. Docket: STAN-2131WO (S23-217) of a target cell), including, but not limited to single chain Fv (scFv), Fab, (Fab’)2, (scFv’)2, and diabodies; chimeric antibodies; monoclonal antibodies, fully human antibodies, humanized antibodies (e.g., humanized whole antibodies, humanized half antibodies, or humanized antibody fragments, e.g., humanized scFv); and fusion proteins comprising an antigen-binding portion of an antibody and a non-antibody protein. In certain embodiments, the antibody is selected from an IgG, single chain Fv (scFv), Fab, (Fab)2, (scFv’)2, or a single variable domain located on a heavy chain (VHH). According to some embodiments, the antibody is a VHH (sometimes referred to herein and elsewhere as a “nanobody”). The antibody may be detectably labeled, e.g., with an in vivo imaging agent, a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and / or the like. In some instances, the antibody is a fully human antibody. An immunoglobulin light or heavy chain variable region is composed of a “framework” region (FR) interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs”. The extent of the framework region and CDRs can be defined based on databases known in the art. See, for example, “Sequences of Proteins of Immunological Interest,” E. Kabat et al., Sequences of proteins of immunological interest, 4th ed. U.S. Dept. Health and Human Services, Public Health Services, Bethesda, MD (1987), Lefranc et al. IMGT, the international ImMunoGeneTics information system®. Nucl. Acids Res., 2005, 33:D593-D597 (www.imgt.org / textes / IMGTScientificChart / ), and / or V Base at vbase.mrc-cpe.cam.ac.uk / ). The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs. The CDRs are primarily responsible for binding to an epitope of an antigen. Any anti-NKp46 antibody of the present disclosure may be a monoclonal antibody. As used herein, the term “monoclonal antibody” refers to an antibody composition having a homogeneous antibody population. The term is not limited by the manner in which it is made. The term encompasses whole immunoglobulin molecules, as well as Fab molecules, F(ab')2 fragments, Fv fragments, single chain fragment variable (scFv), fusion proteins comprising an antigen-binding portion of an antibody and a non-antibody protein, and other molecules that exhibit immunological binding properties of the parent monoclonal antibody molecule. Methods of making monoclonal antibodies are known in the art and described more fully below. Any anti-NKp46 antibody of the present disclosure may be a recombinant or modified antibody, e.g., a chimeric, deimmunized and / or an in vitro generated antibody. The term "recombinant" or "modified" antibody as used herein is intended to include all antibodies that are prepared, expressed, created, or isolated by recombinant means, such as (i) antibodies expressed from one or more recombinant expression vectors transfected into a host cell; (ii) antibodies isolated from a recombinant, combinatorial antibody library; (iii) antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes; or (iv) antibodies prepared, expressed, created, or isolated by any other means that involves splicing of Atty. Docket: STAN-2131WO (S23-217) human immunoglobulin gene sequences to other DNA sequences. Such recombinant antibodies include, e.g., chimeric, deimmunized, and / or in vitro generated antibodies. Any anti-NKp46 antibody of the present disclosure may be isolated. By “isolated” is meant that the antibody is separated from all or some of the components that accompany it in nature. “Isolated” also refers to the state of an antibody separated from all or some of the components that accompany it during manufacture, e.g., chemical synthesis, recombinant expression, culture medium, and / or the like. Any anti-NKp46 antibody of the present disclosure may comprise an extent and / or pattern of glycosylation which is different from the extent and / or pattern of glycosylation of an antibody produced in nature, e.g., produced in an animal (e.g., produced in a human). For example, an anti-NKp46 antibody of the present disclosure may be a recombinant antibody (e.g., a monoclonal antibody) expressed from one or more recombinant expression vectors transfected into a host cell, where the expressed recombinant anti-NKp46 antibody comprises a different extent of glycosylation, a different glycosylation pattern, or both, as compared to the extent of glycosylation and / or glycosylation pattern of a naturally-occurring antibody. In some embodiments, an anti-NKp46 antibody of the present disclosure comprises a heavy chain comprising an Fc region, and the Fc region is heterologous to the VHof the antibody – that is, the Fc region comprises an amino acid sequence (e.g., one or more amino acid substitutions, deletions and / or insertions), one or more post-translational modifications, and / or the like, such that an antibody comprising the combination of the Fc region and the VH does not occur in nature. In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a murine Fc region sequence (e.g.: IgG1, IgG2a or IgG2b) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions (e.g., an IgG4 isotype including the S228P mutation). In certain embodiments, the Fc region is mutated to increase its affinity to FcRn at pH 6.0 and consequently extend the antibody half-life. Antibodies with enhanced affinity to FcRn include those with substitution of one or more of Fc region residues 252, 253, 254, 256, 428, 434, including the so called YTE mutation with substitution M252Y / S254T / T256E (Dall’ Acqua et al, J Immunol.169:5171-5180 (2002)) or LS mutation M428L / N434S (Zalevsky et al, Nat Biotechnol. 28(2): 157–159 (2010)). In certain embodiments, provided is an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement activation and Atty. Docket: STAN-2131WO (S23-217) ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcγR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcγRIII only, whereas monocytes and microglia express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol.9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No.5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499- 1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med.166:1351-1361 (1987)). Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 234, 235, 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No.6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem.9(2): 6591-6604 (2001)). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581) or the so-called “DANG” FC mutant with substitution of residues 265 to alanine and 297 to Glycine. Alternatively, antibodies with reduced effector function include those with substitution of one or more of Fc region residues 234, 235 and 329, so-called “PG-LALA” Fc mutant with substitution of residues 234 and 235 to alanine and 329 to glycine (Lo, M. et al., Journal of Biochemistry, 292, 3900- 3908). Other known mutations at position 234, 235 and 321, the so called TM mutant containing mutations L234F / L235E / P331S in the CH2 domain, can be used (Oganesyan et al. Acta Cryst. D64, 700–704. (2008)). Antibodies from the human IgG4 isotype include mutations S228P / L235E to stabilize the hinge and to reduce FgR binding (Schlothauer et al, PEDS, 29 (10):457–466). Other Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No.7,371,826). See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821. The phrases “specifically binds”, “specific for”, “immunoreactive” and “immunoreactivity”, and “antigen binding specificity”, when referring to an antibody, refer to a binding reaction with an antigen which is highly preferential to the antigen or a fragment thereof, so as to be determinative of the presence of the antigen in the presence of a heterogeneous population of antigens (e.g., proteins and other biologics, e.g., in a sample). Thus, under designated immunoassay conditions, the specified antibodies bind to NKp46 and do not bind in a significant amount to other antigens present in the sample. Specific binding to an antigen under such Atty. Docket: STAN-2131WO (S23-217) conditions may require an antibody that is selected for its specificity for a particular antigen. For example, an anti-NKp46 antibody can specifically bind to NKp46, and does not exhibit comparable binding (e.g., does not exhibit detectable binding) to other proteins present in a sample. In some embodiments, an antibody of the present disclosure “specifically binds” NKp46 if it binds to or associates with NKp46 with an affinity or Ka (that is, an equilibrium association constant of a particular binding interaction with units of 1 / M) of, for example, greater than or equal to about 105M-1. In certain embodiments, the antibody binds to NKp46 with a Kagreater than or equal to about 106M-1, 107M-1, 108M-1, 109M-1, 1010M-1, 1011M-1, 1012M-1, or 1013M-1. “High affinity” binding refers to binding with a Ka of at least 107M-1, at least 108M-1, at least 109M-1, at least 1010M-1, at least 1011M-1, at least 1012M-1, at least 1013M-1, or greater. Alternatively, affinity may be defined as an equilibrium dissociation constant (KD) of a particular binding interaction with units of M (e.g., 10-5M to 10-13M, or less). In some embodiments, specific binding means the antibody binds to NKp46 with a KD of less than or equal to about 10-5M, less than or equal to about 10-6M, less than or equal to about 10-7M, less than or equal to about 10-8M, or less than or equal to about 10-9M, 10-10M, 10-11M, or 10-12M or less. The binding affinity of the antibody for NKp46 can be readily determined using conventional techniques, e.g., by competitive ELISA (enzyme-linked immunosorbent assay), equilibrium dialysis, by using surface plasmon resonance (SPR) technology (e.g., the BIAcore 2000 instrument, using general procedures outlined by the manufacturer); by radioimmunoassay; or the like. An antibody of the present disclosure is said to “cross-react” with (or be "cross-reactive" for) two or more different antigens or antigenic determinants (e.g., NKp46 from two or more different species of mammal, such as human and mouse, and optionally further cynomolgus monkey) if it is specific for (as defined herein) each of these different antigens or antigenic determinants. In certain embodiments, an antibody binding to antigen 1 (Ag1) is "cross-reactive" to antigen 2 (Ag2) when the EC50 and / or KD values are in a similar range for both antigens. According to some embodiments, an antibody binding to Ag1 is cross-reactive to Ag2 when the ratio of affinity for Ag1 to affinity for Ag2 is equal or less 10 (< 10) and equal or greater than 0.1 (>0.1 ), which means that the affinities for Ag1 and Ag2 do not differ more than a factor of 10 (the affinities are within one order of magnitude of monovalent KD), on condition that affinities are measured with the same method in the same experimental setting for both antigens. Accordingly, an antibody of the present disclosure may have a ratio of affinity for human NKp46 to the affinity for mouse NKp46 which is equal or less 10 (< 10) and equal or greater than 0.1 (>0.1 ), which means that the affinities for human and mouse NKp46 do not differ more than a factor of 10 (the affinities are within one order of magnitude of monovalent KD). Alternatively, or additionally, an antibody of the present disclosure may also have a ratio of affinity for human NKp46 to the affinity for cynomolgus NKp46 which is equal or less 10 (< 10) and equal or greater than 0.1 (>0.1 ), which means that the affinities for human and cynomolgus NKp46 do not differ more than a factor Atty. Docket: STAN-2131WO (S23-217) of 10 (the affinities are within one order of magnitude of monovalent KD). Such an antibody may be used, e.g., in toxicological studies performed in cynomolgus monkeys because the toxicity profile observed in cynomolgus monkeys would be relevant to anticipate potential adverse effects in humans. An “epitope” is a site on an antigen to which an antibody binds. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by folding (e.g., tertiary folding) of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a linear or spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed (1996). Several commercial laboratories offer epitope mapping services. Epitopes bound by an antibody immunoreactive with human NKp46 can reside, e.g., on the surface of human NKp46, so that such epitopes are considered human NKp46-surface accessible, solvent accessible, and / or human NKp46-surface exposed. In certain embodiments, the epitope to which an anti-NKp46 antibody of the present disclosure binds comprises the residues Y121A, Y194A and D122A. According to some embodiments, an antibody of the present disclosure specifically binds NKp46 and cross-reacts with human and mouse NKp46 (and optionally further with cynomolgus monkey NKp46 (cNKp46)), wherein the antibody comprises or competes for binding to NKp46 with an antibody comprising: a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:1, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:8; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:15, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:22; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:29, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:36; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:43, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:50; Atty. Docket: STAN-2131WO (S23-217) a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:57, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:64; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:71, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:78; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:85, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:92; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:99, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:106; or a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:113, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:120. In some instances, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:1; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:8. According to some embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or Atty. Docket: STAN-2131WO (S23-217) greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:15; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:22. In certain embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:29; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:36. In some instances, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:43; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:50. According to some embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:57; and Atty. Docket: STAN-2131WO (S23-217) a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:64. In certain embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:71; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:78. In some instances, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:85; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:92. In some instances, the VHof SEQ ID NO:85 comprises F, Y, or C at position 102 rather than R; the VHof SEQ ID NO:85 comprises G, N, C, or T at position 103 rather than A; the VHof SEQ ID NO:85 comprises V at position 104 rather than G; and / or the VHof SEQ ID NO:85 comprises G or S at position 105 rather than N. According to some embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or Atty. Docket: STAN-2131WO (S23-217) greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:99; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:106. In certain embodiments, an antibody of the present disclosure comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:113; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:120. Also provided are multi-specific antibodies. For example, in certain embodiments, a multi- specific antibody of the present disclosure comprises a first antigen-binding domain comprising a VH polypeptide-VL polypeptide pair of any of the anti-NKp46 antibodies of the present disclosure, including any of such antibodies described hereinabove. The multi-specific antibody may include a second antigen-binding domain that specifically binds an NKp46 polypeptide bound by the first antigen-binding domain. In certain embodiments, the multi-specific antibody includes a second antigen-binding domain that specifically binds an antigen other than NKp46. For example, the second antigen- binding domain may specifically bind a tumor antigen. Non-limiting examples of tumor antigens to which the second antigen-binding domain may specifically bind include 5T4, AXL receptor tyrosine kinase (AXL), B-cell maturation antigen (BCMA), c-MET, C4.4a, carbonic anhydrase 6 (CA6), carbonic anhydrase 9 (CA9), Cadherin-6, CD19, CD20, CD22, CD25, CD27L, CD30, CD33, CD37, CD44v6, CD56, CD70, CD74, CD79b, CD123, CD138, carcinoembryonic antigen (CEA), cKit, Cripto protein, CS1, delta-like canonical Notch ligand 3 (DLL3), endothelin receptor type B (EDNRB), EpCAM, ephrin A4 (EFNA4), epidermal growth factor receptor (EGFR), EGFRvIII, ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3), EPH receptor A2 (EPHA2), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), FMS-like tyrosine kinase 3 (FLT3), folate receptor 1 (FOLR1), GLUT3, glycoprotein non-metastatic B (GPNMB), guanylate cyclase 2 C (GUCY2C), HCAM, human epidermal growth Atty. Docket: STAN-2131WO (S23-217) factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), Integrin alpha, lysosomal-associated membrane protein 1 (LAMP-1), Lewis Y, LIV-1, leucine rich repeat containing 15 (LRRC15), mesothelin (MSLN), sodium-dependent phosphate transport protein 2B (NaPi2b), Nectin-4, NMB, NOTCH3, p-cadherin (p-CAD), prostate-specific membrane antigen (PSMA), protein tyrosine kinase 7 (PTK7), solute carrier family 44 member 4 (SLC44A4), SLIT like family member 6 (SLITRK6), STEAP family member 1 (STEAP1), tissue factor (TF), T cell immunoglobulin and mucin protein-1 (TIM-1), trophoblast cell-surface antigen (TROP-2), and VEGF-A. Non-limiting examples of antibodies that specifically bind to tumor antigens whose binding domains may be employed as a second antigen-binding domain include Adecatumumab, Ascrinvacumab, Cixutumumab, Conatumumab, Daratumumab, Drozitumab, Duligotumab, Durvalumab, Dusigitumab, Enfortumab, Enoticumab, Figitumumab, Ganitumab, Glembatumumab, Intetumumab, Ipilimumab, Iratumumab, Icrucumab, Lexatumumab, Lucatumumab, Mapatumumab, Narnatumab, Necitumumab, Nesvacumab, Ofatumumab, Olaratumab, Panitumumab, Patritumab, Pritumumab, Radretumab, Ramucirumab, Rilotumumab, Robatumumab, Seribantumab, Tarextumab, Teprotumumab, Tovetumab, Vantictumab, Vesencumab, Votumumab, Zalutumumab, Flanvotumab, Altumomab, Anatumomab, Arcitumomab, Bectumomab, Blinatumomab, Detumomab, Ibritumomab, Minretumomab, Mitumomab, Moxetumomab, Naptumomab, Nofetumomab, Pemtumomab, Pintumomab, Racotumomab, Satumomab, Solitomab, Taplitumomab, Tenatumomab, Tositumomab, Tremelimumab, Abagovomab, Igovomab, Oregovomab, Capromab, Edrecolomab, Nacolomab, Amatuximab, Bavituximab, Brentuximab, Cetuximab, Derlotuximab, Dinutuximab, Ensituximab, Futuximab, Girentuximab, Indatuximab, Isatuximab, Margetuximab, Rituximab, Siltuximab, Ublituximab, Ecromeximab, Abituzumab, Alemtuzumab, Bevacizumab, Bivatuzumab, Brontictuzumab, Cantuzumab, Cantuzumab, Citatuzumab, Clivatuzumab, Dacetuzumab, Demcizumab, Dalotuzumab, Denintuzumab, Elotuzumab, Emactuzumab, Emibetuzumab, Enoblituzumab, Etaracizumab, Farletuzumab, Ficlatuzumab, Gemtuzumab, Imgatuzumab, Inotuzumab, Labetuzumab, Lifastuzumab, Lintuzumab, Lorvotuzumab, Lumretuzumab, Matuzumab, Milatuzumab, Nimotuzumab, Obinutuzumab, Ocaratuzumab, Otlertuzumab, Onartuzumab, Oportuzumab, Parsatuzumab, Pertuzumab, Pinatuzumab, Polatuzumab, Sibrotuzumab, Simtuzumab, Tacatuzumab, Tigatuzumab, Trastuzumab, Tucotuzumab, Vandortuzumab, Vanucizumab, Veltuzumab, Vorsetuzumab, Sofituzumab, Catumaxomab, Ertumaxomab, Depatuxizumab, Ontuxizumab, Blontuvetmab, Tamtuvetmab, or a tumor antigen-binding variant thereof. Bispecific antibodies of the present disclosure include antibodies having a full-length antibody structure, and bispecific antibody fragments. “Full-length” as used herein refers to an antibody having two full-length antibody heavy chains and two full length antibody light chains. A full-length antibody heavy chain (HC) consists of well-known heavy chain variable and constant Atty. Docket: STAN-2131WO (S23-217) domains VH, CH1, CH2, and CH3. A full-length antibody light chain (LC) consists of well-known light chain variable and constant domains VL and CL. The full-length antibody may be lacking the C-terminal lysine in either one or both heavy chains. The term “Fab arm” refers to one heavy chain:light chain pair that specifically binds an antigen. Full-length bispecific antibodies may be generated for example using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in a cell-free environment or using co-expression. The Fab arm exchange reaction is the result of a disulfide- bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parent monospecific antibodies are reduced. The resulting free cysteines of one of the parent monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parent monospecific antibody molecule and simultaneously CH3 domains of the parent antibodies release and reform by dissociation- association. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope. The “knob-in-hole” strategy (see, e.g., WO 2006 / 028936) may be used to generate full length bispecific antibodies. Briefly, selected amino acids forming the interface of the CHS domains in human lgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob”. Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y7F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T3945 / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V. Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US2010 / 0015133; US2009 / 0182127; US2010 / 028637 or US2011 / 0123532. In other strategies. heterodimerization may be promoted by the following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351 Y_F405A_Y407V T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351 Y_Y407A'T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or Atty. Docket: STAN-2131WO (S23-217) T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in US2012 / 0149876 or US2013 / 0195849. Also provided are single chain bispecific antibodies. In some embodiments, a single chain bispecific antibody of the present disclosure is a bispecific scFv. Details regarding bispecific scFvs may be found, e.g., in Zhou et al. (2017) J Cancer 8(18):3689-3696. Approaches that may be employed to produce multispecific (e.g., bispecific) antibodies from the antibodies described herein include, but are not limited to, Ellerman, D. (2019). "Bispecific T-cell engagers: Towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety." Methods 154: 102- 117; Brinkmann, U. and R. E. Kontermann (2017). "The making of bispecific antibodies." mAbs 9(2): 182-212; and Suurs, F. V., et al. (2019). "A review of bispecific antibodies and antibody constructs in oncology and clinical challenges." Pharmacol Ther 201: 103-119; the disclosures of which are incorporated herein by reference in their entireties for all purposes. Fusion Proteins Also provided are fusion proteins. In certain embodiments, a fusion protein of the present disclosure comprises a chain of any of the anti-NKp46 antibodies of the present disclosure, fused to a heterologous sequence of amino acids. The heterologous sequence of amino acids may be fused to the C-terminus of the chain of the antibody or the N-terminus of the chain of the antibody. In certain embodiments, a fusion protein of the present disclosure includes a heterologous sequence at the C-terminus of the chain of the antibody and a heterologous sequence at the N- terminus of the chain of the antibody, wherein the heterologous sequences may be the same sequence or different sequences. “Heterologous” as used in the context of a nucleic acid or polypeptide generally means that the nucleic acid or polypeptide is from a different origin (e.g., molecule of different sequence, different species origin, and the like) than that with which the nucleic acid or polypeptide is associated or joined, such that the nucleic acid or polypeptide is one that is not found in nature. For example, in a fusion protein, a light chain polypeptide and a reporter polypeptide (e.g., GFP, red fluorescent protein (e.g., mCherry), luciferase, etc.) are said to be “heterologous” to one another. Similarly, a CDR from a mouse antibody and a constant region from a human antibody are “heterologous” to one another. The chain of the anti-NKp46 antibody may be fused to any heterologous sequence of interest. Heterologous sequences of interest include, but are not limited to, an albumin, a transferrin, XTEN, a homo-amino acid polymer, a proline-alanine-serine polymer, an elastin-like peptide, or any combination thereof. In certain aspects, the heterologous polypeptide increases the stability and / or serum half-life of the antibody upon its administration to an individual in need thereof, as compared to the same antibody which is not fused to the heterologous sequence. In certain embodiments, a fusion protein of the present disclosure comprises a single chain antibody, e.g., a single chain antibody (e.g., scFv) comprising a VHpolypeptide-VL Atty. Docket: STAN-2131WO (S23-217) polypeptide pair of any of the anti-NKp46 antibodies of the present disclosure, including any of such antibodies described hereinabove. Conjugates The present disclosure also provides conjugates. According to some embodiments, a conjugate of the present disclosure comprises any of the antibodies or fusion proteins of the present disclosure, and an agent conjugated to the antibody or fusion protein. The term “conjugated” generally refers to a chemical linkage, either covalent or non-covalent, usually covalent, that proximally associates one molecule of interest with a second molecule of interest. In certain embodiments, the agent conjugated to the antibody or fusion protein is a chemotherapeutic agent, a toxin, a radiation-sensitizing agent, a radioactive isotope (e.g., a therapeutic radioactive isotope), a detectable label, or a half-life extending moiety. According to some embodiments, the agent is a labeling agent. By “labeling agent” (or “detectable label”) is meant the agent detectably labels the antibody or fusion protein, such that the antibody or fusion protein may be detected in an application of interest (e.g., in vitro and / or in vivo research and / or clinical applications). Detectable labels of interest include radioisotopes (e.g., gamma or positron emitters), enzymes that generate a detectable product (e.g., horseradish peroxidase, alkaline phosphatase, luciferase, etc.), fluorescent proteins, paramagnetic atoms, and the like. In certain aspects, the antibody or fusion protein is conjugated to a specific binding partner of detectable label, e.g., conjugated to biotin such that detection may occur via a detectable label that includes avidin / streptavidin. In certain embodiments, the agent is a labeling agent that finds use in in vivo imaging, such as near-infrared (NIR) optical imaging, single-photon emission computed tomography (SPECT) ± CT imaging, positron emission tomography (PET) ± CT imaging, nuclear magnetic resonance (NMR) spectroscopy, or the like. Labeling agents that find use in such applications include, but are not limited to, fluorescent labels, radioisotopes, and the like. In certain aspects, the labeling agent is a multi-modal in vivo imaging agent that permits in vivo imaging using two or more imaging approaches (e.g., see Thorp-Greenwood and Coogan (2011) Dalton Trans. 40:6129-6143). In certain embodiments, the labeling agent is an in vivo imaging agent that finds use in near-infrared (NIR) imaging applications. Such agents include, but are not limited to, a Kodak X- SIGHT dye, Pz 247, DyLight 750 and 800 Fluors, Cy 5.5 and 7 Fluors, Alexa Fluor 680 and 750 Dyes, IRDye 680 and 800CW Fluors. According to some embodiments, the labeling agent is an in vivo imaging agent that finds use in SPECT imaging applications, non-limiting examples of which include99mTc,111In,123I,201Tl, and133Xe. In certain embodiments, the labeling agent is an in vivo imaging agent that finds use in PET imaging applications, e.g.,11C,13N,15O,18F,64Cu,62Cu,124I,76Br,82Rb,68Ga, or the like. Atty. Docket: STAN-2131WO (S23-217) For half-life extension, the antibodies and fusion proteins of the present disclosure may be conjugated to an agent that provides for an improved pharmacokinetic profile (e.g., by PEGylation, hyperglycosylation, and the like). Modifications that can enhance serum half-life are of interest. A subject antibody or fusion protein may be “PEGylated”, as containing one or more poly(ethylene glycol) (PEG) moieties. Methods and reagents suitable for PEGylation of a protein are well known in the art and may be found, e.g., in US Pat. No. 5,849,860. PEG suitable for conjugation to a protein is generally soluble in water at room temperature and has the general formula R(O-CH2-CH2)nO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons. The PEG conjugated to the subject antibody or fusion protein can be linear. The PEG conjugated to the subject antibody or fusion protein may also be branched. Branched PEG derivatives such as those described in U.S. Pat. No.5,643,575, “star- PEGs” and multi-armed PEGs. Star PEGs are described in the art including, e.g., in U.S. Patent No.6,046,305. Where the subject antibody or fusion protein is to be isolated from a source, the antibody or fusion protein may be conjugated to one or more moieties that facilitate purification, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), a lectin, and the like. The antibody can also be bound to (e.g., immobilized onto) a solid support, including, but not limited to, polystyrene plates or beads, magnetic beads, test strips, membranes, and the like. Where the antibodies or fusion proteins are to be detected in an assay, the antibodies or fusion proteins may contain a detectable label, e.g., a radioisotope (e.g.,89Zr;111In, and the like), an enzyme which generates a detectable product (e.g., luciferase, β-galactosidase, horse radish peroxidase, alkaline phosphatase, and the like), a fluorescent protein, a chromogenic protein, dye (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g.,152Eu, or others of the lanthanide series, attached to the protein through metal chelating groups such as EDTA; chemiluminescent compounds, e.g., luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g., luciferin; fluorescent proteins; and the like. Indirect labels include antibodies specific for a subject protein, wherein the antibody may be detected via a secondary antibody; and members of specific binding pairs, e.g., biotin-avidin, and the like. Any of the above agents may be conjugated to the antibody or fusion protein via a linker. If present, the linker molecule(s) may be of sufficient length to permit the antibody or fusion protein and the linked agent to allow some flexible movement between the antibody or fusion protein and the linked agent. Linker molecules may be, e.g., about 6-50 atoms long. Linker molecules may also be, e.g., aryl acetylene, ethylene glycol oligomers containing 2-10 monomer units, diamines, diacids, amino acids, or combinations thereof. Atty. Docket: STAN-2131WO (S23-217) Where the linkers are peptides, the linkers can be of any suitable length, such as from 1 amino acid (e.g., Gly) to 20 or more amino acids, from 2 amino acids to 15 amino acids, from 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and may be 1, 2, 3, 4, 5, 6, or 7 amino acids in length. Flexible linkers include glycine polymers (G)n, glycine-serine polymers, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers may be used where relatively unstructured amino acids are of interest, and may serve as a neutral tether between components. The ordinarily skilled artisan will recognize that design of an antibody or fusion protein conjugated to any agents described above can include linkers that are all or partially flexible, such that the linker can include a flexible linker as well as one or more portions that confer a less flexible structure. According to some embodiments, the antibody or fusion protein is conjugated to the agent via a non-cleavable linker. Non-cleavable linkers of interest include, but are not limited to, thioether linkers. An example of a thioether linker that may be employed includes a succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker. In certain embodiments, the antibody is conjugated to the agent via a cleavable linker. According to some embodiments, the linker is a chemically-labile linker, such as an acid- cleavable linker that is stable at neutral pH (bloodstream pH 7.3-7.5) but undergoes hydrolysis upon internalization into the mildly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) of a target cell (e.g., a cancer cell). Chemically-labile linkers include, but are not limited to, hydrazone-based linkers, oxime-based linkers, carbonate-based linkers, ester-based linkers, etc. In certain embodiments, the linker is an enzyme-labile linker, such as an enzyme-labile linker that is stable in the bloodstream but undergoes enzymatic cleavage upon internalization into a target cell, e.g., by a lysosomal protease (such as cathepsin or plasmin) in a lysosome of the target cell (e.g., a cancer cell). Enzyme-labile linkers include, but are not limited to, linkers that include peptidic bonds, e.g., dipeptide-based linkers such as valine-citrulline (VC) linkers, such as a maleimidocaproyl-valine-citruline-p-aminobenzyl (MC-vc-PAB) linker, a valyl-alanyl-para- aminobenzyloxy (Val-Ala-PAB) linker, and the like. Chemically-labile linkers, enzyme-labile, and non-cleavable linkers are known and described in detail, e.g., in Ducry & Stump (2010) Bioconjugate Chem.21:5-13; Nolting, B. (2013) Methods Mol Biol.1045:71-100; Tsuchikama and An (2018) Protein & Cell 9(1):33-46; and elsewhere. Numerous strategies are available for linking agents to an antibody or fusion protein directly, or indirectly via a linker. For example, the agent may be derivatized by covalently attaching a linker to the agent, where the linker has a functional group capable of reacting with a “chemical handle” on the antibody or fusion protein. The functional group on the linker may vary and may be selected based on compatibility with the chemical handle on the antibody or fusion protein. According to one embodiment, the chemical handle on the antibody or fusion protein is Atty. Docket: STAN-2131WO (S23-217) provided by incorporation of an unnatural amino acid having the chemical handle into the antibody or fusion protein. Unnatural amino acids which find use for preparing the conjugates of the present disclosure include those having a functional group selected from an azide, alkyne, alkene, amino-oxy, hydrazine, aldehyde (e.g., formylglycine, e.g., SMARTagTMtechnology from Catalent Pharma Solutions), nitrone, nitrile oxide, cyclopropene, norbornene, iso-cyanide, aryl halide, and boronic acid functional group. Unnatural amino acids which may be incorporated into an antibody of a conjugate of the present disclosure, which unnatural amino acid may be selected to provide a functional group of interest, are known and described in, e.g., Maza et al. (2015) Bioconjug. Chem.26(9):1884-9; Patterson et al. (2014) ACS Chem. Biol.9:592−605; Adumeau et al. (2016) Mol. Imaging Biol. (2):153-65; and elsewhere. An unnatural amino acid may be incorporated into an antibody or fusion protein via chemical synthesis or recombinant approaches, e.g., using a suitable orthogonal amino acyl tRNA synthetase-tRNA pair for incorporation of the unnatural amino acid during translation of the antibody or fusion protein in a host cell. The functional group of an unnatural amino acid present in the antibody or fusion protein may be an azide, alkyne, alkene, amino-oxy, hydrazine, aldehyde, asaldehyde, nitrone, nitrile oxide, cyclopropene, norbornene, iso-cyanide, aryl halide, boronic acid, diazo, tetrazine, tetrazole, quadrocyclane, iodobenzene, or other suitable functional group, and the functional group on the linker is selected to react with the functional group of the unnatural amino acid (or vice versa). As just one example, an azide-bearing unnatural amino acid (e.g., 5-azido-L- norvaline, or the like) may be incorporated into the antibody or fusion protein and the linker portion of a linker-agent moiety may include an alkyne functional group, such that the antibody or fusion protein and linker-agent moiety are covalently conjugated via azide-alkyne cycloaddition. Conjugation may be carried out using, e.g., a copper-catalyzed azide-alkyne cycloaddition reaction. In certain embodiments, the chemical handle on the antibody or fusion protein does not involve an unnatural amino acid. An antibody containing no unnatural amino acids may be conjugated to the agent by utilizing, e.g., nucleophilic functional groups of the antibody or fusion protein (such as the N-terminal amine or the primary amine of lysine, or any other nucleophilic amino acid residue) as a nucleophile in a substitution reaction with a moiety bearing a reactive leaving group or other electrophilic group. An example would be to prepare an agent-linker moiety bearing an N-hydroxysuccinimidyl (NHS) ester and allow it to react with the antibody or fusion protein under aqueous conditions at elevated pH (~10) or in polar organic solvents such as DMSO with an added non-nucleophilic base, such as N,N-diisopropylethylamine. It will be appreciated that the particular approach for attaching a linker, agent and / or antibody or fusion protein to each other may vary depending upon the particular linker, agent and / or antibody or fusion protein and functional groups selected and employed for conjugating the various components to each other. Atty. Docket: STAN-2131WO (S23-217) Methods of Producing Antibodies Using the information provided herein, the anti-NKp46 antibodies and fusion proteins of the present disclosure may be prepared using standard techniques well known to those of skill in the art. For example, a nucleic acid sequence(s) encoding the amino acid sequence of an antibody or fusion protein of the present disclosure can be used to express the antibodies or fusion proteins. Because of the knowledge of the codons corresponding to the various amino acids, availability of an amino acid sequence of a polypeptide of interest provides a description of all the polynucleotides capable of encoding the polypeptide of interest. The degeneracy of the genetic code, where the same amino acids are encoded by alternative or synonymous codons allows an extremely large number of nucleic acids to be made, all of which encode the enzymes disclosed herein. Thus, having identified a particular amino acid sequence, those of ordinary skill in the art could make any number of different nucleic acids by simply modifying the sequence of one or more codons in a way which does not change the amino acid sequence of the polypeptide of interest. In this regard, the present disclosure specifically contemplates each and every possible variation of polynucleotides that could be made by selecting combinations based upon the possible codon choices, and all such variations are to be considered specifically disclosed for any polypeptide disclosed herein, including the amino acid sequences of SEQ ID NOs.1-26. The nucleotide sequences of the nucleic acids of the present disclosure may be codon- optimized. “Codon-optimized” refers to changes in the codons of the polynucleotide encoding a polypeptide to those preferentially used in a particular organism such that the encoded protein is efficiently expressed in the organism of interest. Although the genetic code is degenerate in that most amino acids are represented by several codons, called “synonyms” or “synonymous” codons, it is well known that codon usage by particular organisms is nonrandom and biased towards particular codon triplets. This codon usage bias may be higher in reference to a given gene, genes of common function or ancestral origin, highly expressed proteins versus low copy number proteins, and the aggregate protein coding regions of an organism's genome. In some embodiments, a nucleic acid of the present disclosure encoding a polypeptide may be codon- optimized for optimal production from the host organism selected for expression, e.g., human cells (e.g., CHO cells, HEK293 cells, or the like). Once a nucleic acid(s) encoding a subject antibody is synthesized, it can be amplified and / or cloned according to standard methods. Molecular cloning techniques to achieve these ends are known in the art. A wide variety of cloning and in vitro amplification methods suitable for the construction of recombinant nucleic acids are known to persons of skill in the art and are the subjects of numerous textbooks and laboratory manuals. Expression of natural or synthetic nucleic acids encoding the antibodies and fusion proteins of the present disclosure can be achieved by operably linking a nucleic acid encoding the antibody or fusion protein to a promoter (which is either constitutive or inducible), and Atty. Docket: STAN-2131WO (S23-217) incorporating the construct into an expression vector to generate a recombinant expression vector. The vectors can be suitable for replication and integration in prokaryotes, eukaryotes, or both. Typical cloning vectors contain functionally appropriately oriented transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the nucleic acid encoding the antibody. The vectors optionally contain generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in both eukaryotes and prokaryotes, e.g., as found in shuttle vectors, and selection markers for both prokaryotic and eukaryotic systems. To obtain high levels of expression of a cloned nucleic acid it is common to construct expression plasmids which typically contain a strong promoter to direct transcription, a ribosome binding site for translational initiation, and a transcription / translation terminator, each in functional orientation to each other and to the protein-encoding sequence. Examples of regulatory regions suitable for this purpose in E. coli are the promoter and operator region of the E. coli tryptophan biosynthetic pathway, the leftward promoter of phage lambda (PL), and the L-arabinose (araBAD) operon. The inclusion of selection markers in DNA vectors transformed in E. coli is also useful. Examples of such markers include genes specifying resistance to ampicillin, tetracycline, or chloramphenicol. Expression systems for expressing antibodies are available using, for example, E. coli, Bacillus sp. and Salmonella. E. coli systems may also be used. The antibody gene(s) may also be subcloned into an expression vector that allows for the addition of a tag (e.g., FLAG, hexahistidine, and the like) at the C-terminal end or the N-terminal end of the antibody (e.g., IgG, Fab, scFv, etc.) to facilitate purification. Methods of transfecting and expressing genes in mammalian cells are known in the art. Transducing cells with nucleic acids can involve, for example, incubating lipidic microparticles containing nucleic acids with cells or incubating viral vectors containing nucleic acids with cells within the host range of the vector. The culture of cells used in the present disclosure, including cell lines and cultured cells from tissue (e.g., tumor) or blood samples is well known in the art. Once the nucleic acid encoding a subject antibody is isolated and cloned, one can express the nucleic acid in a variety of recombinantly engineered cells known to those of skill in the art. Examples of such cells include bacteria, yeast, filamentous fungi, insect (e.g. those employing baculoviral vectors), and mammalian cells. Isolation and purification of a subject antibody can be accomplished according to methods known in the art. For example, a protein can be isolated from a lysate of cells genetically modified to express the protein constitutively and / or upon induction, or from a synthetic reaction mixture, by immunoaffinity purification (or precipitation using Protein L or A), washing to remove non- specifically bound material, and eluting the specifically bound antibody. The isolated antibody can be further purified by dialysis and other methods normally employed in protein purification methods. In one embodiment, the antibody may be isolated using metal chelate chromatography Atty. Docket: STAN-2131WO (S23-217) methods. Antibodies of the present disclosure may contain modifications to facilitate isolation, as discussed above. The antibodies may be prepared in substantially pure or isolated form (e.g., free from other polypeptides). The protein can be present in a composition that is enriched for the polypeptide relative to other components that may be present (e.g., other polypeptides or other host cell components). Purified antibodies may be provided such that the antibody is present in a composition that is substantially free of other expressed proteins, e.g., less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of other expressed proteins. The antibodies produced by prokaryotic cells may require exposure to chaotropic agents for proper folding. During purification from E. coli, for example, the expressed protein can be optionally denatured and then renatured. This can be accomplished, e.g., by solubilizing the bacterially produced antibodies in a chaotropic agent such as guanidine HCl. The antibody is then renatured, either by slow dialysis or by gel filtration. Alternatively, nucleic acid encoding the antibodies may be operably linked to a secretion signal sequence such as pelB so that the antibodies are secreted into the periplasm in correctly-folded form. The present disclosure also provides cells that produce the antibodies of the present disclosure, where suitable cells include eukaryotic cells, e.g., mammalian cells. The cells can be a hybrid cell or “hybridoma” that is capable of reproducing antibodies in vitro (e.g. monoclonal antibodies, such as IgG). For example, the present disclosure provides a recombinant host cell (also referred to herein as a “genetically modified host cell”) that is genetically modified with one or more nucleic acids comprising a nucleotide sequence encoding a heavy and / or light chain of an antibody of the present disclosure. Techniques for creating recombinant DNA versions of the antigen-binding regions of antibody molecules which bypass the generation of hybridomas are also contemplated herein. DNA is cloned into a bacterial (e.g., bacteriophage), yeast (e.g. Saccharomyces or Pichia), insect or mammalian expression system, for example. One example of a suitable technique uses a bacteriophage lambda vector system having a leader sequence that causes the expressed antibody (e.g. Fab or scFv) to migrate to the periplasmic space (between the bacterial cell membrane and the cell wall) or to be secreted. One can rapidly generate great numbers of functional fragments (e.g. Fab or scFv) for those which bind the antigen of interest. Antibodies that specifically bind NK-p46 can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, phage display technologies, Selected Lymphocyte Antibody Method (SLAM), or a combination thereof. For example, an antibody may be made and isolated using methods of phage display. Phage display is used for the high-throughput screening of protein interactions. Phages may be utilized to display antigen-binding domains expressed from a repertoire or combinatorial antibody library Atty. Docket: STAN-2131WO (S23-217) (e.g., human or murine). Phage expressing an antigen binding domain that binds human NKp46 can be selected or identified with human NKp46, e.g., using labeled human NKp46 bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv (individual Fv region from light or heavy chains) or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. The production of high affinity human antibodies by chain shuffling is known, as are combinatorial infection and in vivo recombination as a strategy for constructing large phage libraries. In another embodiment, ribosomal display can be used to replace bacteriophage as the display platform. Cell surface libraries may be screened for antibodies. Such procedures provide alternatives to traditional hybridoma techniques for the isolation and subsequent cloning of monoclonal antibodies. After phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria. For example, techniques to recombinantly produce Fv, scFv, Fab, F(ab')2, and Fab' fragments may be employed using methods known in the art. Nucleic Acids, Expression Vectors and Cells In view of the section above regarding methods of producing the antibodies and fusion proteins of the present disclosure, it will be appreciated that the present disclosure also provides nucleic acids, expression vectors and cells. In certain embodiments, provided is a nucleic acid encoding a variable heavy chain (VH) polypeptide, a variable light chain (VL) polypeptide, or both, of an antibody or fusion protein of the present disclosure, including any of the anti-NKp46 antibodies of the present disclosure, e.g., any of such antibodies described hereinabove. According to some embodiments, the antibody is a single chain antibody (e.g., an scFv), and the nucleic acid encodes the single chain antibody. According to some embodiments, provided is a nucleic acid that encodes a CAR of the present disclosure, e.g., a CAR comprising: a single chain antibody comprising a VHpolypeptide and a VL polypeptide of an anti-NKp46 antibody of the present disclosure; a transmembrane domain; and an intracellular signaling domain. Examples of such single chain antibodies, transmembrane domains, and intracellular signaling domains are described in detail above. Also provided are expression vectors comprising any of the nucleic acids of the present disclosure. Expression of natural or synthetic nucleic acids encoding the antibodies and fusion proteins of the present disclosure can be achieved by operably linking a nucleic acid encoding the antibody or fusion protein to a promoter (which is either constitutive or inducible) and incorporating the construct into an expression vector to generate a recombinant expression vector. The vectors can be suitable for replication and integration in prokaryotes, eukaryotes, or Atty. Docket: STAN-2131WO (S23-217) both. Typical cloning vectors contain functionally appropriately oriented transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the nucleic acid encoding the antibody. The vectors optionally contain generic expression cassettes containing at least one independent terminator sequence, sequences permitting replication of the cassette in both eukaryotes and prokaryotes, e.g., as found in shuttle vectors, and selection markers for both prokaryotic and eukaryotic systems. Cells that comprise any of the nucleic acids and / or expression vectors of the present disclosure are also provided. According to some embodiments, a cell of the present disclosure includes a nucleic acid that encodes the VH polypeptide of the antibody and the VL polypeptide of the antibody. In certain such embodiments, the antibody is a single chain antibody (e.g., an scFv), and the nucleic acid encodes the single chain antibody. According to some embodiments, provided is a cell comprising a first nucleic acid encoding a variable heavy chain (VH) polypeptide of an antibody of the present disclosure, and a second nucleic acid encoding a variable light chain (VL) polypeptide of the antibody. In certain embodiments, such as cell comprises a first expression vector comprising the first nucleic acid, and a second expression vector comprising the second nucleic acid. Also provided are methods of making an antibody or fusion protein of the present disclosure, the methods including culturing a cell of the present disclosure under conditions suitable for the cell to express the antibody or fusion protein, wherein the antibody or fusion protein is produced. The conditions for culturing the cell such that the antibody or fusion protein is expressed may vary. Such conditions may include culturing the cell in a suitable container (e.g., a cell culture plate or well thereof), in suitable medium (e.g., cell culture medium, such as DMEM, RPMI, MEM, IMDM, DMEM / F-12, or the like) at a suitable temperature (e.g., 32°C - 42°C, such as 37°C) and pH (e.g., pH 7.0 - 7.7, such as pH 7.4) in an environment having a suitable percentage of CO2, e.g., 3% to 10%, such as 5%). COMPOSITIONS As summarized above, the present disclosure also provides compositions. According to some embodiments, a composition of the present disclosure includes an antibody, fusion protein, or conjugate of the present disclosure. For example, the antibody, fusion protein, or conjugate may be any of the antibodies, fusion proteins, or conjugates described in the Antibodies section hereinabove, which descriptions are incorporated but not reiterated herein for purposes of brevity. In certain aspects, a composition of the present disclosure includes the antibody, fusion protein, or conjugate present in a liquid medium. The liquid medium may be an aqueous liquid medium, such as water, a buffered solution, or the like. One or more additives such as a salt (e.g., NaCl, MgCl2, KCl, MgSO4), a buffering agent (a Tris buffer, N-(2-Hydroxyethyl)piperazine- N'-(2-ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid Atty. Docket: STAN-2131WO (S23-217) (MOPS), N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), etc.), a solubilizing agent, a detergent (e.g., a non-ionic detergent such as Tween-20, etc.), a nuclease inhibitor, a protease inhibitor, glycerol, a chelating agent, and the like may be present in such compositions. Aspects of the present disclosure further include pharmaceutical compositions. In some embodiments, a pharmaceutical composition of the present disclosure includes an anti-NKp46 antibody of the present disclosure (or conjugate or fusion protein comprising same), and a pharmaceutically acceptable carrier. The antibodies, fusion proteins, or conjugates can be incorporated into a variety of formulations for therapeutic administration. More particularly, the antibodies, fusion proteins, or conjugates can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable excipients or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, inhalants and aerosols. Formulations of the antibodies, fusion proteins, or conjugates for administration to an individual (e.g., suitable for human administration) are generally sterile and may further be free of detectable pyrogens or other contaminants contraindicated for administration to a patient according to a selected route of administration. In pharmaceutical dosage forms, the antibodies, fusion proteins, or conjugates can be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and carriers / excipients are merely examples and are in no way limiting. For oral preparations, the antibodies, fusion proteins, or conjugates can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents. The antibodies, fusion proteins, or conjugates can be formulated for parenteral (e.g., intravenous, intra-arterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrathecal, subcutaneous, etc.) administration. In certain aspects, the antibodies, fusion proteins, or conjugates are formulated for injection by dissolving, suspending or emulsifying the antibodies, fusion proteins, or conjugates in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Atty. Docket: STAN-2131WO (S23-217) Pharmaceutical compositions that include the antibodies, fusion proteins, or conjugates may be prepared by mixing the antibodies, fusion proteins, or conjugates having the desired degree of purity with optional physiologically acceptable carriers, excipients, stabilizers, surfactants, buffers and / or tonicity agents. Acceptable carriers, excipients and / or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid, glutathione, cysteine, methionine and citric acid; preservatives (such as ethanol, benzyl alcohol, phenol, m- cresol, p-chlor-m-cresol, methyl or propyl parabens, benzalkonium chloride, or combinations thereof); amino acids such as arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, proline and combinations thereof; monosaccharides, disaccharides and other carbohydrates; low molecular weight (less than about 10 residues) polypeptides; proteins, such as gelatin or serum albumin; chelating agents such as EDTA; sugars such as trehalose, sucrose, lactose, glucose, mannose, maltose, galactose, fructose, sorbose, raffinose, glucosamine, N-methylglucosamine, galactosamine, and neuraminic acid; and / or non-ionic surfactants such as Tween, Brij Pluronics, Triton-X, or polyethylene glycol (PEG). The pharmaceutical composition may be in a liquid form, a lyophilized form or a liquid form reconstituted from a lyophilized form, wherein the lyophilized preparation is to be reconstituted with a sterile solution prior to administration. The standard procedure for reconstituting a lyophilized composition is to add back a volume of pure water (typically equivalent to the volume removed during lyophilization); however solutions comprising antibacterial agents may be used for the production of pharmaceutical compositions for parenteral administration. An aqueous formulation of the antibodies, fusion proteins, or conjugates may be prepared in a pH-buffered solution, e.g., at pH ranging from about 4.0 to about 7.0, or from about 5.0 to about 6.0, or alternatively about 5.5. Examples of buffers that are suitable for a pH within this range include phosphate-, histidine-, citrate-, succinate-, acetate-buffers and other organic acid buffers. The buffer concentration can be from about 1 mM to about 100 mM, or from about 5 mM to about 50 mM, depending, e.g., on the buffer and the desired tonicity of the formulation. A tonicity agent may be included to modulate the tonicity of the formulation. Example tonicity agents include sodium chloride, potassium chloride, glycerin and any component from the group of amino acids, sugars as well as combinations thereof. In some embodiments, the aqueous formulation is isotonic, although hypertonic or hypotonic solutions may be suitable. The term "isotonic" denotes a solution having the same tonicity as some other solution with which it is compared, such as physiological salt solution or serum. Tonicity agents may be used in an amount of about 5 mM to about 350 mM, e.g., in an amount of 100 mM to 350 mM. A surfactant may also be added to the formulation to reduce aggregation and / or minimize the formation of particulates in the formulation and / or reduce adsorption. Example surfactants include polyoxyethylensorbitan fatty acid esters (Tween), polyoxyethylene alkyl ethers (Brij), Atty. Docket: STAN-2131WO (S23-217) alkylphenylpolyoxyethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic), and sodium dodecyl sulfate (SDS). Examples of suitable polyoxyethylenesorbitan-fatty acid esters are polysorbate 20, (sold under the trademark Tween 20™) and polysorbate 80 (sold under the trademark Tween 80™). Examples of suitable polyethylene-polypropylene copolymers are those sold under the names Pluronic® F68 or Poloxamer 188™. Examples of suitable Polyoxyethylene alkyl ethers are those sold under the trademark Brij™. Example concentrations of surfactant may range from about 0.001% to about 1% w / v. A lyoprotectant may also be added in order to protect the antibody, fusion protein, or conjugate against destabilizing conditions during a lyophilization process. For example, known lyoprotectants include sugars (including glucose and sucrose); polyols (including mannitol, sorbitol and glycerol); and amino acids (including alanine, glycine and glutamic acid). Lyoprotectants can be included, e.g., in an amount of about 10 mM to 500 nM. In some embodiments, the pharmaceutical composition includes the antibody, fusion protein, or conjugate, and one or more of the above-identified components (e.g., a surfactant, a buffer, a stabilizer, a tonicity agent) and is essentially free of one or more preservatives, such as ethanol, benzyl alcohol, phenol, m-cresol, p-chlor-m-cresol, methyl or propyl parabens, benzalkonium chloride, and combinations thereof. In other embodiments, a preservative is included in the formulation, e.g., at concentrations ranging from about 0.001 to about 2% (w / v). KITS Aspects of the present disclosure further include kits. In certain embodiments, the kits find use in practicing the methods of the present disclosure, including but not limited to, methods of activating natural killer (NK) cells in a subject in need thereof, and methods of increasing NK cell cytotoxicity in a subject in need thereof. Accordingly, in certain embodiments, a kit of the present disclosure comprises any of the pharmaceutical compositions of the present disclosure, and instructions for administering the pharmaceutical composition to an individual in need thereof. The pharmaceutical composition included in the kit may include any of the antibodies, fusion proteins, and / or conjugates of the present disclosure, e.g., any of the antibodies, fusion proteins, and / or conjugates described hereinabove. As will be appreciated, the kits of the present disclosure may include any of the agents and features described above in the sections relating to the subject antibodies, fusion proteins, conjugates and compositions, which are not reiterated herein for purposes of brevity. The kits of the present disclosure may include a quantity of the compositions, present in unit dosages, e.g., ampoules, or a multi-dosage format. As such, in certain embodiments, the kits may include one or more (e.g., two or more) unit dosages (e.g., ampoules) of a composition that includes an antibody, fusion protein, and / or conjugate of the present disclosure. The term “unit dosage”, as used herein, refers to physically discrete units suitable as unitary dosages for human Atty. Docket: STAN-2131WO (S23-217) and animal subjects, each unit containing a predetermined quantity of the composition calculated in an amount sufficient to produce the desired effect. The amount of the unit dosage depends on various factors, such as the particular antibody, fusion protein, and / or conjugate employed, the effect to be achieved, and the pharmacodynamics associated with the antibody, fusion protein, and / or conjugate, in the individual. In yet other embodiments, the kits may include a single multi dosage amount of the composition. The instructions (e.g., instructions for use (IFU)) included in the kits may be recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g., portable flash drive, DVD, CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded. As with the instructions, the means for obtaining the instructions is recorded on a suitable substrate. METHODS OF USE Aspects of the present disclosure further include methods of using the antibodies, fusion proteins, and conjugates of the present disclosure. The methods are useful in a variety of contexts, including in vitro and / or in vivo research and / or clinical applications. In certain embodiments, provided are methods of activating natural killer (NK) cells in a subject in need thereof, the methods comprising administering to the subject any of the antibodies, fusion proteins, or conjugates of the present disclosure in an amount effective to activate NK cells in the subject. Also provided are methods of increasing NK cell cytotoxicity in a subject in need thereof, the methods comprising administering to the subject any of the antibodies, fusion proteins, or conjugates of the present disclosure in an amount effective to increase NK cell cytotoxicity in the subject. According to some embodiments, the subject has cancer. The subject methods may be employed for the treatment of a large variety of cancers. The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. In certain embodiments, the cancer comprises a solid tumor. “Tumor”, as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. According to some embodiments, the solid tumor is a carcinoma, lymphoma, blastoma, or sarcoma. In some embodiments, the cancer comprises a solid tumor comprising NK cells in the tumor Atty. Docket: STAN-2131WO (S23-217) microenvironment, and the antibody increases cytotoxicity of the NK cells against cells of the solid tumor. Examples of cancers that may be treated using the subject methods include, but are not limited to, carcinoma, sarcoma, lymphoma, myeloma, leukemia, or a mixed type cancer. More particular examples of such cancers include renal cancer; kidney cancer; glioblastoma multiforme; metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non- Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget's disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease (including juvenile Paget's disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and ciliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, squamous cell carcinoma, and Atty. Docket: STAN-2131WO (S23-217) adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer, KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to papillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgendependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and / or uterer); renal carcinoma; Wilms' tumor; and bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In some embodiments, the cancer is myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, or papillary adenocarcinomas. In certain embodiments, the cancer comprises a hematological malignancy. Non-limiting examples of hematological malignancies include leukemia, lymphoma, and multiple myeloma. The antibodies, fusion proteins and conjugates of the present disclosure may be administered via any suitable route of administration, e.g., oral (e.g., in tablet form, capsule form, liquid form, or the like), parenteral (e.g., by intravenous, intra-arterial, subcutaneous, intramuscular, or epidural injection), topical, intra-nasal, intra-tumoral administration, or the like. Atty. Docket: STAN-2131WO (S23-217) The antibodies, fusion proteins and conjugates of the present disclosure may be administered in an effective amount. By “therapeutically effective amount” is meant a dosage sufficient to produce a desired result, e.g., an amount sufficient to effect beneficial or desired therapeutic (including preventative) results, such as a reduction in a symptom of a cancer, as compared to a control. With respect to cancer, in some embodiments, the therapeutically effective amount is sufficient to slow the growth of a tumor, reduce the size of a tumor, and / or the like. An effective amount can be administered in one or more administrations. Aspects of the present disclosure include methods of treating cancer in a subject in need thereof. By treatment is meant at least an amelioration of one or more symptoms associated with the cancer of the subject, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the cancer being treated. As such, treatment also includes situations where the cancer, or at least one or more symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the individual no longer suffers from the cancer, or at least the symptoms that characterize the cancer. An antibody, fusion protein, or conjugate of the present disclosure may be administered to the individual alone or in combination with a second agent. Second agents of interest include, but are not limited to, agents approved by the United States Food and Drug Administration and / or the European Medicines Agency (EMA) for use in treating cancer. In some embodiments, the second agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors of interest include, but are not limited to, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a programmed cell death-1 (PD-1) inhibitor, a programmed cell death ligand-1 (PD-L1) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a T-cell immunoglobulin domain and mucin domain 3 (TIM-3) inhibitor, an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, a B7-H3 inhibitor, and any combination thereof. When an antibody, fusion protein, or conjugate of the present disclosure is administered with a second agent, the antibody, fusion protein, or conjugate and the second agent may be administered to the individual according to any suitable administration regimen. According to certain embodiments, the antibody, fusion protein, or conjugate and the second agent are administered according to a dosing regimen approved for individual use. In some embodiments, the administration of the antibody, fusion protein, or conjugate permits the second agent to be administered according to a dosing regimen that involves one or more lower and / or less frequent doses, and / or a reduced number of cycles as compared with that utilized when the second agent is administered without administration of the antibody, fusion protein, or conjugate. In certain aspects, the administration of the second agent permits the antibody, fusion protein, or conjugate to be administered according to a dosing regimen that involves one or more lower and / or less Atty. Docket: STAN-2131WO (S23-217) frequent doses, and / or a reduced number of cycles as compared with that utilized when the antibody, fusion protein, or conjugate is administered without administration of the second agent. In some embodiments, one or more doses of the antibody, fusion protein, or conjugate and the second agent are administered concurrently to the individual. By “concurrently” is meant the antibody, fusion protein, or conjugate and the second agent are either present in the same pharmaceutical composition, or the antibody, fusion protein, or conjugate and the second agent are administered as separate pharmaceutical compositions within 1 hour or less, 30 minutes or less, or 15 minutes or less. In some embodiments, one or more doses of the antibody, fusion protein, or conjugate and the second agent are administered sequentially to the individual. In some embodiments, the antibody, fusion protein, or conjugate and the second agent are administered to the individual in different compositions and / or at different times. For example, the antibody, fusion protein, or conjugate may be administered prior to administration of the second agent, e.g., in a particular cycle. Alternatively, the second agent may be administered prior to administration of the antibody, fusion protein, or conjugate, e.g., in a particular cycle. The second agent to be administered may be administered a period of time that starts at least 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, or up to 5 days or more after the administration of the first agent to be administered. In one example, the second agent is administered to the individual for a desirable period of time prior to administration of the antibody, fusion protein, or conjugate. In certain aspects, such a regimen “primes” the cancer cells to potentiate the anti-cancer effect of the antibody, fusion protein, or conjugate. Such a period of time separating a step of administering the second agent from a step of administering the antibody, fusion protein, or conjugate is of sufficient length to permit priming of the cancer cells, desirably so that the anti-cancer effect of the antibody, fusion protein, or conjugate is increased. In some embodiments, administration of one agent is specifically timed relative to administration of the other agent. For example, in some embodiments, the antibody, fusion protein, or conjugate is administered so that a particular effect is observed (or expected to be observed, for example based on population studies showing a correlation between a given dosing regimen and the particular effect of interest). In certain aspects, desired relative dosing regimens for agents administered in combination may be assessed or determined empirically, for example using ex vivo, in vivo and / or in vitro models; in some embodiments, such assessment or empirical determination is made in vivo, in a patient population (e.g., so that a correlation is established), or alternatively in a particular individual of interest. In some embodiments, the antibody, fusion protein, or conjugate and the second agent are administered according to an intermittent dosing regimen including at least two cycles. Where Atty. Docket: STAN-2131WO (S23-217) two or more agents are administered in combination, and each by such an intermittent, cycling, regimen, individual doses of different agents may be interdigitated with one another. In certain aspects, one or more doses of a second agent is administered a period of time after a dose of the first agent. In some embodiments, each dose of the second agent is administered a period of time after a dose of the first agent. In certain aspects, each dose of the first agent is followed after a period of time by a dose of the second agent. In some embodiments, two or more doses of the first agent are administered between at least one pair of doses of the second agent; in certain aspects, two or more doses of the second agent are administered between at least one pair of doses of the first agent. In some embodiments, different doses of the same agent are separated by a common interval of time; in some embodiments, the interval of time between different doses of the same agent varies. In certain aspects, different doses of the antibody, fusion protein, or conjugate and the second agent are separated from one another by a common interval of time; in some embodiments, different doses of the different agents are separated from one another by different intervals of time. One exemplary protocol for interdigitating two intermittent, cycled dosing regimens may include: (a) a first dosing period during which a therapeutically effective amount the antibody, fusion protein, or conjugate is administered to the individual; (b) a first resting period; (c) a second dosing period during which a therapeutically effective amount of the second agent is administered to the individual; and (d) a second resting period. A second exemplary protocol for interdigitating two intermittent, cycled dosing regimens may include: (a) a first dosing period during which a therapeutically effective amount the second agent is administered to the individual; (b) a first resting period; (c) a second dosing period during which a therapeutically effective amount of the antibody, fusion protein, or conjugate is administered to the individual; and (d) a second resting period. In some embodiments, the first resting period and second resting period may correspond to an identical number of hours or days. Alternatively, in some embodiments, the first resting period and second resting period are different, with either the first resting period being longer than the second one or, vice versa. In some embodiments, each of the resting periods corresponds to 120 hours, 96 hours, 72 hours, 48 hours, 24 hours, 12 hours, 6 hours, 30 hours, 1 hour, or less. In some embodiments, if the second resting period is longer than the first resting period, it can be defined as a number of days or weeks rather than hours (for instance 1 day, 3 days, 5 days, 1 week, 2, weeks, 4 weeks or more). If the first resting period’s length is determined by existence or development of a particular biological or therapeutic event, then the second resting period’s length may be determined on the basis of different factors, separately or in combination. Exemplary such factors may include type and / or stage of a cancer against which the therapy is administered; properties (e.g., pharmacokinetic properties) of the antibody, fusion protein, or conjugate, and / or one or more features of the patient’s response to therapy with the antibody, fusion protein, or conjugate. In Atty. Docket: STAN-2131WO (S23-217) some embodiments, length of one or both resting periods may be adjusted in light of pharmacokinetic properties (e.g., as assessed via plasma concentration levels) of one or the other of the administered agents. For example, a relevant resting period might be deemed to be completed when plasma concentration of the relevant agent is below a pre-determined level, optionally upon evaluation or other consideration of one or more features of the individual’s response. In certain aspects, the number of cycles for which a particular agent is administered may be determined empirically. Also, in some embodiments, the precise regimen followed (e.g., number of doses, spacing of doses (e.g., relative to each other or to another event such as administration of another therapy), amount of doses, etc.) may be different for one or more cycles as compared with one or more other cycles. The antibody, fusion protein, or conjugate and the second agent may be administered together or independently via any suitable route of administration. The antibody, fusion protein, or conjugate and the second agent may be administered via a route of administration independently selected from oral, parenteral (e.g., by intravenous, intra-arterial, subcutaneous, intramuscular, or epidural injection), topical, intra-nasal, intra-tumoral administration, or the like. According to certain embodiments, antibody, fusion protein, or conjugate and the second agent are both administered orally or parenterally (e.g., in tablet form, capsule form, liquid form, or the like) either concurrently (in the same pharmaceutical composition or separate pharmaceutical compositions) or sequentially. The following examples are offered by way of illustration and not by way of limitation. EXPERIMENTAL Example 1 – Discovery and Engineering of a Species Cross-reactive anti-NKp46 Antibody Phage panning and yeast surface display of a human single-chain variable fragment (scFv) library was used to identify a cross-reactive anti-NKp46 scFv domain. First, a human scFv phage library was panned against magnetic streptavidin beads complexed with biotinylated human NKp46 (hNKp46), mouse NKp46 (mNKp46), and hNKp46 again for three total rounds of panning (Fig.1a, Fig.6a). Alternating the target ligand between hNKp46 and mNKp46 allowed for isolation of species cross-reactive clones. In between each round of panning, the bound phage were eluted with trypsin digestion and infected into TG1 E. coli to isolate the enriched library. After three rounds of panning, the DNA template pool from the enriched phage library was cloned into the pCTCON2 vector and transformed into S. cerevisiae strain EBY100 for yeast surface display37. Binding of the enriched yeast-displayed library to mNKp46 was considerably weaker than binding to hNKp46, so the library was screened twice against decreasing concentrations of mNKp46 using fluorescence-activated cell sorting (FACS) (Fig. 6a-c). The best clone bound Atty. Docket: STAN-2131WO (S23-217) hNKp46 with an apparent affinity (KD) of 1.5 ± 0.4nM and mNKp46 with an apparent affinity of 18 ± 4 nM (Fig.1b). Affinity maturation on the top scFv clone was then performed to increase the affinity to mNKp46. Four residues in the CDRH3 region were subjected to site-saturation mutagenesis via NNT degenerate codons to produce a second library, which was transformed into and displayed on the surface of yeast. The resulting library was sorted three times against decreasing concentrations of mNKp46 using FACS, with effective mutations beginning to enrich at the second sort (Fig.1c, Fig.6d). The final clone from this second library, subsequently referred to as RLN131, binds with an apparent KDof 0.2 ± 0.04 nM to hNKp46 and 0.3 ± 0.07 nM to mNKp46 when displayed on the yeast surface (Fig. 1d). The affinity improvement to mNKp46 is nearly hundred-fold compared to the wild-type scFv; the affinity to hNKp46 increased around tenfold as well despite not sorting against the human homolog (Fig.6e). The RLN131 scFv was converted into a bivalent, full length monoclonal antibody and recombinantly expressed and purified, and its affinity was measured via biolayer interferometry (BLI) to hNKp46, mNKp46, and cynomolgus monkey NKp46 (cNKp46), with apparent affinities (KDvalues) of 130 ± 5 pM, 110 ± 3 pM and 580 ± 140 pM, respectively (Fig. 1e). A Fab version of RLN131 was also recombinantly expressed and bound to soluble hNKp46 and mNKp46 with affinities of 1.25 ± 0.02 nM and 3.51 ± 0.07 nM, respectively (Fig. 1f). RLN131 also specifically bound HEK293T cells expressing hNKp46 or mNKp46 with affinities similar to the ones measured with yeast and BLI, demonstrating that the antibody can bind NKp46 in a cellular context (Fig.6f). Example 2 – RLN131 Binds a Unique Species Cross-reactive Epitope on NKp46 To determine the structural basis for the species cross-reactivity of RLN131, the binding epitope on both hNKp46 and mNKp46 was identified. It was confirmed that RLN131 binds a conformational epitope on hNKp46 and mNKp46, as binding was abolished after both ligands were heat denatured (Fig. 7a). Epitope binning by competition binding with BLI using other available anti-hNKp46 and anti-mNKp46 antibodies was then performed to narrow down the epitope of RLN131. RLN131 and the panel of antibodies were successively associated pairwise against hNKp46 or mNKp46. A panel of antibodies (termed D1, D1, and D1-2), that bound to either hNKp46 domain 1, domain 2, or the elbow region between domains 1 and 2, whose nonoverlapping epitopes had previously been identified were tested19(Fig. 7b). Binding of antibodies D1 and D2 were unaffected by RLN131 and exhibited strong binding signal to hNKp46 after RLN131 association (Fig. 2a). In contrast, binding of D1-2 was completely ablated after RLN131 binding, suggesting that RLN131 binds hNKp46 in the region between domains 1 and 2. This result was validated by performing a competition binding using yeast surface display, with RLN131 reducing binding of hNKp46 in a concentration-dependent manner to antibodies D1-2 but not D1 or D2 (Fig.7c). The epitope regions of commercial anti-NKp46 antibodies was also investigated. Anti-hNKp46 clone 9E2 competes for binding with antibodies D1 and RLN131, Atty. Docket: STAN-2131WO (S23-217) suggesting that it binds domain 1 (Fig.7d, e). Similarly, antibody Mab1850 also appears to bind to domain 1, although with a slightly different epitope, as it competes with antibodies D1 and 9E2 but not RLN131 (Fig.7f). A suite of antibodies against mNKP46 with known epitopes was not tested; however, RLN131 did not compete for binding with 29A1.4, a commonly used anti- mNKp46 antibody (Fig.7g). In previous work, antibody D1-2 was shown to bind at the junction of domains 1 and 2 and is reliant on the K41, E42, Y121, and D122 residues of hNKp46 for binding19. hNKp46 was expressed on the surface of Expi293 cells and these residues were mutated in a pairwise manner. As expected, binding of antibody D1-2 was eliminated when the mutations K41S / E42A or Y121A / D122A were introduced to hNKp46, whereas binding of antibody D2 was unaffected by these mutations (Fig. 2b). Interestingly, the binding of RLN131 was completely abrogated with hNKp46 Y121A / D122A but was unaffected by the K41S / E42A mutations, suggesting that RLN131 binds a similar, yet distinct epitope from previously studied antibodies. While Y121 and D122 are conserved in mNKp46, K41 and E42 are not, which may explain why D1-2 does not bind mNKp46 (data not shown). After narrowing down the epitope to the junction between domains 1 and 2, fine epitope mapping techniques were used to further identify the binding site of RLN131 to hNKp46 and mNKp46. The solvent-exposed residues of hNKp46 and mNKp46 spatially located near Y121 / D122 were first identified using the previously solved or predicted three-dimensional structures. Due to the homology between the two proteins and the fact that the extracellular domains of the two receptors are the same length, almost all of the solvent-exposed residues lay in the same position between hNKp46 and mNKp46, and many were indeed the same amino acid. Single alanine mutations were introduced at these sites and the mutants were individually transfected into Expi293 cells. Binding of antibody D1 to all the mutants was unaffected, suggesting that the local structures of hNKp46 and mNKp46 were preserved (Fig. S2h). In contrast, binding of RLN131 was significantly reduced for mutants Y121A and Y194A, and partially reduced at D122A for both human and mouse NKp46 (Fig.2c). These three conserved residues thus constitute part of the binding epitope of RLN131 and are likely responsible for the unique species cross-reactive property of RLN131 (Fig.2d). Example 3 – RLN131 Induces Activation and Proliferation of Primary Human Natural Killer Cells Next, the effects of RLN131 treatment on primary NK cells were determined. Primary human NK cells were purified from donor whole blood, and mouse NK cells were purified from fresh C57BL / 6J splenocytes. As a full-length hIgG1 antibody, RLN131 bound primary human NK cells with an apparent KD of 2.6 ± 0.1 nM and mouse NK cells with an apparent KD of 3.3 ± 0.2 nM, demonstrating the species cross-reactive properties of RLN131 on NK cells (Fig. 3a). Furthermore, RLN131 expressed with L234A, L235A, and P329G (LALA-PG) mutations to ablate Fc-mediated effector function bound primary human NK cells with similar affinity, confirming Atty. Docket: STAN-2131WO (S23-217) specificity to NKp46 irrespective of Fc receptor binding (Fig.3e). Next, the ability of RLN131 to activate primary human NK cells was tested. Frozen primary human NK cells were recovered overnight in RPMI media. The following day, they were treated with either plate-coated or soluble RLN131 antibody for 4 hours in the absence of other activating cytokines. NK cells were activated after treatment with RLN131 as measured by increased TNFα and IFNγ expression, and also exhibited degranulation as measured by CD107a expression (Fig.3b, Fig.8). Greater activation was observed with plate-coated RLN131, which in addition to the fact that NKp46 and CD16a share intracellular signaling mechanisms, supports the hypothesis that NKp46 receptor clustering is vital for signaling and activation. In a redirected lysis assay to measure cytotoxicity from NKp46 activation, CD64- expressing THP-1 human leukemia monocytic cells were loaded with calcein-AM and incubated with primary human NK cells in the presence of RLN131 antibody in mIgG1 format38. The mIgG1 Fc domain does not activate NK cells via CD16a but instead binds THP-1 cells via FcγRI (CD64) (Fig. 3c, left panel). Using this experimental setup, NK cells activated through NKp46 engagement demonstrated activation and cytotoxicity of THP-1 tumor cells in a concentration- dependent manner (Fig. 3c, right panel). RLN131 also increases NK cell proliferation in conjunction with cytokine treatment. NK cells were stained with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE) and incubated with IL-2, IL-15, or both, and cultured in isotype control- or RLN131-coated plates for 11 days. RLN131 treatment induced greater proliferation in all conditions as measured by decreased CFSE signal with the exception of the no cytokine treated samples, which exhibited no proliferation (Fig. 3d). Thus, RLN131 binding to NKp46 induces NK cell activation and proliferation. Example 4 – Increased Cytotoxicity of NKp46-based Multi-specific NK cell Engagers To evaluate the effect of binding NKp46 in a multi-specific antibody format, a panel of bispecific NK cell engagers (NKCEs) was constructed with a model protein, CD20, as the tumor antigen (FIG. 9). The panel of NKCEs included 2+2 symmetric tetravalent constructs with a RLN131 scFv fused to the N- or C-terminus of the heavy or light chain of an anti-CD20 antibody in a variety of formats, resulting in tetravalent anti-NKp46 and anti-CD20 constructs in designs. Specifically, fusion of RLN131 to the N-terminus of the anti-CD20 heavy chain, N-terminus of the light chain, C-terminus of the heavy chain, and C-terminus of the light chain resulted in NKCE1, NKCE2, NKCE3, and NKCE4, respectively. Additionally, a 1+1 asymmetric bivalent anti-NKp46 and anti-CD20 construct NKCE5 was created using standard knobs-into-holes mutations combined with CrossMab domain swapping39,40. Finally, fusion of an anti-CD20 scFv to the RLN131 scFv resulted in NKCE6, also known as a bi-specific killer engager (BiKE)41. Where applicable, matched antibody constructs were also expressed with the L234A, L235A, and P329G (LALA-PG) mutations to ablate Fc-mediated effector function (denotedFc-)42. The NKCEs were expressed in Expi293 cells and purified via protein A chromatography. All constructs Atty. Docket: STAN-2131WO (S23-217) demonstrated binding to hNKp46-expressing HEK293Tcells and CD20-expressing Raji cells (Fig. 10a). Nearly all of the NKp46-engaging bispecific constructs were more potent than the wild- type anti-CD20 antibody as measured via calcein release from Raji cells co-cultured with primary human NK cells. Incubation with NKCE1, NKCE1Fc-, NKCE2, NKCE2Fc-, NKCE3, NKCE3Fc-, NKCE4, and NKCE4Fc-, which fuse the RLN131 scFv to the N- or C- termini of the light or heavy chains of the anti-CD20 antibody all resulted in more potent NK-cell mediated cytotoxicity compared to anti-CD20 (Fig.4a-d, Table 2). The EC50of the eight constructs are all approximately 2 pM, which is more than ten-fold lower than the EC50of the unmodified anti-CD20 antibody, which was around 50pM (Table 2). The knobs-into-holes bivalent construct NKCE5 also outperformed the anti-CD20 antibody (EC5014 ± 2pM), albeit not as strongly as the tetravalent NKCEs, and NKCE5Fc-had substantially less activity (Fig.4e). The BiKE construct NKCE6 also had an EC50comparable to the other NKCEs (Fig. 4f). Interestingly, for all constructs lower maximum killing was observed compared to anti-CD20. Although increased opportunities for NK cell binding can result in unwanted cytotoxicity against effector cells, minimal levels of NK cell fratricide for all constructs were observed (Fig.10b). Given these results, it was concluded that depending on the NKCE design, NKp46 engagement can augment or replace Fc-mediated ADCC. Table 2 – Cytotoxicity EC50 values for antibodies and NKCEs EC50s ± SEM and 95% confidence intervals shown in Table 2 were calculated using Prism ([Agonist] vs. response, three parameters) for the data shown in Fig.4. Atty. Docket: STAN-2131WO (S23-217) These constructs allowed for detailed probing of the effect of valency, RLN131 scFv fusion location, and Fc effector function on NKCE cytotoxicity. Firstly, when considered in isolation, greater valency resulted in increased cytotoxicity, with the tetravalent NKCE1-NKCE4 demonstrating greater cytotoxicity compared to the bivalent NKCE5 and NKCE6, perhaps due to avidity effects or increased clustering of activating receptors. Secondly, the various tetravalent NKCE configurations generally performed similarly regardless of RLN131 scFv fusion location, suggesting that a lytic synapse was formed in all of the activating receptor arrangements. Lastly, all NKCEs that had abolished Fc effector function retained some level of cytotoxic activity, with NKCE1Fc-, NKCE2Fc-and NKCE4Fc-exhibiting nearly identical cytotoxicity profiles as their Fc active counterparts, and many constructs demonstrated greater potency than Fc-active anti- CD20. This was in contrast with the anti-CD20 antibody, whose activity was abolished for the Fc- null variant, further demonstrating the ability of RLN131 to activate NK cells against tumor cells in the absence of other activating signals (Fig.10c). A major advantage of the comprehensive panel of NKCEs was that it allowed for analysis of the interconnected nature of these factors to better inform bispecific NKCE design. For example, the location of additional coactivating receptor binding domains on NKCEs appears to dictate the contribution of Fc engagement on cytotoxicity. Given that the pairs of NKCE1 / NKCE1Fc-, NKCE2 / NKCE2Fc-, and NKCE4 / NKCE4Fc-have similar cytotoxicity profiles, it was hypothesized that the Fc domain plays a minor role in the cytotoxic effect. These may be effectively operating as dimeric BiKEs, at which point increased valency may improve avidity and efficacy, potential circulation half-life and stability advantages notwithstanding. In contrast, when RLN131 was fused to the C-terminus of the heavy chain (NKCE3 / NKCE3Fc-), Fc effector ablation resulted in markedly less cytotoxicity, indicating the importance of CD16a binding for this configuration. It is likely that the physical arrangement and spatial distance of the binding domains plays a role in determining the relative contributions of the engaged receptors, with implications for future NKCE design. Example 5 – NKCE1 and NKCE1Fc-Induce Cytotoxicity of Human PBMCs and Mouse Splenocytes Next, a subset of the antibody panel was used for further characterization of NKCE- mediated cytotoxicity. For NKCE1 and NKCE3, the effect of linker length was tested by varying the length of the (G4S)nlinker between the RLN131 scFv and the N- or C-terminus of the anti- CD20 antibody. The EC50 values of these bispecific antibodies were unchanged when the linker length was varied between 0 and 17-18 amino acids for both the N- and C-terminal scFv fusions, demonstrating that at these linker lengths, sufficient engagement of NKp46 was achieved to generate a cytolytic response (Fig 5a, Fig.11a). The cytotoxicity of NKp46-engaging NKCEs was then tested using primary human PBMCs as effector cells. As was observed with purified human NK cells, the N-terminal fusions of the RLN131 scFv (NKCE1 and NKCE1Fc-) induced greater lysis of tumor cells at lower Atty. Docket: STAN-2131WO (S23-217) concentrations compared to anti-CD20 as measured by calcein release when PBMCs were used as effector cells, irrespective of Fc effector activity (Fig.5b). One advantage of using a species cross-reactive antibody such as RLN131 is that the same molecule can be used in different models for preclinical testing. To demonstrate this feature, NKCE1 and NKCE1Fc-were introduced to a cytotoxicity assay with mouse splenocytes as effector cells, and both again had a lower EC50 compared to the wild-type anti-CD20 antibody (Fig.5c). Finally, the effect of RLN131-based NKCEs on NK cell activation was measured. In addition to inducing increased cytotoxicity, NKp46 targeted NKCEs activate NK cells in the presence of tumor cells to a greater degree than traditional monoclonal antibodies. NK cells treated with NKCE1 and NKCE1Fc-and co-cultured with Raji cells exhibited increased activation compared to the anti-CD20 antibody as measured by cytokine secretion (TNFα, IFNγ) and degranulation (CD107a), particularly at lower antibody concentrations, which appropriately matches their increased cytotoxicity (Fig.5d, e; Fig.11b). Materials and Methods Protein expression hNKp46-his (Acro Biosystems NC1-H52H4), mNKp46-his (Sino Biological 50702-M08H), cNKp46-his (Acro Biosystems NC1-C52H4), anti-hNKp46 (clone 195314, R&D Systems; clone 9E2, Miltenyi Biotec), anti-mNKp46 (clone 29A1.4, Biolegend 137601) were purchased. When necessary, protein was biotinylated with biotin-NHS ester using the manufacturer’s protocol (Thermo Fisher PI21326). RLN131 antibodies in various formats, antibodies D1, D2, D1-2, Fabs, and NKCEs were expressed in the Abvec vector using the human Ig heavy chain signal peptide. Extracellular domain fusions hNKp46-Fc and mNKp46-Fc were expressed using the pAdd2 vector using the endogenous signal peptides. Plasmids were purified using Genejet Plasmid Miniprep kits (Thermo Fisher FERK0503). All proteins were expressed in Expi283 cells following the manufacturer’s transfection protocol. Expi293 supernatants were harvested 5-7 days post- transfection by centrifugation, pH adjustment, and filtering. Proteins were purified with Protein A (Thermo Fisher 101142) or Ni-NTA chromatography (GoldBio H350). Proteins were buffer exchanged using Amicon®Ultra centrifugation filters (EMD Millipore) and stored at 4C. Phage panning The hyperimmune scFv library from Twist Biosciences was panned against NKp46. TG1 E. coli cells (Antibody Design Labs PC001) were grown in 2xYT medium with carbenicillin and glucose at 37C. Phage production was induced by addition of M13KO7 helper phage (Antibody Design Labs PH010L) at an OD600 of 0.8 for 30 min. Cells were resuspended in 2xYT medium with carbenicillin and kanamycin and cultured overnight. Phage supernatant was collected and precipitated in 0.5M NaCl, 5% PEG-8000 for 1 hour on ice. Phage was collected by centrifugation Atty. Docket: STAN-2131WO (S23-217) and blocked in PBS, 0.5% BSA. Streptavidin Dynabeads (ThermoFisher M-280) was washed in PBS + 0.1% Tween-20 and conjugated to biotinylated NKp46 protein in PBS, 0.5% BSA. Blocked phage was added to beads with no protein to remove nonspecific binders, followed by NKp46- coated beads for 1 hour. Beads were washed three times with PBS + 0.1% Tween-20 and bound phage was eluted with 10mg / mL trypsin. Eluted phage was added to TG1 cells to repeat for the next round of panning. Yeast surface display Yeast surface display was performed using the EBY100 yeast strain and the pCTCON2 vector. Prior to transformation, EBY100 was grown in YPD media (10g / L yeast extract, 20g / L peptone, 20g / L dextrose). Electrocompetent yeast were transformed with a BioRad GenePulser Xcell electroporation system. After transformation, yeast was grown in selective SD-CAA media (75mM citrate, 20g / L dextrose, 6.7g / L yeast nitrogenous base without amino acids, 5g / L casamino acids, pH 4.5). Yeast was induced for yeast surface display by transferring to SG-CAA (50mM phosphate, 2g / L dextrose, 18g / L galactose, 6.7g / L yeast nitrogenous base without amino acids, 5g / L casamino acids, pH 6.0) at an OD600 of 1.0 at 20C overnight. Yeast binding for analysis and sorting For FACS sorting or for yeast binding assays, induced yeast was resuspended in PBSA (PBS, 0.1% BSA) and incubated with the ligand of interest and anti-cMyc antibody (Thermo Fisher A21281) at 20C or at 4C for at least two hours. Cells were washed by adding excess PBSA, centrifuging the cells (>3500xg for 60 seconds at 4C) and removing the supernatant by aspiration. Ligand-bound yeast cells were then stained with secondary antibody solution for 30 minutes on ice. Secondary antibodies used included 1:1000 dilutions of anti-chicken-AF488 (Thermo Fisher A11039) and either anti-6his-AF647 antibody (Thermo Fisher MA1135A647) or streptavidin-AF647 (Thermo Fisher S21374) in PBSA, depending on the ligand used. Cells were washed again and run on a Sony SH800 for sorting or BD Accuri for analysis. Data was analyzed using FlowJo software and GraphPad Prism. Yeast competition binding assays were performed by complexing varying concentrations of RLN131 in Fab format to 3nM his-tagged hNKp46 for 1 hour at 20C. The complexed protein was then added to yeast displaying the competitor antibody in scFv format for 2 hours at 20C in PBSA and 1:1000 dilution of anti-cmyc antibody. After washing, the yeast was stained with secondary antibodies (1:1000 anti-chicken-AF488, anti-his-AF647) for 20 minutes at 4C, followed by a second wash and flow cytometric analysis. Mammalian cell binding HEK293T cells were resuspended after incubation with TrypLE Express (Thermo Fisher 12605010) or non-enzymatic dissociation buffer (Thermo Fisher 13151014). NK cells, HEK293T, Atty. Docket: STAN-2131WO (S23-217) Expi293, and Raji cells were incubated for 30 min at 4C with antibody prelabeled with AF647- NHS ester (Thermo Fisher A37573) or with unlabeled antibody. In the case of binding to prelabeled proteins, cells were washed with PBSA (excess PBSA was added, cells were centrifuged at 300xg for 5 min, and supernatant was removed) and run on a BD Accuri for analysis. In the case of binding to unlabeled proteins, cells were washed with PBSA and incubated in a secondary antibody solution of 1:1000 anti-6his-AF647 antibody or anti-human- AF647 antibody (Southern Biotech 2040-31) for 20 min at 4C. Cells were washed and run on BD Accuri for flow cytometry analysis. Where applicable, statistical significance was tested with one- way ANOVA (Graphpad Prism). Mammalian cell lines and primary immune cell isolation HEK293T cells were cultured in DMEM medium, 10% FBS, 100U / mL (1%) penicillin / streptomycin. Raji and THP-1 cells were cultured in RPMI 1640 medium, 10% FBS, 1% penicillin / streptomycin. Expi293 (Thermo Fisher A14527) cells were cultured following the manufacturer’s protocol. HEK293T-hNKp46-GFP and HEK293T-mNKp46-GFP cell lines were produced retrovirally and transduced cells were isolated with FACS. PBMCs were purified from human blood using density gradient separation via Ficoll- Paque (Cytiva 17-1440-02) and SepMate-50 tubes (STEMCELL Technologies 85450) per the manufacturer’s protocol. Primary human NK cells were purified from donor blood using the RosetteSep Human NK Cell Enrichment Cocktail (STEMCELL Technologies 15025) per the manufacturer’s protocol. When necessary, primary human cells were frozen in 90% FBS, 10% DMSO and stored in liquid nitrogen. Mouse splenocytes were isolated from 4-8 weeks old C57BL / 6 mice (Jackson Laboratory). Mouse NK cells were purified from mouse splenocytes using EasySep Mouse NK Cell Isolation Kit (STEMCELL Technologies 19855). Mouse cells were cultured in RPMI 1640 medium, 10% FBS, 1% penicillin / streptomycin, 1000U / mL hIL-2 for seven days prior to use. Biolayer interferometry For affinity determination, his-tagged hNKp46, mNKp46, and cNKp46 were loaded on Octet®NTA biosensors (Sartorius) at 5 ug / mL in PBS + 0.02% Tween-20 + 0.1% BSA for 150 seconds. The biosensors were rinsed in the same buffer and two-fold dilutions of RLN131 were associated for 350 seconds, followed by dissociation for 1800 seconds. Affinity was calculated with Octet data analysis software. For competition assays, his-tagged hNKp46 or mNKp46 were loaded onto biosensors and RLN131 was associated at 100nM for 250-350 seconds. Following a rinse, competitor antibodies were associated at 100nM for 150 seconds. Atty. Docket: STAN-2131WO (S23-217) Epitope mapping Solvent accessibility was predicted using the three crystal structures of hNKp46 available at the time of the work (PDB 6IAP, 1OLL, 1P6F) and a predicted structure of mNKp46 generated with Alphafold. Two solvent accessibility calculators were used for each structure (http: / / cib.cf.ocha.ac.jp / bitool / ASA, http: / / curie.utmb.edu / getarea.html). The scores for each structure were averaged across the two calculators, and in the case of hNKp46 across the different structures as well. Alanine mutants were generated using PCR and Gibson assembly for hNKp46-T2A-GFP or mNKp46-T2A-GFP (where h / mNKp46 contains the signal peptide, extracellular domain and transmembrane domain) in the pAdd2 vector. Expi293 cells were transiently transfected with these plasmids per the manufacturer’s protocol. The following day, transfected cells were incubated in PBSA with anti-hNKp46 or anti-mNKp46 antibodies prelabeled with AF647-NHS ester at a concentration of 1nM for 30 min at 4C. Cells were washed with PBSA and analyzed with a BD Accuri. Calcein release assays NK cell, PBMC, and splenocyte cytotoxicity was measured via calcein release. Human effector cells were thawed overnight in RPMI 1640 + 10% FBS + 1% pen / strep in a humidified incubator at 37C with 5% CO2. Splenocytes were incubated in media containing 1000U / mL hIL- 2 for seven days. Target cells (Raji, THP-1) were labeled with 15µM calcein-AM (Thermo Fisher C1430) for 30 minutes at 37C. Cells were washed and 20,000 target cells were coincubated with antibodies at varying concentrations and effector cells at the described E:T ratios for 4 hours. After centrifugation, supernatants were collected and calcein release was measured with a BioTek Synergy H4 Hybrid plate reader (Ex: 485nm / Em: 530nm). Maximum lysis was induced with 1% Triton X-100. Specific antibody-mediated lysis was calculated as lysis = (experimental calcein release – no antibody calcein release) / (maximum calcein release – no antibody calcein release). To measure NK cell fratricide, primary human NK cells were labeled with calcein blue (Thermo Fisher C1429) in the same manner as the target cells. After coculture as described above, calcein blue release was measured alongside calcein AM release (Ex: 350nm / Em: 450nm). NK cell activation assays Microtiter plates were coated with PBS or PBS + 5ug / mL RLN131 overnight at 4C and washed the following day with PBS. Primary human NK cells were thawed in RPMI 1640 + 10% FBS + 1% pen / strep + 1% 2-mercaptoethanol + 1% HEPES + 1% Nonessential Amino Acids + 1% sodium pyruvate overnight at 37C. The following day, NK cells were transferred to the plates and 10ng / mL hIL-15 and / or 5ug / mL RLN131 antibody was added, depending on the sample. NK Atty. Docket: STAN-2131WO (S23-217) cells were incubated at 37C for 4 hours in the presence of brefeldin and monensin and addition of CD107a staining antibody. CD3- / CD56+ NK cells were stained for IFNγ, TNFα, and CD107a and analyzed by flow cytometry. In other experiments, NK cells were cocultured with target Raji cells and varying antibody concentrations for 4 hours in a manner similar to the cytotoxicity experiments prior to fixation, permeabilization, and staining. NK cell proliferation assay High protein binding microtiter plates were coated with PBS + 3ug / mL RLN131 (in mIgG1 format) or isotype control antibody overnight at 4C and washed the following day with PBS. Freshly purified NK cells were washed, resuspended in PBS, and labeled with 500nM CFSE for 20 min at 37C. Then they were washed and incubated in AIM-V medium + 10% FBS in the antibody-coated microtiter plates for 11 days at 37C. 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Phenotypic and Functional Plasticity of Murine Intestinal NKp46+ Group 3 Innate Lymphoid Cells. J. Immunol.196, 4731–4738 (2016). 24. Stewart, C. A. et al. Germ-line and rearranged Tcrd transcription distinguish bona fide NK cells and NK-like gammadelta T cells. Eur. J. Immunol.37, 1442–1452 (2007). 25. Correia, D. V. et al. Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118, 992– 1001 (2011). 26. Almeida, F. F. et al. A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets. Oncoimmunology 7, e1475875 (2018). Atty. Docket: STAN-2131WO (S23-217) 27. Abel, A. M., Yang, C., Thakar, M. S. & Malarkannan, S. Natural killer cells: Development, maturation, and clinical utilization. Front. Immunol.9, 1869 (2018). 28. Joyce, M. G. & Sun, P. D. The structural basis of ligand recognition by natural killer cell receptors. J. Biomed. 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NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J. Clin. Invest.119, 1251–1263 (2009). 35. Glasner, A. et al. Recognition and prevention of tumor metastasis by the NK receptor NKp46 / NCR1. J. Immunol.188, 2509–2515 (2012). 36. Cruz, S. M. et al. Intratumoral NKp46+ natural killer cells are spatially distanced from T and MHC-I+ cells with prognostic implications in soft tissue sarcoma. Front. Immunol. 14, 1230534 (2023). 37. Boder, E. T. & Wittrup, K. D. Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol.15, 553–557 (1997). 38. Kang, E., Kadoch, C., Rubenstein, J. L., Lanier, L. L. & Wells, J. A. A functional mammalian display screen identifies rare antibodies that stimulate NK cell-mediated cytotoxicity. Proc. Natl. Acad. Sci. U. S. A.118, (2021). 39. Merchant, A. M. et al. An efficient route to human bispecific IgG. Nat. Biotechnol.16, 677– 681 (1998). 40. Schaefer, W. et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc. Natl. Acad. Sci. U. S. A.108, 11187–11192 (2011). 41. Gleason, M. K. et al. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol. Cancer Ther.11, 2674–2684 (2012). 42. Lo, M. et al. Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice*. J. Biol. Chem.292, 3900–3908 (2017). Atty. Docket: STAN-2131WO (S23-217) 43. Mehta, N. et al. An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA. Sci. Rep.10, 15171 (2020). 44. McIntosh, B. J. et al. An engineered interleukin-11 decoy cytokine inhibits receptor signaling and proliferation in lung adenocarcinoma. Bioeng Transl Med 8, e10573 (2023). 45. Zhang, M.-Y. et al. Broadly cross-reactive HIV neutralizing human monoclonal antibody Fab selected by sequential antigen panning of a phage display library. J. Immunol. Methods 283, 17–25 (2003). 46. Shemer-Avni, Y. et al. Expression of NKp46 Splice Variants in Nasal Lavage Following Respiratory Viral Infection: Domain 1-Negative Isoforms Predominate and Manifest Higher Activity. Front. Immunol.8, 161 (2017). 47. Zhuang, X. & Long, E. O. Complement factor P: promoting the antibacterial activity of natural killer cells. Cellular & molecular immunology vol.14797–799 (2017). 48. Pazina, T. et al. The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms. Oncoimmunology 6, e1339853 (2017). 49. Li, J. et al. PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia. Haematologica 106, 3115–3124 (2021). 50. Zamai, L. et al. Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy. Cells 9, (2020). 51. Bryceson, Y. T., March, M. E., Ljunggren, H. G. & Long, E. O. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107, 159–166 (2006). 52. Nakazawa, T. et al. Establishment of an efficient ex vivo expansion strategy for human natural killer cells stimulated by defined cytokine cocktail and antibodies against natural killer cell activating receptors. Regenerative Therapy 21, 185 (2022). 53. Gauthier, L. et al. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nat. Biotechnol.41, 1296–1306 (2023). 54. Lipinski, B. et al. NKp46-specific single domain antibodies enable facile engineering of various potent NK cell engager formats. Protein Sci.32, e4593 (2023). 55. Colomar-Carando, N. et al. Exploiting Natural Killer Cell Engagers to Control Pediatric B- cell Precursor Acute Lymphoblastic Leukemia. Cancer Immunology Research 10, 291 (2022). 56. Demaria, O. et al. Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. Cell Reports Medicine 3, 100783 (2022). 57. Santich, B. H. et al. Interdomain spacing and spatial configuration drive the potency of IgG-[L]-scFv T cell bispecific antibodies. Sci. Transl. Med.12, (2020). Atty. Docket: STAN-2131WO (S23-217) Accordingly, the preceding merely illustrates the principles of the present disclosure. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein.

Claims

Atty. Docket: STAN-2131WO (S23-217) WHAT IS CLAIMED IS:

1. An antibody that specifically binds NKp46 and cross-reacts with human and mouse NKp46, wherein the antibody competes for binding to NKp46 with an antibody comprising: a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:1, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:5; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:9, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:13; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:17, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:21; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:25, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:29; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:33, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:37; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:41, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:45; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:49, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:53; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:57, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:61; or a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:65, andAtty. Docket: STAN-2131WO (S23-217) a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:

69.

2. The antibody of claim 1, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:1, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:5; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:9, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:13; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:17, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:21; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:25, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:29; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:33, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:37; a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:41, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:45; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:49, and a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:53; a variable heavy chain (VH) polypeptide comprising the VH CDR1, VH CDR2 and VH CDR3 of the VH set forth in SEQ ID NO:57, and a variable light chain (VL) polypeptide comprising the VL CDR1, VL CDR2 and VL CDR3 of the VL set forth in SEQ ID NO:61; or a variable heavy chain (VH) polypeptide comprising the VHCDR1, VHCDR2 and VHCDR3 of the VHset forth in SEQ ID NO:65, andAtty. Docket: STAN-2131WO (S23-217) a variable light chain (VL) polypeptide comprising the VLCDR1, VLCDR2 and VLCDR3 of the VLset forth in SEQ ID NO:

69.

3. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:1; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

5.

4. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:9; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

13.

5. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:17; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:21.Atty. Docket: STAN-2131WO (S23-217) 6. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:25; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

29.

7. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:33; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

37.

8. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:41; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:45.Atty. Docket: STAN-2131WO (S23-217) 9. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:49; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

53.

10. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:57; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

61.

11. The antibody of claim 1 or claim 2, wherein the antibody comprises: a variable heavy chain (VH) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:65; and a variable light chain (VL) polypeptide comprising an amino acid sequence having 70% or greater, 75% or greater, 80% or greater, 85% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, 99% or greater, or 100% identity to the amino acid sequence set forth in SEQ ID NO:

69.

12. The antibody of any one of claims 1-11, wherein the antibody further cross-reacts with cynomolgus NKp46.Atty. Docket: STAN-2131WO (S23-217) 13. The antibody of any one of claims 1-12, wherein the antibody is a fully human antibody.

14. The antibody of any one of claims 1-13, wherein the antibody is an IgG.

15. The antibody of claim 14, wherein the antibody is an IgG1.

16. The antibody of any one of claims 1-15, wherein the antibody comprises an Fc region, and the Fc region is heterologous to the VHof the antibody.

17. The antibody of claim 16, wherein the Fc region is a variant Fc region.

18. The antibody of claim 17, wherein the variant Fc region comprises one or more amino acid substitutions, one or more amino acid insertions, one or more amino acid deletions, or any combination thereof, relative to a wild-type Fc region.

19. The antibody of any one of claims 1-13, wherein the antibody is a Fab.

20. The antibody of any one of claims 1-13, wherein the antibody is a single chain antibody.

21. The antibody of claim 20, wherein the antibody is an scFv.

22. The antibody of any one of claims 1-21, wherein the antibody is a multi-specific antibody comprising a first antigen-binding domain and a second antigen-binding domain, and wherein the first antigen binding domain comprises a VH polypeptide-VL polypeptide pair as defined in any one of claims 1-13.

23. The antibody of claim 22, wherein the second antigen-binding domain specifically binds a second NK cell antigen.

24. The antibody of claim 23, wherein the second NK cell antigen is cluster of differentiation 16 (CD16), natural killer group 2D (NKG2D), a signaling lymphocyte activation molecule (SLAM) family member, NKp30, or NKp44.

25. The antibody of claim 22, wherein the second antigen-binding domain specifically binds a tumor antigen.Atty. Docket: STAN-2131WO (S23-217) 26. The antibody of claim 25, wherein the tumor antigen is 5T4, AXL receptor tyrosine kinase (AXL), B-cell maturation antigen (BCMA), c-MET, C4.4a, carbonic anhydrase 6 (CA6), carbonic anhydrase 9 (CA9), Cadherin-6, CD19, CD20, CD22, CD25, CD27L, CD30, CD33, CD37, CD44v6, CD56, CD70, CD74, CD79b, CD123, CD138, carcinoembryonic antigen (CEA), cKit, Cripto protein, CS1, delta-like canonical Notch ligand 3 (DLL3), endothelin receptor type B (EDNRB), EpCAM, ephrin A4 (EFNA4), epidermal growth factor receptor (EGFR), EGFRvIII, ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3), EPH receptor A2 (EPHA2), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), FMS- like tyrosine kinase 3 (FLT3), folate receptor 1 (FOLR1), GLUT3, glycoprotein non-metastatic B (GPNMB), guanylate cyclase 2 C (GUCY2C), HCAM, human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), Integrin alpha, lysosomal- associated membrane protein 1 (LAMP-1), Lewis Y, LIV-1, leucine rich repeat containing 15 (LRRC15), mesothelin (MSLN), sodium-dependent phosphate transport protein 2B (NaPi2b), Nectin-4, NMB, NOTCH3, p-cadherin (p-CAD), prostate-specific membrane antigen (PSMA), protein tyrosine kinase 7 (PTK7), solute carrier family 44 member 4 (SLC44A4), SLIT like family member 6 (SLITRK6), STEAP family member 1 (STEAP1), tissue factor (TF), T cell immunoglobulin and mucin protein-1 (TIM-1), trophoblast cell-surface antigen (TROP-2), or VEGF-A.

27. The antibody of claim 25 or 26, wherein the antibody is a bispecific killer cell engager (BiKE).

28. The antibody of any one of claims 22-26, wherein the antibody comprises a third antigen-binding domain.

29. The antibody of claim 28, wherein the antibody is a trispecific killer cell engager (TriKE).

30. A nucleic acid encoding a variable heavy chain (VH) polypeptide, a variable light chain (VL) polypeptide, or both, of the antibody of any one of claims 1-29.

31. The nucleic acid of claim 30, wherein the antibody is a single chain antibody, and wherein the nucleic acid encodes the single chain antibody.

32. An expression construct comprising the nucleic acid of claim 30 or 31 operably linked to a promoter.

33. A cell comprising the expression construct of claim 32.Atty. Docket: STAN-2131WO (S23-217) 34. A cell comprising: (1) an expression construct comprising a nucleic acid that encodes a variable heavy chain (VH) polypeptide and a variable light chain (VL) polypeptide of the antibody of any one of claims 1-28; or (2) a first expression construct comprising a nucleic acid that encodes a variable heavy chain (VH) polypeptide of the antibody of any one of claims 1-28, and a second expression construct comprising a nucleic acid that encodes a variable light chain (VL) polypeptide of the antibody.

35. A method of making the antibody of any one of claims 1-28, comprising culturing the cell of claim 34 under conditions suitable for the cell to express the antibody, wherein the antibody is produced.

36. A composition comprising the antibody of any one of claims 1-28.

37. The composition of claim 36, wherein the composition is formulated for administration to a subject in need thereof.

38. The composition of claim 37, wherein the composition is formulated for parenteral administration to the subject.

39. A method of activating natural killer (NK) cells in a subject in need thereof, the method comprising administering to the subject the antibody of any one of claims 1-28 in an amount effective to activate NK cells in the subject.

40. A method of increasing NK cell cytotoxicity in a subject in need thereof, the method comprising administering to the subject the antibody of any one of claims 1-28 in an amount effective to increase NK cell cytotoxicity in the subject.

41. The method of claim 39 or 40, wherein the subject has cancer.

42. The method of claim 41, wherein the cancer is a carcinoma, a sarcoma, a lymphoma, a myeloma, a leukemia, or mixed type.

43. The method of claim 41 or 42, wherein the cancer comprises a solid tumor comprising NK cells in the tumor microenvironment, and wherein the antibody increases cytotoxicity of the NK cells against cells of the solid tumor.Atty. Docket: STAN-2131WO (S23-217) 44. The method of any one of claims 39-43, further comprising administering an agent that stimulates one or more cytokine receptors on the surface of the NK cells.

45. The method of claim 44, wherein the one or more cytokine receptors comprise a receptor for IL-2, IL-15, IL-12, IL-18, IL-21, or any combination thereof.

46. The method of claim 45, wherein the one or more cytokine receptors comprise a receptor for IL-15.

47. The method of any one of claims 39-46, wherein the NK cells are endogenous to the subject.

48. The method of any one of claims 39-47, wherein the NK cells comprise therapeutic NK cells which were administered to the subject.

49. The method of claim 48, wherein the therapeutic NK cells express a recombinant receptor.

50. The method of claim 49, wherein the recombinant receptor is a chimeric antigen receptor (CAR).

51. The method of claim 50, wherein the CAR comprises an extracellular binding domain that binds to a tumor antigen.

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