CD-40 targeting compositions, dosing regimens, and formulations thereof

Abstract

Disclosed herein are injectable formulations of CD-40 targeting compositions that comprise a CD-40 targeting moiety; and in some embodiments, comprises a CD-20 targeting moiety. Methods of making and using the compositions are further described. Various pharmaceutical compositions, delivery devices, and configurations of the CD-40 targeting compositions are provided. Also disclosed are methods for treating a disease with the CD-40 targeting compositions, methods for inducing tolerance, and methods for reducing inflammation in a subject.

Description

Attorney Docket No. 199830-739601CD-40 TARGETING COMPOSITIONS, DOSING REGIMENS, AND FORMULATIONS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application, under 35 U.S.C. § 119(e), claims the benefit of and priority to U.S. Provisional Application No. 63 / 736,800 filed on December 20, 2024, the entire contents of which is incorporated by reference herein in its entirety.BACKGROUND

[0002] The immune system is involved in the pathogenesis of several diseases, including but not limited to cancer, autoimmune diseases, obesity, type 1 diabetes, neurodegenerative diseases, and cardiovascular diseases. At the same time, the immune system can be harnessed to treat various diseases or can be targeted to reverse disease pathogenesis. The ability to harness the immune system for therapeutic purposes has been tenuous in the field of medicine as there is a delicate balancing act of maintaining both pro-inflammatory function and anti-inflammatory function of the immune system while still targeting the root cause of the disease. Antibody -based therapeutics have been used successfully to treat a variety of diseases, including cancer and autoimmune / inflammatory disorders. Yet improvements to this class of drugs are still needed, particularly with respect to enhancing their clinical efficacy and safety.SUMMARY

[0003] Provided herein are compositions, wherein the compositions target cluster of differentiation 40 (CD-40) and / or CD-20, B-cell activating factor (BAFF), A proliferationinducing ligand (APRIL), and / or an interferon receptor. The compositions provided herein are formulated for administration to a subject via injection, such as a subcutaneous injection and / or an intravenous injection, and can be used as a therapeutic agent to treat a disease.

[0004] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising RYSVY (SEQ ID NO: 1), GFSLSRY (SEQ ID NO: 2), GFSISRY (SEQ ID NO: 3), GFSVSRY (SEQ ID NO: 4), GFSLSRYSVY (SEQ ID NO: 5), GFSISRYSVY (SEQ ID NO: 6), or GFSVSRYSVY (SEQ ID NO: 7) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 7; (ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO:Attorney Docket No. 199830-73960120 or SEQ ID NO: 21; and (iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34.

[0005] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 19 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34 to SEQ ID NO: 44

[0006] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a light chain variable region, wherein the light chain variable region comprises: (i) a CDR1 comprising any one of SEQ ID NO: 87 to SEQ ID NO: 95 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 87 to SEQ ID NO: 95; (ii) a CDR2 comprising any one of SEQ ID NO: 96 to SEQ ID NO: 109 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96 to SEQ ID NO: 109; and (iii) a CDR3 comprising any one of SEQ ID NO: 110 to SEQ ID NO: 125 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125

[0007] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises: (a) a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 19 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34 to SEQ ID NO:Attorney Docket No. 199830-73960144; and (b) a light chain comprising: (i) a CDR1 comprising any one of SEQ ID NO: 87 to SEQ ID NO: 95 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 87 to SEQ ID NO: 95; (ii) a CDR2 comprising any one of SEQ ID NO: 96 to SEQ ID NO: 109 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96 to SEQ ID NO: 109; and (iii) a CDR3 comprising any one of SEQ ID NO: 110 to SEQ ID NO: 125 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125.

[0008] Provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide constructs comprise: (a) a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising RYSVY (SEQ ID NO: 1), GFSLSRY (SEQ ID NO: 2), GFSISRY (SEQ ID NO: 3), GFSVSRY (SEQ ID NO: 4), GFSLSRYSVY (SEQ ID NO: 5), GFSISRYSVY (SEQ ID NO: 6), or GFSVSRYSVY (SEQ ID NO: 7) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 7; (ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and (iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and (b) a CD-20 targeting moiety.

[0009] Provided herein are compositions, wherein the compositions comprise: a bispecific polypeptide construct comprising: a CD-40 targeting moiety comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 1 to SEQ ID NO: 161 or any sequence in Table 35; and a CD-20 targeting moiety comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 200 or any sequence in Table 35.

[0010] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: (a) a CD-40 targeting moiety; and a B-cell activating factor (BAFF)-targeting moiety. Further provided herein are polypeptide constructs, wherein the polypeptide constructs further comprise an APRIL-targeting moiety, an interferon receptor (IFNR)-targeting moiety, a CD-20 targeting moiety, or any combination thereof.

[0011] Provided herein are injectable formulations, wherein the injectable formulations comprise: a polypeptide construct comprising: a CD-40 targeting moiety, wherein the CD-40Attorney Docket No. 199830-739601 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43.

[0012] Provided herein are injectable formulations, wherein the injectable formulations comprise: a polypeptide construct comprising a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises: a light chain comprising: (i) a CDR1 comprising any one of SEQ ID NO: 87 to SEQ ID NO: 95 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 87 to SEQ ID NO: 95; (ii) a CDR2 comprising any one of SEQ ID NO: 96 to SEQ ID NO: 109 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96 to SEQ ID NO: 109; and (iii) a CDR3 comprising any one of SEQ ID NO: 110 to SEQ ID NO: 125 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125

[0013] Provided herein are injectable formulations, wherein the injectable formulations comprise: a polypeptide construct comprising: (a) a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises any polypeptide construct provided herein; and (b) a CD-20 targeting moiety.

[0014] Provided herein are dosing regimens for use in the treatment of a disease in a subject in need thereof, wherein the dosing regimens comprise: a first liquid formulation comprising a dose of at least about 30 mg / kg of a CD-40 targeting moiety, wherein the CD-40 targeting moiety is any polypeptide construct provided herein. Further provided herein are dosing regimens further comprising: (b) a second liquid formulation comprising a dose of at least about 150 mg / kg of the CD-40 targeting moiety, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation.

[0015] Provided herein are dosing regimens for use in the treatment of a disease in a subject in need thereof, wherein the dosing regimens comprise: a first liquid formulation comprising a dose of at least about 30 mg / kg of a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or twoAttorney Docket No. 199830-739601 amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43; and (b) a second liquid formulation comprising a dose of at least about 150 mg / kg of the CD-40 targeting moiety, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation.

[0016] Provided herein are pharmaceutical compositions, wherein the pharmaceutical compositions comprise: a subcutaneous liquid formulation comprising a polypeptide construct that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising(i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: a sugar; a polysorbate; and arginine or a salt thereof.

[0017] Provided herein are pharmaceutical compositions, wherein the pharmaceutical compositions comprise: (a) an anti-CD-40 antibody comprising a heavy chain variable region that comprises: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43; and (b) a pharmaceutically acceptable excipient, wherein the anti-CD-40 antibody is present in an amount of at least 150 milligrams per milliliter (mg / mL) of the pharmaceutical composition, and wherein the pharmaceutical composition is an injectable liquid formulation.Attorney Docket No. 199830-739601

[0018] Provided herein are pharmaceutical compositions, wherein the pharmaceutical compositions comprise: a polypeptide construct or a nucleic acid encoding for the polypeptide construct, wherein the polypeptide construct comprises an amino acid sequence that is at least 80% identical to any one of the sequences listed in Table 35.

[0019] Provided herein are hydrogels comprising: a protein that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise one or more of: poly-s-caprolactone (PCL); polyethylene glycol (PEG); polyethylene oxide (PEO); alginate; chitosan; or polyglutamic acid.

[0020] Provided herein are pharmaceutical compositions for subcutaneous administration, wherein the pharmaceutical compositions comprise: 200.0 mg / mL of any polypeptide construct provided herein; 20 mM Histidine buffer; 2% (w / v) Sucrose; 100 mM L-Arginine monohydrochloride; and 0.02% (w / v) polysorbate 80, optionally wherein the pharmaceutical composition comprises a pH of 5.8.

[0021] Provided herein are drug delivery devices, wherein the drug delivery devices comprises a reservoir comprising a polypeptide construct, a pharmaceutical composition, or a dosing regimen provided herein.

[0022] Provided herein are methods for treating a disease in a subject, wherein the methods comprise: administering to the subject a therapeutically effective amount of a pharmaceutical composition provided herein or a dosing regimen provided herein, thereby treating the disease in the subject.

[0023] Provided herein are methods for reducing inflammation in a subject, wherein the methods comprise: administering to the subject a therapeutically effective amount of a pharmaceutical composition provided herein or a dosing regimen provided herein, thereby reducing inflammation in the subject relative to a level of inflammation in the subject prior to administering the pharmaceutical composition.

[0024] Provided herein are methods of treating a disease in a subject, wherein the methods comprise: administering to the subject a therapeutically effective amount of a polypeptideAttorney Docket No. 199830-739601 construct provided herein, a pharmaceutical composition provided herein, or a dosing regimen provided herein, thereby treating the disease in the subject.

[0025] Provided herein are methods of inducing immune tolerance in a subject, wherein the methods comprise: administering to the subject a therapeutically effective amount of a polypeptide construct provided herein, a pharmaceutical composition provided herein, or a dosing regimen provided herein, thereby inducing immune tolerance in the subject.

[0026] Provided herein are compositions, wherein the compositions are for use in treating systemic lupus erythematosus in a subject, wherein the compositions comprise: a polypeptide construct provided herein, wherein the composition is administered to a subject in need thereof thereby treating systemic lupus erythematosus in the subject.

[0027] Provided herein are compositions, wherein the compositions are for use in treating multiple sclerosis in a subject, wherein the composition comprises: a polypeptide construct provided herein, wherein the composition is administered to a subject in need thereof, thereby treating multiple sclerosis in the subject.

[0028] Provided herein are compositions, wherein the compositions are for use in treating an autoimmune disease in a subject, wherein the compositions comprise: a polypeptide construct provided herein, wherein the composition is administered to a subject in need thereof, thereby treating the autoimmune disease in the subject.

[0029] Provided herein are compositions, wherein the compositions are for use in treating diabetes in a subject, wherein the compositions comprise: a polypeptide construct provided herein, wherein the composition is administered to a subject in need thereof, thereby treating diabetes in the subject.

[0030] Provided herein are methods of alleviating at least one symptom of a disease or a disorder by subcutaneously administering any one or more of the polypeptide constructs provided herein to a subject in need thereof.

[0031] Provided herein are polypeptide constructs, wherein the polypeptide constructs upon contact with a cell or a population of cells: (a) depletes a number of memory B cells as assessed by measuring memory B cell markers; (b) reduces an amount of innate pro-inflammatory cytokines; (c) increases a number of T regulatory cells; (d) increases a number of exhausted effector T cells; (e) reduces a number of CD3+, CD20+ T cells; (f) reduces a number of CD 19+ CD20+ B cells; (g) reduces a number of tissue resident activated B cells in a tissue; or (i) any combination of (a)-(g).Attorney Docket No. 199830-739601INCORPORATION BY REFERENCE

[0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0034] FIGURE 1 shows a schematic representation of a CD-40 targeting moiety provided herein.

[0035] FIGURE 2A-2E shows schematic representations of exemplary CD-40 and CD-20 targeting proteins. FIG. 2A shows Crossmab 1 and Crossmab 2 for CD-40 and CD-20 targeting bispecific antibodies. FIG. 2B shows FabScfvl and FabScfv2. FIG. 2C shows diabody formats and cross VH-VL formats for DFI105 and ofatumumab antibody fragments. FIG. 2D shows cross CH1 / CL and Fab antibodies, Fab-Scfv-VH-VL-heavy chain, and Fab-Scfv-VL-VH-heavy chain formats. FIG. 2E shows Fab ofatumumab - ds ScFv- DFI105 (VH-VL or VL-VH) heavy chain formats.

[0036] FIGURE 3A-3B shows a schematic representation of CD-40, and BAFF targeting proteins. FIG. 3A shows Crossmab 3 and Crossmab 4 formats for CD-40 and BAFF targeting bispecific antibodies. FIG. 3B shows FabScfv3 and FabScfv4 formats for CD-40 and BAFF targeting bispecific antibodies.

[0037] FIGURE 3C shows a table of performance ranking for various subcutaneous formulations of the CD-40 targeting moiety, DFI105. Sequences for DFI105 are shown in Table 31

[0038] FIGURE 4A-4B show schematic representations of exemplary CD-40, and IFNR targeting proteins. FIG. 4A shows Crossmab 5 and Crossmab 6 formats for CD-40 and IFNR targeting bispecific antibodies. FIG. 4B shows FabScfv5 and FabScfv6 formats for CD-40 and IFNR targeting bispecific antibodies.

[0039] FIGURE 5A-5B shows schematic representations of exemplary of CD-40 and APRIL targeting proteins. FIG. 5A shows Crossmab 7 and Crossmab 8 formats for CD-40 and APRIL targeting bispecific antibodies. FIG. 5B shows FabScfv7 and FabScfv8 formats for CD-40 and APRIL targeting bispecific antibodies.Attorney Docket No. 199830-739601

[0040] FIGURES 6A-6E show graphs showing CD19+CD20+B cells in the total B cell population in peripheral blood and various tissues in response to antibody treatments. FIG. 6A shows a graph of CD19+CD20+B cells in the peripheral blood following treatment with DFI105, rituximab (Rituxan®), ofatumumab (Kesimpta®), a combination of Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: cells per microliter (pL). FIG. 6B shows a graph of CD19+CD20+B cells in the bone marrow following treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: percentage of CD19+CD20+B cells in the total population of cells. FIG. 6C shows a graph of CD19+CD20+B cells in lymph node. X-axis: Time; Y-axis: percentage of CD19+CD20+B cells in the total population of cells. FIG. 6D shows a graph of CD19+CD20+B cells in the spleen 21 days after treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: percentage of CD19+CD20+B cells in the total population of cells. FIG. 6E shows a graph of a survey of CD19+CD20+B cell populations in peripheral blood and tissues 21 days after treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, and vehicle control. X-axis: condition; Y-axis: percentage of CD19+CD20+B cells in the total population of cells surveyed.

[0041] FIGURE 7 shows a graph showing the concentration of memory B cells in peripheral blood samples following treatment with Rituxan and DFI105, Kesimpta and DFI105, and control. X-axis: time in days; Y-axis: cells per microliter.

[0042] FIGURES 8A-8D show graphs showing the percentage of various memory B cell populations in the total B cell population in peripheral blood in response to antibody treatments. FIG. 8A shows a graph of bone marrow unswitched memory B cell in total B cells population in the peripheral blood following treatment with Kesimpta, a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of bone marrow unswitched memory B cell in the total B cell population. FIG. 8B shows a graph of lymph node unswitched memory B cell in the total B cell population in peripheral blood following treatment with Kesimpta, a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of lymph node unswitched memory B cell in the total B cell population. FIG. 8C shows a graph of bone marrow switched memory B cell in the total B cell population in peripheral blood following treatment with Kesimpta, a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of bone marrow switched memory B cell in the total B cell population. FIG. 8D shows a graph of lymph node switched memory B cell in the total B cell population in peripheral blood following treatment with Kesimpta, a combination of Rituxan and DFI105,Attorney Docket No. 199830-739601Kesimpta and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of lymph node switched memory B cell in the total B cell population.

[0043] FIGURES 9A-9D show graphs showing the percentage of various B cell subtypes in the total B cell population from the spleen in response to different antibody treatments. FIG. 9A shows a graph of memory B cells in total B cell population from the spleen following treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, Rituxan and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of spleen memory B cells in the total B cell population. FIG. 9B shows a graph of spleen switched memory B cells in the total B cell population in spleen following treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, Rituxan and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of spleen switched memory B cells in the total B cell population. FIG. 9C shows a graph of exhausted B cells in the total B cell population from the spleen following treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, Rituxan and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of spleen exhausted B cell in the total B cell population. FIG. 9D shows a graph of unswitched memory B cells in the total B cell population from the spleen following treatment with DFI105, Rituxan, Kesimpta, a combination of Kesimpta and DFI105, Rituxan and DFI105, and vehicle control. X-axis: time in days; Y-axis: percentage of spleen unswitched memory B cells in the total B cell population.

[0044] FIGURE 10 shows graph showing concentration of non-classical monocytes in peripheral blood following treatment with DFI105, Kesimpta, Rituxan, and a combination of Rituxan and DFI105, Kesimpta and DFI105 and vehicle control. X-axis: time in days; Y-axis: cells per microliter.

[0045] FIGURE 11 shows a graph of the concentration of classical monocytes in the peripheral blood following treatment with DFI105, Kesimpta, Rituxan, and a combination of Rituxan and DFI105, Kesimpta and DFI105 and vehicle control. Y-axis: cells per microliter.

[0046] FIGURES 12A-12B show graphs showing the correlation between monocyte count and different antibody concentrations. FIG. 12A shows a graph of the correlation between non- classical monocyte count and different antibody concentrations following treatment with Kesimpta and a combination of Rituxan and DFI105. X-axis antibody concentration in ng per milliliter; Y- axis: antibody concentration in nanogram per milliliter. FIG. 12B shows a graph of correlation between classical monocyte count and different antibody concentrations following treatment with Kesimpta and a combination of Rituxan and DFI105. X-axis antibody concentration in ng per mL; Y-axis antibody concentration in nanogram per milliliter.

[0047] FIGURES 13A-13B show graphs showing concentration of blood conventional dendritic cells in peripheral blood in response to different antibody treatments. FIG. 13A shows aAttorney Docket No. 199830-739601 graph for the concentration of type 1 conventional dendritic cells (DC1) in peripheral blood following treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: cells per microliter. FIG. 13B shows a graph for the concentration of type 2 conventional dendritic cells (DC2) in peripheral blood following treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: cells per microliter.

[0048] FIGURES 14A-14C show graphs showing abundance and distribution of T cell subtypes in peripheral blood and different tissues in response to different antibody treatments. FIG. 14A shows a graph of the concentration of regulatory T cells (Tregs) in peripheral blood samples following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: absolute cell counting in cells per microliter. FIG. 14B shows a graph for the percentage of Tregs in lymph node following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: Percentage. FIG. 14C shows a graph for the percentage of Treg population in spleen following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: Percentage.

[0049] FIGURES 15A-15C show graphs showing the abundance and distribution of exhausted T cells in peripheral blood samples and different tissues in response to various antibody treatments. FIG. 15A shows a graph for the population of exhausted T cells in the peripheral blood following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: Absolute cell counting in cells per microliter. FIG. 15B shows a graph for the percentage of exhausted T cell population in lymph node following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: Percentage. FIG. 15C shows a graph for the percentage of exhausted T cell in spleen following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time; Y-axis: Percentage.

[0050] FIGURES 16A-16B show graphs showing concentration of CD3+CD20+ T Cell Population in peripheral blood and spleen in response to different antibody treatments. FIG. 16A shows a graph for the concentration of CD3+CD20+ T Cell Population in peripheral blood following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time Y-axis: cells per microliter. FIG. 16B shows a graph for the concentration of CD3+CD20+ T Cell population in spleenAttorney Docket No. 199830-739601 following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time Y-axis: cells per microliter.

[0051] FIGURES 17A-17B show graphs showing the concentration of Keyhole Limpet Hemocyanin (KLH) specific antibody levels in response to different antibody treatments. FIG. 17A shows a graph for the concentration of KLH specific IgG level in the serum following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time Y-axis: nanogram per milliliter. FIG. 17B shows a graph for the concentration of KLH specific IgM level in the serum following the treatment with DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time Y-axis: nanogram per milliliter.

[0052] FIGURES 18A-18C show graphs showing cell lysis abilities of different antibodies in different tumor cell models. FIG. 18A shows the cell lysis rate in NALM-6-Luc cell line following the treatment with Kesimpta, a combination of Kesimpta and DFI105, human IgGl (negative control), 72458_9Pro-A pilot (positive control). X-axis: Antibody concentration in nanogram per milliliter; Y-axis: cell lysis rate in percentage. FIG. 18B shows the cell lysis rate in WSU DLCL2 cell line following the treatment with a combination of Kesimpta and DFI105, and a positive control. X-axis: Antibody concentration in nanogram per milliliter; Y-axis: cell lysis rate in percentage. FIG. 18C shows the cell lysis rate in Raji-Luc cell line following the treatment with a combination of Kesimpta and DFI105, 72458_9Pro-A pilot (positive control). X-axis: antibody concentration in nanogram per milliliter; Y-axis: cell lysis rate in percentage.

[0053] FIGURE 19 shows a graph showing reduction of tumor cells as measured by bioluminescence intensity following the treatment of DFI105, Rituxan, Kesimpta, or a combination of Rituxan and DFI105, Kesimpta and DFI105, and vehicle control. X-axis: Time Y- axis: bioluminescence intensity in photons per second.

[0054] FIGURE 20 shows a graph showing the binding activity of DFI105, rituximab, and a human IgGl isotype control to FcyR in Raji cells expressing both CD40 and CD20. X- axis: concentration (nM); Y-axis: mean fluorescence intensity (MFI).

[0055] FIGURE 21 shows a graph showing antibody-dependent cell-mediated cytotoxicity (ADCC) of DFI105, a bispecific DFI105 / ofatumumab antibody (Crossmab 2), a bispecific DFI105 / ofatumumab FabScfvl, and a human IgG4 isotype control in Raji / PBMCs. X-axis: concentration (nM); Y-axis: % cytotoxicity.

[0056] FIGURE 22 shows a graph showing ADCC of a bispecific DFI105 / ofatumumab antibody (Crossmab 2), a bispecific DFI105 / ofatumumab FabScfvl, rituximab, ofatumumab, and a human IgGl isotype control in Raji / PBMCs. X-axis: concentration (nM); Y-axis: % cytotoxicity.Attorney Docket No. 199830-739601

[0057] FIGURE 23 shows a graph showing antibody-dependent cellular phagocytosis (ADCP) activity of DFI105, Crossmab2, FabScfvl, and a human IgG4 isotype control in Macrophage / Raji cells. X-axis: concentration (nM); Y-axis: % phagocytosis.

[0058] FIGURE 24 shows a graph showing antibody-dependent cellular phagocytosis (ADCP) activity of a bispecific DFI105 / ofatumumab antibody (Crossmab 2), a bispecific DFI105 / ofatumumab FabScfvl, rituximab, ofatumumab, and a human IgGl isotype control in macrophage / Raji cells. X-axis: concentration (nM); Y-axis: % phagocytosis.

[0059] FIGURE 25 shows a graph showing antibody-dependent cellular phagocytosis (ADCP) activity of DFI105, Crossmab2, FabScfvl, and a human IgG4 isotype control in Macrophage / Raji cells from a different human donor. X-axis: concentration (nM); Y-axis: % phagocytosis.

[0060] FIGURE 26 shows a graph showing antibody-dependent cellular phagocytosis (ADCP) activity of a bispecific DFI105 / ofatumumab antibody (Crossmab 2), a bispecific DFI105 / ofatumumab FabScfvl, rituximab, ofatumumab, and a human IgGl isotype control in Macrophage / Raji cells from a different human donor. X-axis: concentration (nM); Y-axis: % phagocytosis.

[0061] FIGURE 27 shows a graph showing complement-dependent cytotoxicity (CDC) of DFI105, Crossmab2, FabScfvl, and a human IgG4 isotype control in Raji. X-axis: concentration (nM); Y-axis: % CDC.

[0062] FIGURE 28 shows a graph showing CDC of a bispecific DFI105 / ofatumumab antibody (Crossmab 2), a bispecific DFI105 / ofatumumab FabScfvl, rituximab, ofatumumab, DFI105, and a human IgGl isotype control in Macrophage / Raji cells. X-axis: concentration (nM); Y-axis: % CDC.

[0063] FIGURE 29 shows a graph showing CD40L-induced upregulation of CD69 by human B cells. X-axis: concentration (micrograms per milliliter, pg / mL); Y-axis: % CD69+ CD19+ B cells.

[0064] FIGURE 30 shows a graph showing the effect of antibodies on upregulation of CD69 induced by CD40L on human B cells. Data shown for DFI105, Crossmab2, FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: % CD69+ B cells.

[0065] FIGURE 31 shows a graph showing the effect of antibodies on CD40L and IL-4-induced proliferation of human B cells from a first donor. Data shown for DFI105, Crossmab2, FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0066] FIGURE 32 shows a graph showing the effect of antibodies on CD40L and IL-4-induced proliferation of human B cells from a second donor. Data shown for DFI105, Crossmab2,Attorney Docket No. 199830-739601FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0067] FIGURE 33 shows a graph showing the effect of antibodies on CD40L and IL-4-induced proliferation of human B cells from a third donor. Data shown for DFI105, Crossmab2, FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0068] FIGURE 34 shows a graph showing the effect of antibodies on CD40L and IL-4-induced proliferation of human B cells from all human donors. Data shown for DFI105, Crossmab2, FabScfvl, IgG4 isotype, DFI105 / ofatumumab Crossmab2, DFI105 / ofatumumab FabScfv, rituximab, ofatumumab, and IgGl isotype. X-axis: concentration (nM); Y-axis: cell numbers.

[0069] FIGURE 35 shows a graph showing BAFF and CD40L induced phospho-lkB alpha for 15 and 30min (top) and for 30 and 60 min (bottom). Stimulators: CD40L, CD40L and BAFF, and BAFF. X-axis: Stimulator concentration; Y-axis: MFI of phosphor-IkB alpha.

[0070] FIGURE 36 shows a graph showing a dose-response of antibody inhibition of CD40L- CD40 interaction in B cells. Data is shown for WBP72458 9 - FAB_Ofatumumab-ds- ScFv_DFI105 VH.VL; WBP72458 6 - CrossCHlCl_Ofatumumab-FAB_DFH05-FAB_Ofatumumab-ds- ScFv_DFH05 VH.VL; WBP72458 3 - CrossVHVL_DFH05- FAB Ofatumumab; WBP72458 1 - Diabody_DFH05- FAB Ofatumumab; scFv(Ofat / DFI); Crossmab(RTX / DFI); DFI105; and WBP72458 10 - FAB_Ofatumumab-ds- ScFv_DFH05 VL.VH; DFI105. X-axis: Concentration (ng / ml); Y-axis: % inhibition.

[0071] FIGURE 37 shows a graph showing a dose-response of antibody inhibition of CD40L- CD40 interaction in B cells. Data is shown for: WBP72458 9 - FAB_Ofatumumab-ds- ScFv_DFI105 VH.VL; WBP72458 10 - FAB_Ofatumumab-ds- ScFv_DFI105 VL.VH; DFI105; scFv(Ofat / DFI); Crossmab (RTX / DFI); Dacetuzumab; Isotype IgGl; and Isotype IgG4. X-axis: Concentration (ng / ml); Y-axis: % inhibition.

[0072] FIGURE 38 shows an experimental timeline for human islet microtissue preparation, PBMC stimulation, and treatment with the DFI105 and DFI205 antibodies.

[0073] FIGURE 39 shows a graph of basal insulin secretion for human islet microtissues treated with or without activated PBMCs, a solvent or an antibody as indicated. Data represent mean + SEM of 1 donor with n =11-12 technical replicates. After outlier removal with ROUT 5% outlier test, a One-way ANOVA with Dunnett’s multiple comparisons test was performed comparing the “Solvent with PBMCs” vs. all other experimental groups containing PBMCs (black stars). An unpaired t-test was performed between the “hlsMT-solvent with PBMCs” vs. “hlsMT only” (stars). An unpaired t-test was performed between “hlsMT-solvent with PBMCs” vs. experimental groups (stars). *p < 0.05, **p < 0.01, ***p < 0.001.Attorney Docket No. 199830-739601

[0074] FIGURE 40 shows a graph shows a graph of glucose stimulated insulin secretion for human islet microtissues treated with or without activated PBMCs, a solvent or an antibody as indicated. Data represent mean + SEM of 1 donor with n =11-12 technical replicates. After outlier removal with ROUT 5% outlier test, a One-way ANOVA with Dunnett’s multiple comparisons test was performed comparing the “Solvent with PBMCs” vs. all other experimental groups containing PBMCs (black stars). An unpaired t-test was performed between the “hlsMT-solvent with PBMCs” vs. “hlsMT only” (stars). An unpaired t-test was performed between “hlsMT- solvent with PBMCs” vs. experimental groups (stars). *p < 0.05, **p < 0.01, ***p < 0.001.

[0075] FIGURE 41 shows a graph of the fold-change in glucose stimulation for human islet microtissues treated with or without activated PBMCs, a solvent, or an antibody as indicated. Data represent mean + SEM of 1 donor with n =11-12 technical replicates. After outlier removal with ROUT 5% outlier test, a One-way ANOVA with Dunnett’s multiple comparisons test was performed comparing the “Solvent with PBMCs” vs. all other experimental groups containing PBMCs (black stars). An unpaired t-test was performed between the “hlsMT-solvent with PBMCs” vs. “hlsMT only” (stars). An unpaired t-test was performed between “hlsMT-solvent with PBMCs” vs. experimental groups (stars). *p < 0.05, **p < 0.01, ***p < 0.001.

[0076] FIGURE 42 shows a graph of total insulin content in glucose stimulation for human islet microtissues treated with or without activated PBMCs, a solvent, or an antibody as indicated. Data represent mean + SEM of 1 donor with n =11-12 technical replicates. After outlier removal with ROUT 5% outlier test, a One-way ANOVA with Dunnett’s multiple comparisons test was performed comparing the “Solvent with PBMCs” vs. all other experimental groups containing PBMCs (black stars). An unpaired t-test was performed between the “hlsMT-solvent with PBMCs” vs. “hlsMT only” (stars). An unpaired t-test was performed between “hlsMT-solvent with PBMCs” vs. experimental groups (stars). *p < 0.05, **p < 0.01, ***p < 0.001.

[0077] FIGURE 43 shows a graph of ATP content for human islet microtissues treated with or without activated PBMCs, a solvent, or an antibody as indicated. Data represent mean + SEM of 1 donor with n =11-12 technical replicates. After outlier removal with ROUT 5% outlier test, a One-way ANOVA with Dunnett’s multiple comparisons test was performed comparing the “Solvent with PBMCs” vs. all other experimental groups containing PBMCs (black stars). An unpaired t-test was performed between the “hlsMT-solvent with PBMCs” vs. “hlsMT only” (stars). An unpaired t-test was performed between “hlsMT-solvent with PBMCs” vs. experimental groups (stars). *p < 0.05, **p < 0.01, ***p < 0.001.

[0078] FIGURE 44A- FIGURE 44G show graphs of the total cell count, organoid volume, NKC6.1, ARX, and CD3+ cell counts for human islet microtissues treated with or without activated PBMCs, a solvent, or an antibody as indicated FIG. 44A show a graph of the total cellAttorney Docket No. 199830-739601 count. FIG. 44B shows a graph of the NKX6.1 cell count. FIG. 44C shows a graph of the hlsMT cell volume.. FIG. 44D shows a graph of the ARX cell count. FIG. 44E shows a graph of the CD3+ cell count. FIG. 44F shows a graph of the mean ARX intensity. FIG. 44G. shows a graph of the mean NKX6.1 intensity.

[0079] FIGURE 45 shows an image of the localization of DFI105 in the brain or marmosets with Experimental Autoimmune Encephalomyelitis (EAE).

[0080] FIGURE 46 shows brain MRIs of marmosets with induce EAE that were treated with DFI105 or control. 4 monkeys were assigned to a PBS-treatment group (left) and 3 monkeys that were assigned to the DFI105 treatment group (right). The two left columns depict the situation at the start of treatment, while the two right columns depict the identical slice in the last MRI recording before the monkey was sacrificed. Arrows point at visible T2 lesions. The differential images visualizing brain barrier leakage were created by subtraction of T1 -weighted images recorded before and after intravenous injection of 300 AM / kg Gd-DTPA.

[0081] FIGURE 47A - FIGURE 47C show graphs of the pharmacokinetic and pharmacodynamic effects of monoclonal antibodies relative to the bispecific CD40 / CD20- targeting antibody in non-human primates. FIG. 47A shows a graph of the pharmacokinetic effects of monoclonal and bispecific antibodies relative to control in non-human primates. FIG. 47B shows a graph of the pharmacodynamic effects of monoclonal and bispecific antibodies relative to control in non-human primates. FIG. 47C shows the concentration of IgA, IgG, and IgM in response to the indicated antibodies and controls.DETAILED DESCRIPTION OF THE INVENTION

[0082] Briefly, provided herein are CD-40 targeting compositions. The central role of CD40- CD40L interaction in the initiation, amplification and prolongation of immune responses makes the CD-40 targeting compositions suitable for immune modulation in an autoimmune disorder and in the treatment of cancers. The compositions provided herein enhance targeted immunosuppression in a subject that can be used to treat autoimmune diseases or tolerize a subject for the administration of a gene therapy or a transplantation. In some cases, the compositions are for use in ameliorating a symptom of an autoimmune disease or inflammatory disorder; can be used to reduce graft rejection or induce immune tolerance to a transplant; and / or can be used in the treatment of CD-40 positive cancers. The CD-40 targeting compositions inhibit T cell activation and deplete memory B cell populations when administered to a subject.

[0083] In some cases, the CD-40 targeting compositions further comprise a CD-20 targeting moiety. CD-20 is a protein that regulates the development and differentiation of B-cells intoAttorney Docket No. 199830-739601 plasma cells. Thus, in combination, a CD-40 targeting moiety and a CD-20 targeting moiety reduces B cell expansion further slowing disease progression and alleviating symptoms of a disease. The synergy between the CD-40-targeting moiety and the CD-20-targeting moiety of the polypeptide constructs described herein provide a safe and effective therapeutic that depletes the population of CD19+CD20+B cells while inhibition T cells which results in broad humoral and cellular immunity.

[0084] In some embodiments, the CD-40 targeting compositions provided herein further comprise a B-cell Activating Factor of the Tumor Necrosis Factor Family (BAFF)-targeting moiety. BAFF is a protein that promotes B cell maturation and activation. Targeting BAFF can also reduce B cell populations. In some embodiments, the CD-40 targeting compositions further comprise an interferon receptor-targeting moiety. In some embodiments, the interferon receptortargeting moiety is a type 1 interferon receptor subunit (IFNARl)-targeting moiety. In some embodiments, the interferon receptor-targeting moiety is a type 2 interferon receptor subunit (IFNAR2)-targeting moiety. In some embodiments, the CD-40 targeting compositions further comprise A proliferation-inducing ligand (APRIL)-targeting moiety. APRIL is also referred to as a tumor necrosis factor ligand superfamily 13 (TNFSF13) and cluster of differentiation 256 (CD256).

[0085] Provided herein are (1) CD-40 targeting moieties; (2) CD-20 targeting moieties; (3) BAFF-targeting moieties; (4) APRIL-targeting moieties; (5) interferon receptor-targeting moieties; (6) combination compositions; (7) nucleic acids and vectors; (8) pharmaceutical compositions; (9) drug delivery devices; (10) dosing, administration, and efficacy; (11) methods of treating a disease; and (12) kits.Definitions

[0086] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0087] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0088] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specificallyAttorney Docket No. 199830-739601 identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0089] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0090] As used herein, “optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0091] As used herein, the term “about” or “approximately” means a range of up to ± 20 % of a given value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.

[0092] The term “effective amount” or “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired effect.

[0093] The term "antibody fragments" and its grammatical equivalents as used herein refers to a portion of an intact antibody. For example, the antigen binding or variable region of the intact antibody.

[0094] The term "binding" and its grammatical equivalents as used herein refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, ionic and / or hydrogen-bond interactions, including interactions such as salt bridges and water bridges. In some cases, the first member of a specific binding pair present on the proteins provided herein binds specifically to a second member of the specific binding pair, such as a receptor on a surface of a cell. "Specific binding" refers to binding with an affinity of at least about 10'7M or greater. "Non-specific binding" refers to binding with an affinity of less than about 10'7M.Attorney Docket No. 199830-739601

[0095] The term “expression” and its grammatical equivalents as used herein refers to the biosynthesis of a gene product. For example, in the case of a structural gene, expression involves transcription of the structural gene into mRNA and the translation of mRNA into one or more polypeptides.

[0096] As used herein, unless otherwise indicated, the term “antibody” is understood to mean an intact antibody (e.g., an intact monoclonal antibody), or a fragment thereof, such as a Fc fragment of an antibody (e.g., an Fc fragment of a monoclonal antibody), or an antigen-binding fragment of an antibody (e.g, an antigen-binding fragment of a monoclonal antibody), including an intact antibody, antigen-binding fragment, or Fc fragment that has been modified, engineered, or chemically conjugated. In general, antibodies are multimeric proteins that contain four polypeptide chains. Two of the polypeptide chains are called immunoglobulin heavy chains (H chains), and two of the polypeptide chains are called immunoglobulin light chains (L chains). The immunoglobulin heavy and light chains are connected by an interchain disulfide bond. The immunoglobulin heavy chains are connected by interchain disulfide bonds. A light chain consists of one variable region (VL) and one constant region (CL). The heavy chain consists of one variable region (VH) and at least three constant regions (CHI, CH2 and CH3). The variable regions determine the binding specificity of the antibody. Each variable region contains three hypervariable regions known as complementarity determining regions (CDRs) flanked by four relatively conserved regions known as framework regions (FRs). The extent of the FRs and CDRs has been defined (Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. Naturally occurring antibodies have been used as starting material for engineered antibodies, such as chimeric antibodies and humanized antibodies. Examples of antibody-based antigen-binding fragments include Fab, Fab’, (Fab’)2, Fv, single chain antibodies (e.g, scFv), minibodies, and diabodies. Examples of antibodies that have been modified or engineered include chimeric antibodies, humanized antibodies, and multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies, or tetraspecific antibodies).

[0097] The terms “variable domain” and “variable region” are used interchangeably and refer to the portions of the antibody or immunoglobulin domains that exhibit variability in their sequence and that are involved in determining the specificity and binding affinity of a particular antibody. Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These subdomains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are called theAttorney Docket No. 199830-739601“framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface.

[0098] An “Fc polypeptide” of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e., a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 8, a, y, and p, respectively. Several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0099] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs. FcRs are reviewed, for example, in de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995).

[0100] The terms “VHH” or “nanobody” and their grammatical equivalents are used interchangeably herein to refer to a single variable domain heavy chain antibody.

[0101] Percent (%) sequence identity for a given sequence relative to a reference sequence is defined as the percentage of identical residues identified after aligning the two sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Percent identity can be calculated using alignment methods known in the art, for instance alignment of the sequences can be conducted using publicly available software such as BLAST, Align, ClustalW2. Those skilled in the art can determine the appropriate parameters for alignment, but the default parameters for BLAST are specifically contemplated.(1) CD-40 Targeting Moieties.

[0102] Provided herein are CD-40 targeting moieties and compositions thereof. In some embodiments, the CD-40 targeting moiety binds to a CD-40 molecule, epitope, or antigen on a cell. In some embodiments, the CD-40 molecule is on the surface of a cell. In some embodiments, the cell is a leukocyte, a lymphocyte, a B cell, a dendritic cell, a monocyte, a platelet, a macrophage, a myofibroblast, a fibroblast, an epithelial cell, an endothelial cell, a hematopoietic progenitor cell, a neuronal cell, a stem cell, or an in iv' / ra-differentiated cell. In some embodiments,Attorney Docket No. 199830-739601 the CD-40 targeting moiety does not bind to a CD-40 ligand (CD-40L). In some embodiments, the CD-40 targeting moiety inhibits or blocks a CD-40 ligand from binding to CD-40. In some embodiments, the CD-40 targeting moiety binds directly to CD-40. In some embodiments, the CD- 40 targeting moiety binds to an allosteric site on CD-40. In some embodiments, the CD-40 targeting moiety binds to a TNF receptor-associated factor (TRAF) protein binding site, for example a TRAF2 binding site.

[0103] Provided herein are CD-40 targeting moieties that comprise an antibody or an antibody fragment. In some embodiments, the CD-40 targeting moiety comprises an antibody fragment that is selected from the group consisting of: a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. In some embodiments, the CD-40 targeting moiety comprises a Fab region. In some embodiments, the CD-40 targeting moiety comprises an ScFv region. In some embodiments, the CD-40 targeting moiety comprises a CD-40 binding Fc region. In some embodiments, the CD-40 targeting moiety comprises an scFv-Fc region.

[0104] In some embodiments, the CD-40 targeting moiety comprises a PG102 antibody or an antigen binding fragment thereof; a ch5D12 antibody or an antigen binding fragment thereof; a 2C10R4 antibody or an antigen binding fragment thereof; a BI 655064 antibody or an antigen binding fragment thereof; KPL-404 or an antigen binding fragment thereof; iscalimab or an antigen binding fragment thereof; bleselumab or an antigen binding fragment thereof; ravagalimab or an antigen binding fragment thereof; mitazalimab or an antigen binding fragment thereof; variants, biosimilars, or any combinations thereof.CD-40 Tarsetins Heavy Chain Compositions

[0105] In some embodiments, the CD-40 targeting moiety comprises a heavy chain. In some embodiments, the heavy chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the heavy chain comprises a heavy chain variable region. In some embodiments, the heavy chain comprises a heavy chain constant region. In some embodiments, the heavy chain further comprises a signal sequence.

[0106] In some embodiments, the CD-40 targeting moiety comprises a heavy chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or atAttorney Docket No. 199830-739601 least 600 amino acids in length. In some embodiments, the CD-40 targeting moiety comprises a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0107] In some embodiments, the CD-40 targeting moiety comprises a heavy chain comprising a CDR1 region. Non-limiting examples of heavy chain CDR1 sequences and amino acid modifications are provided in Table 1 below.Table 1. CD-40 Targeting Moiety Heavy Chain CDR1.

[0108] In some embodiments, a CD-40 targeting moiety comprises a sequence that is at least 60% identical to any one of SEQ ID NO: 1 to SEQ ID NO: 19. In some embodiments, a CD-40 targeting moiety comprises a sequence that is at least 70% identical to any one of SEQ ID NO: 1 to SEQ ID NO: 19 In some embodiments, a CD-40 targeting moiety comprises a sequence thatAttorney Docket No. 199830-739601 is at least 80% identical to any one of SEQ ID NO: 1 to SEQ ID NO: 19. In some embodiments, a CD-40 targeting moiety comprises a sequence that is at least 90% identical to any one of SEQ ID NO: 1 to SEQ ID NO: 19 In some embodiments, a CD-40 targeting moiety comprises or consists of a sequence having 100% sequence identity with any one of SEQ ID NO: 1 to SEQ ID NO: 19

[0109] In some embodiments, a CD-40 targeting moiety comprises a single amino acid substitution relative to any one of SEQ ID NO: 1 to SEQ ID NO: 19. In some embodiments, a CD-40 targeting moiety comprises two amino acid substitutions relative to any one of SEQ ID NO: 1 to SEQ ID NO: 19 In some embodiments, a CD-40 targeting moiety comprises three amino acid substitutions relative to any one of SEQ ID NO: 1 to SEQ ID NO: 19. In some embodiments, a CD-40 targeting moiety comprises four amino acid substitutions relative to any one of SEQ ID NO: 1 to SEQ ID NO: 19 In some embodiments, the amino acid substitution comprises a substitution of an amino acid residue of any one of SEQ ID NO: 1 to SEQ ID NO: 19 to a different amino acid residue, wherein the different amino acid residue is a hydrophobic amino acid residue, a hydrophilic amino acid residue, a charged amino acid residue that is a basic amino acid residue or an acidic amino acid residue, or an aliphatic amino acid residue.

[0110] In some embodiments, the CD-40 targeting moiety comprises a heavy chain comprising a CDR2 region. In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or a functional variant thereof. In some embodiments, a heavy chain CDR2 comprises a CDR2 listed in Table 2.Table 2. CD-40 Targeting Moiety Heavy Chain CDR2.Attorney Docket No. 199830-739601

[0111] In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising a sequence that is at least 57% identical to any one of SEQ ID NO: 20 to SEQ ID NO: 33. In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising a sequence that is at least 71% identical to any one of SEQ ID NO: 20 to SEQ ID NO: 33. In some embodiments, the CD- 40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising a sequence that is at least 85% identical to any one of SEQ ID NO: 20 to SEQ ID NO: 33. In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising a sequence that is 100% identical to any one of SEQ ID NO: 20 to SEQ ID NO: 33

[0112] In some embodiments, a CD-40 targeting moiety comprises a single amino acid substitution relative to any one of SEQ ID NO: 20 to SEQ ID NO: 33. In some embodiments, a CD-40 targeting moiety comprises two amino acid substitutions relative to any one of SEQ ID NO: 20 to SEQ ID NO: 33 In some embodiments, a CD-40 targeting moiety comprises three amino acid substitutions relative to any one of SEQ ID NO: 20 to SEQ ID NO: 33.

[0113] In some embodiments, the CD-40 targeting moiety comprises a heavy chain comprising a CDR3 region. In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof. In some embodiments, a heavy chain CDR3 comprises a CDR3 listed in Table 3.Table 3. CD-40 Targeting Moiety Heavy Chain CDR3.Attorney Docket No. 199830-739601

[0114] In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising a sequence that is at least 60% identical to any one of SEQ ID NO: 34 to SEQ ID NO: 44. In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising a sequence that is at least 80% identical to any one of SEQ ID NO: 34 to SEQ ID NO: 44. In some embodiments, the CD- 40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising a sequence that is 100% identical to any one of SEQ ID NO: 34 to SEQ ID NO: 44.

[0115] In some embodiments, a CD-40 targeting moiety comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 34 to SEQ ID NO: 44. In some embodiments, a CD-40 targeting moiety comprises two amino acid substitutions relative to any one of SEQ ID NO: 34 to SEQ ID NO: 44

[0116] In some embodiments, the CD-40 targeting moiety comprises the heavy chain variable region, wherein the heavy chain variable region comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to a sequence in Table 4 below (SEQ ID NO: 45 to SEQ ID NO: 61)Table 4. CD-40 Targeting Moiety Heavy Chain Variable Regions.Attorney Docket No. 199830-739601Attorney Docket No. 199830-739601jold text: CDR sequences X = any amino acid

[0117] In some embodiments, the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region. In some embodiments, the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region. In some embodiments, the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMAttorney Docket No. 199830-739601TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 62).

[0118] In some embodiments, the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to a sequence in Table 5 below (SEQ ID NO:63 to SEQ ID NO: 81)Table 5. CD-40 Targeting Moiety Heavy Chain Sequences.Attorney Docket No. 199830-739601Attorney Docket No. 199830-739601Attorney Docket No. 199830-739601underlined font: variable region

[0119] In some embodiments, the heavy chain further comprises a heavy chain signal sequence, wherein the heavy chain signal sequence comprises: MKHLWFFLLLVAAPRWVLS (SEQ ID NO: 82); MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 83); METDTLLLWVLLLWVPGSTG (SEQ ID NO: 84); MGWSCIILFLVATATGVHS (SEQ ID NO: 85); MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO: 154); or MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 155) In some embodiments, the heavy chain signal sequence is cleaved upon contact with a cell or cell-free system by an enzyme.

[0120] In some embodiments, the CD-40 targeting moiety comprises a full-length antibody comprising a heavy chain amino acid sequence comprising a sequence that is at least 80%Attorney Docket No. 199830-739601 identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0121] WJ^F FFZlXr 4 l?F ^QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVROPPGKGLEWMGMMWGGGSTDYSTSLKSRLTISKDTSKSOVSLKMSSLTAADTA VYYCVRTDGDYWGOGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFN WYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 86). The signal sequence for the heavy chain is provided in bold italicized font above. The CDRs are provided in bold and underlined font above. N290 of the heavy chain is also underlined, as this residue has an N-linked glycan after translation of the polypeptide. Additional full length antibodies, antibody fragments, and polypeptide constructs are described in the Examples provided herein.CD-40 Targeting Light Chain Compositions

[0122] In some embodiments, the CD-40 targeting moiety comprises a light chain. In some embodiments, the light chain comprises a light chain variable region. In some embodiments, the light chain comprises a light chain constant region. In some embodiments, the light chain comprises three CDRs. In some embodiments, the light chain further comprises a signal sequence.

[0123] In some embodiments, the CD-40 targeting moiety comprises a light chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, or at least 500 amino acids in length. In some embodiments, the CD-40 targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0124] In some embodiments, the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 region. In some embodiments, the light chain CDR1 comprises RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acidAttorney Docket No. 199830-739601 substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88. Non-limiting examples of light chain CDR1 sequences and amino acid modifications are provided in Table 6 below.Table 6. CD-40 Targeting Moiety Light Chain CDR1.

[0125] In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 62% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 68% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 75% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 81% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95 In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 87% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is at least 93% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises a light chain CDR1 sequence that is 100% identical to any one of SEQ ID NO: 87 to SEQ ID NO: 95

[0126] In some embodiments, a CD-40 targeting moiety comprises a single amino acid substitution relative to SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises two amino acid substitutions relative to SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises three amino acid substitutions relative to SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40Attorney Docket No. 199830-739601 targeting moiety comprises four amino acid substitutions relative to SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises five amino acid substitutions relative SEQ ID NO: 87 to SEQ ID NO: 95. In some embodiments, a CD-40 targeting moiety comprises six amino acid substitutions relative to SEQ ID NO: 87 to SEQ ID NO: 95.

[0127] In some embodiments, the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 region. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR2 comprising KVSNRFS (SEQ ID NO: 96), or a functional variant thereof. Non-limiting examples of light chain CDR2 sequences and amino acid modifications are provided in Table 7 below.Table 7. CD-40 Targeting Moiety Light Chain CDR2.

[0128] In some embodiments, a CD-40 targeting moiety comprises a light chain CDR2 sequence comprising a sequence that is at 1 least 57% identical to any one of SEQ ID NO: 96 to SEQ ID NO: 109. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR2 comprising a sequence that is at least 71% identical to any one of SEQ ID NO: 96 to SEQ ID NO: 109. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR2Attorney Docket No. 199830-739601 comprising a sequence that is at least 85% identical to any one of SEQ ID NO: 96 to SEQ ID NO: 109. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR2 comprising a sequence that is 100% identical to any one of SEQ ID NO: 96 to SEQ ID NO: 109.

[0129] In some embodiments, a CD-40 targeting moiety comprises a single amino acid substitution relative to any one of SEQ ID NO: 96 to SEQ ID NO: 109. In some embodiments, a CD-40 targeting moiety comprises two amino acid substitutions relative to any one of SEQ ID NO: 96 to SEQ ID NO: 109 In some embodiments, a CD-40 targeting moiety comprises three amino acid substitutions relative to any one of SEQ ID NO: 96 to SEQ ID NO: 109.

[0130] In some embodiments, the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 region. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising SQSTHVPWT (SEQ ID NO: 110) or a functional variant thereof. Non-limiting examples of light chain CDR3 sequences and amino acid modifications are provided in Table 8 below.Table 8. CD-40 Targeting Moiety Light Chain CDR3.Attorney Docket No. 199830-739601

[0131] In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising a sequence that is at least 66% identical to any one of SEQ ID NO: 110 to SEQ ID NO: 125. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising a sequence that is at least 77% identical to any one of SEQ ID NO: 110 to SEQ ID NO: 125. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising a sequence that is at least 88% identical to any one of SEQ ID NO: 110 to SEQ ID NO: 125. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising a sequence that is at least 100% identical to any one of SEQ ID NO: 110 to SEQ ID NO: 125

[0132] In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising one or two amino acid substitutions relative to any one of SEQ ID NO: 110 to SEQ ID NO: 125. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising two amino acid substitutions relative to any one of SEQ ID NO: 110 to SEQ ID NO: 125. In some embodiments, the CD-40 targeting moiety comprises a light chain CDR3 comprising three amino acid substitutions relative to any one of SEQ ID NO: 110 to SEQ ID NO: 125.

[0133] In some embodiments, the CD-40 targeting moiety comprises the light chain variable region, wherein the light chain variable region comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to a sequence listed in Table 9 below (SEQ ID NO: 126 to SEQ ID NO: 137)Table 9. CD-40 Targeting Moiety Light Chain Variable Regions.Attorney Docket No. 199830-739601bold text: CDRsAttorney Docket No. 199830-739601

[0134] In some embodiments, the CD-40 targeting moiety comprises a light chain constant region, wherein the light chain constant region comprises an Immunoglobulin G (IgG) light chain constant region. In some embodiments, the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 light chain constant region.

[0135] In some embodiments, the CD-40 targeting moiety comprises a light chain constant region, wherein the light chain constant region comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138).

[0136] In some embodiments, the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to a sequence listed in Table 10 below (SEQ ID NO: 139 to SEQ ID NO: 153)Table 10. CD-40 Targeting Moiety Light Chain Sequences.Attorney Docket No. 199830-739601Attorney Docket No. 199830-739601underlined text: light chain variable region

[0137] In some embodiments, the light chain further comprises a light chain signal sequence, wherein the light chain signal sequence comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:Attorney Docket No. 199830-739601

[0138] SEQ ID NO: 82; SEQ ID NO: 83; SEQ ID NO: 84; SEQ ID NO: 85; MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO: 154); or MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 155). In some embodiments, the light chain signal sequence is cleaved upon contact with a cell or cell-free system by an enzyme.

[0139] Provided herein are compositions, wherein the compositions comprise an anti-CD40 antibody or antigen binding fragment thereof comprising: a light chain variable region, wherein the light chain variable region comprises: a CDR1 having the sequence RSSQSLAZ6SZ7GNTYLH, wherein Z6is S, and Z7is S or Q (SEQ ID NO: 156); a CDR2 having the sequence KVSNRFS (SEQ ID NO: 96); and a CDR3 having the sequence SQSTHVPWT (SEQ ID NO: 110); and a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 having the sequence GFSXnSRY, wherein Xu is I, L, or V, preferably wherein Xu is L (SEQ ID NO: 157); a CDR2 having the sequence WGGGSTD (SEQ ID NO: 20); and a CDR3 having the sequence TDGDY (SEQ ID NO: 34).

[0140] In some embodiments, the CD-40 targeting moiety comprises an anti-CD-40 antibody or antigen binding fragment thereof that comprises a light chain variable region comprising the sequence:

[0141] ZIZ2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZSPGQSPRL LIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEI KR; wherein: Zi, Z2, Z3and Z4are ELQL (SEQ ID NO: 332) or DIVM (SEQ ID NO: 333); Z5is L or P; Ze is S or D; Z7is S or Q; and Zs is R or K (SEQ ID NO: 158).

[0142] In some embodiments, the anti-CD-40 antibody or antigen binding fragment thereof comprises a light chain variable region comprising the sequence:

[0143] Z1Z2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZ8PGQSPRL LIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEI KR; wherein: Zi, Z2, Z3 and Z4are ELQL (SEQ ID NO: 332); Z5 is L; and Zs is R (SEQ ID NO: 159)

[0144] In some embodiments, the anti-CD-40 antibody or antigen binding fragment thereof comprises a light chain variable region comprising the sequence:

[0145] ZIZ2Z3Z4TQSPLSLPVTZ5GQPASISCRSSQSLAZ6SZ7GNTYLHWYLQZ8PGQSPRL LIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEI KR; wherein: Zi, Z2, Z3 and Z4are DIVM (SEQ ID NO: 333); Z5 is P; Ze is S; Z7is Q; and Zs is K (SEQ ID NO: 160)

[0146] In some embodiments, the CD-40 targeting moiety comprises a full-length antibody comprising a light chain amino acid sequence comprising a sequence that is at least 80% identical,Attorney Docket No. 199830-739601 at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0147] D / ?E 4 ZZGZZZZRZ / ?G,A / ?CELOLTOSPLSLPVTLGOPASISCRSSOSLASS OGNTYLHWYLORPGOSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVY YCSQSTHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEOLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQES VTEQD SKD ST YSLS STLTLSKADYEKHKVYACEVTHQGLS S PVTKSFNRGEC (SEQ ID NO: 161). The signal sequence for the light chain is provided in bold italicized font above. The CDRs are provided in bold and underlined font above.CD-40 targeting moiety structure and modi fications

[0148] Provided herein are compositions comprising a CD-40 targeting moiety that binds to CD- 40 protein. In some embodiments, the CD-40 protein (also referred to as tumor necrosis factor receptor superfamily member 5) comprises an amino acid sequence that is at least 90% identical to: NCBI Reference No. NP_001241.1. An exemplary amino acid sequence of human CD-40 in is shown below:

[0149] MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTE FTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCT SEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDL VVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEP QEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ (SEQ ID NO: 162).

[0150] CD-40 binds to its ligand CD40L, which activates dendritic cells and enhances antigenspecific T cell responses by upregulating molecules like MHC, CD86 / CD80, and IL-12 production. Additionally, the CD40 / CD40L pathway is involved in regulating immune cell homeostasis, B cell activation, and effective antigen presentation. In some embodiments, the CD- 40 targeting moiety inhibits or blocks a CD-40 ligand from binding to CD-40. In some embodiments, the CD-40 targeting moiety binds directly to CD-40. In some embodiments, the CD- 40 targeting moiety binds to an allosteric site on CD-40. In some embodiments, the CD-40 targeting moiety binds to a protein scaffold site on CD-40. In addition to interacting with CD40 ligand, CD-40 also interacts with several members of the TNF receptor-associated factor (TRAF) family proteins (e.g., TRAF2, TRAF3, TRAF5, TRAF6), with TRAF4 indirectly regulating its signaling. In some embodiments, the CD-40 targeting moiety binds to a TNF receptor-associated factor (TRAF) protein binding site on CD-40, for example the cytoplasmic tail of CD-40 at the PVQET (SEQ ID NO: 334) amino acid residues or QEPQEINF (SEQ ID NO: 335) amino acid residues.Attorney Docket No. 199830-739601

[0151] In some embodiments, the CD-40 targeting moiety comprises an antibody or antigen binding fragment thereof that is an antagonistic anti-human CD-40 monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof, comprises a constant region of a human antibody, for example, an IgG constant region. In some embodiments, the constant region is a region that is deficient in complement activation, for example, a human IgGi constant region or a mutated human IgGi constant region.

[0152] In some embodiments, the CD-40 targeting moiety provided herein comprises one light chain. In some embodiments, the CD-40 targeting moiety comprises two light chains. In some embodiments, the CD-40 targeting moiety comprises one light chain and one heavy chain. In some embodiments, the CD-40 targeting moiety comprises two light chains and one heavy chain. In some embodiments, the CD-40 targeting moiety comprises one heavy chain. In some embodiments, the CD-40 targeting moiety comprises two heavy chains. In some embodiments, the CD-40 targeting moiety comprises one light chain and two heavy chains. In some embodiments, the CD-40 targeting moiety comprises two light chains and two heavy chains.

[0153] In some embodiments, the CD-40 targeting moiety comprises cysteine linked pairs of light and heavy chains. In some embodiments, the CD-40 targeting moiety comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 cysteine residues. In some embodiments, the CD-40 targeting moiety comprises about 32 cysteine residues. In some embodiments, the CD-40 targeting moiety comprises a constant domain, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0154] In some embodiments, the CD-40 targeting moiety comprises post-translational modifications. In some embodiments, the CD-40 targeting moiety comprises an N-linked glycan. In some embodiments, the N-linked glycan is present on a residue of a heavy chain constant region of the CD-40 targeting moiety. In some embodiments, the N-linked glycan is on residue N290 of the amino acid sequence shown in SEQ ID NO: 86.

[0155] In some embodiments, the CD-40 targeting moiety comprises a modification that enhances multimerization to another targeting moiety, delivery, and stability of the CD-40 target moiety. Non-limiting examples of such modifications include: half-life extending agents, fusing amphipathic helices or leucine zippers to the CD-40 targeting moiety; pegylation; introducing a positively charged amino acids (for example, a Glu345Arg mutation in the IgGl Fc can create multimeric IgGl that binds more strongly to a given target); adding an IgM tailpiece to create IgG hexamers; covalent modifications, e.g., isomerization, deamidation, oxidation, glycation, or fragmentation, and conjugating multimeric cell-penetrating peptides. In some embodiments, theAttorney Docket No. 199830-739601 covalent modifications are in the CD-40 CDR regions. In some embodiments, at least one, e.g., 1, 2, 3, 4, 5, 6, CDR regions comprise at least one type of covalent modification, e.g., isomerization, deamidation, and oxidation, or combinations thereof. In some embodiments, the CD-40 targeting moiety comprises at least one, at least two, at least three, at least four, at least five, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.

[0156] In some embodiments, the CD-40 targeting moiety comprises a disulfide bridge that connect two cysteine residues of the CD-40 antibody. In some embodiments, the disulfide bridge is formed in a single-chain of the CD-40 variable fragment. In some embodiments, the disulfide bonds are formed by the oxidation of 2 thiol groups within the Cystine residues of the CD-40 variable fragment. In some embodiments, the disulfide bridge stabilizes the tertiary structures of the CD-40 antibody.

[0157] In some embodiments, the CD-40 targeting moiety comprises a knob and hole modification or amino acid substitution. In some embodiments, the knob and hole modification is in the constant region of the heavy chain or the constant region of the light chain. In some embodiments, the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. In some embodiments, the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). In some embodiments, the CD-40 targeting moiety comprises a knob in the heavy chain constant region. In some embodiments, the CD-40 targeting moiety comprises a Y to a W amino acid substitution. In some embodiments, the CD-40 targeting moiety comprises a hole mutation in the heavy chain constant region. In some embodiments, the CD-40 targeting moiety comprises a T to S amino acid substitution; an L to A amino acid substitution; a Y to V amino acid substation, or any combination thereof relative to the reference sequence of the CD-40 targeting moiety. In some embodiments, the knob modification and hole modification facilitate heterodimerization of an antibody fragment to another antibody fragment (e.g., an Fc region or a CH2 / CH3 region of an Fc). The Fc regions can be identical or different from each other.

[0158] In some embodiments, the CD-40 targeting moiety comprises an IgA fragment for multimerization of the CD-40 targeting moiety to another targeting moiety, antibody, or polypeptide.

[0159] In some embodiments, the CD-40 targeting moiety comprises a half-life extension agent. In some embodiments, the half-life extension agent is an albumin or a biotin.Attorney Docket No. 199830-739601

[0160] In some embodiments, the CD-40 targeting moiety comprises an N-terminal glutamine that is modified as pyro-glutamic acid. In some embodiments, the CD-40 targeting moiety comprises one or more glycosylation sites within a heavy chain sequence. In some embodiments, the CD-40 targeting moiety comprises reduced deamination relative to a PG102 CD-40 targeting antibody. In some embodiments, the CD-40 targeting moiety comprises a binding affinity for CD- 40 that is increased relative to a PG102 CD-40 targeting antibody. In some embodiments, the PG102 CD-40 targeting antibody comprises a heavy chain comprising SEQ ID NO: 63 or SEQ ID NO: 64. In some embodiments, the PG102 CD-40 targeting antibody comprises a light chain comprising SEQ ID NO: 126 or SEQ ID NO: 127

[0161] The CD-40 targeting moieties provided herein induce immune tolerance to antigens in a subject (e.g., a cell antigen or an antigen expressed by a transplant graft) by inhibiting cytotoxic T cells, thereby reducing the immune response to an antigen in the subject. The CD-40 targeting moiety also inhibits CD40-CD40L signaling on macrophages and antigen presenting cells when the CD-40 targeting moiety is administered to a subject. In some cases, the CD-40 targeting moiety is an allosteric inhibitor of CD40. In some cases, anti-CD40 disrupts pathogenic T cell / B cell interactions in lymphoid follicles in a subject. In some cases, the CD-40 targeting moiety suppresses germinal center formation and B cell proliferation in a subject relative to germinal center formation and B cell proliferation in the subject prior to administration of the CD-40 targeting moiety. In some cases, the CD-40 targeting moiety reduces the level of at least one proinflammatory cytokine in a subject relative to the level of the at least one proinflammatory cytokine prior to administration of the CD-40 targeting moiety to the subject. In some embodiments, the at least one proinflammatory cytokine comprises interleukin 12 (IL-12), IL-6, or tumor necrosis factor-alpha (TNF-a). The CD-40 targeting moieties provided herein can be combined with one or more additional targeting moieties provided herein, in any combination, to form bispecific, trispecific, tetraspecific, and multispecific constructs. Moreover, a polypeptide construct provided herein can comprise one or more CD-40 targeting moieties (e.g., two, three, four, etc.) that increase the engagement of CD-40 by the construct with a cell of interest in a subject.(2) CD-20 Targeting Moieties.

[0162] Provided herein are CD-20 targeting moieties and compositions thereof. In some embodiments, a CD-20 targeting moiety binds to a CD-20 molecule, epitope, or antigen on a cell. In some embodiments, the CD-20 molecule is on the surface of a cell. In some embodiments, the cell is a leukocyte, a lymphocyte, a B cell, a CD3+ T cell, or an in vzfro-differentiated cell. In some embodiments, the CD-20 molecule (also referred to as MS4A1 or membrane spanning 4-domainsAttorney Docket No. 199830-739601Al) comprises a sequence that is at least 90% identical to: NCBI Reference No. NP_068769.2 B- lymphocyte antigen CD20 [Homo sapiens]

[0163] MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLG AVQIMNGLFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLV KGKMIMNSLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEK NSPSTQYCYSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKKE QTIEIKEEVVGLTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP (SEQ ID NO: 163)

[0164] Provided herein are CD-20 targeting moieties that comprises an antibody or an antibody fragment. In some embodiments, the CD-20 targeting moiety comprises an antibody fragment that is selected from the group consisting of: a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. In some embodiments, the CD-20 targeting moiety comprises a CD-20 targeting antibody. In some embodiments, the CD-20 targeting antibody comprises rituximab (RITUXAN®) or an antigen binding fragment thereof; ocrelizumab (OCREVUS®) or an antigen binding fragment thereof; ofatumumab (KESIMPTA®) or an antigen binding fragment thereof; obinutuzumab (GAZYVA®) or an antigen binding fragment thereof; ibritumomab tiuxetan (ZEVALIN®) or an antigen binding fragment thereof; tositumomab (BEXXAR®) or an antigen binding fragment thereof; ublituximab (BRIUMVI®) or an antigen binding fragment thereof; ocaratuzumab (AME-133v) or an antigen binding fragment thereof; TRU-015 or an antigen binding fragment thereof; veltuzumab (IMMU-106) or an antigen binding fragment thereof; derivatives, variants, or combinations thereof.CD-20 Targeting Heavy Chain Compositions

[0165] Provided herein are compositions comprising a CD-20 targeting moiety, wherein the CD- 20 targeting moiety comprises a heavy chain. In some embodiments, the heavy chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the heavy chain comprises a heavy chain variable region. In some embodiments, the heavy chain comprises a heavy chain constant region. In some embodiments, the heavy chain further comprises a signal sequence.

[0166] In some embodiments, the CD-20 targeting moiety comprises a heavy chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440Attorney Docket No. 199830-739601 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the CD-20 targeting moiety comprises a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0167] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a CDR1 region. Non-limiting examples of heavy chain CDR1 sequences are provided in Table 11 (SEQ ID NO: 164 to SEQ ID NO: 169)Table 11. CD-20 Targeting Moiety Heavy Chain CDR1 Sequences.

[0168] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169 some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that is 100% identical to any one of SEQ ID NO: 164 to SEQ ID NO: 169.

[0169] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises threeAttorney Docket No. 199830-739601 amino acid substitutions as compared to any one of SEQ ID NO: 164 to SEQ ID NO: 169. In some embodiments,

[0170] the CD-20 targeting moiety comprises a heavy chain comprising a CDR2 region. Nonlimiting examples of heavy chain CDR2 sequences are provided in Table 12.Table 12. CD-20 Targeting Moiety Heavy Chain CDR2 Sequences.

[0171] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 62% identical to any one of SEQ ID NO: 170 to SEQ ID NO: 174. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 75% identical to any one of SEQ ID NO: 170 to SEQ ID NO: 174. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 87% identical to any one of SEQ ID NO: 170 to SEQ ID NO: 174. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 170 to SEQ ID NO: 174.

[0172] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 170 to SEQ ID NO: 174. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 170 to SEQ ID NO: 174. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 170 to SEQ ID NO: 174.

[0173] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a CDR3 region. Non-limiting examples of heavy chain CDR3 sequences are provided in Table 13Table 13. CD-20 Targeting Moiety Heavy Chain CDR3 Sequences.Attorney Docket No. 199830-739601

[0174] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 63% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 64% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 72% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 78% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 85% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 92% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 175 to SEQ ID NO: 181.

[0175] In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises two amino acid substitutions asAttorney Docket No. 199830-739601 compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181. In some embodiments, a CD-20 targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises six amino acid substitutions as compared to any one of SEQ ID NO: 175 to SEQ ID NO: 181.

[0176] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0177] EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTIS WNSGSIGYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 328).

[0178] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGD TS YNQKFKGKATLT ADKS S STAYMQLS SLTSEDS AVYYC ARST YYGGDWYFNVWGAG TTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 330).Attorney Docket No. 199830-739601

[0179] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDGD TDYNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNVFDGYWLVYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 329).

[0180] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGNGD TSYNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 182).

[0181] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGGIYPGNGD TSYNQKFKGKATLTVGKSSSTAYMQLSSLTSEDSAVYFCARYDYNYAMDYWGQGTSV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTAttorney Docket No. 199830-739601LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 183).

[0182] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QIQLVQSGPVLKQPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGE STYADDFKGRFAFSLETFVTTACLQINNLKNEDTATYFCARWGPHTAPYSMDNWGQGT SVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFP AVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAP NLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTH REDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVL PPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSK LRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 184).

[0183] In some embodiments, the CD-20 targeting moiety comprises a heavy chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:EVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGLEWVSTISWNSGSI GYADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDIQYGNYYYGMDVWGQ GTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 185).CD-20 Targeting Light Chain Compositions

[0184] Provided herein are compositions comprising a CD-20 targeting moiety, wherein the CD- 20 targeting moiety comprises a light chain. In some embodiments, the light chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the light chain comprises a light chain variable region. In some embodiments, the light chain comprises a light chain constant region. In some embodiments, the light chain further comprises a signal sequence.

[0185] In some embodiments, the CD-20 targeting moiety comprises a light chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length,Attorney Docket No. 199830-739601 at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the CD-20 targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0186] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a CDR1 region. Non-limiting examples of light chain CDR1 sequences are provided in Table 14.Table 14. CD-20 Targeting Moiety Light Chain CDR1 Sequences.

[0187] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that is 100% identical to any one of SEQ ID NO: 186 to SEQ ID NO: 188.

[0188] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 186 to SEQ ID NO: 188. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR1 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 186 to SEQ ID NO: 188.Attorney Docket No. 199830-739601

[0189] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising aCDR2 region. Non-limiting examples of light chain CDR2 sequences are provided in Table 15.Table 15. CD-20 Targeting Moiety Light Chain CDR2 Sequences.

[0190] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 66% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 70% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 75% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192. . In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 80% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 85% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 189 to SEQ ID NO: 192.

[0191] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 189 to SEQ ID NO: 192. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR2 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 189 to SEQ ID NO: 192.

[0192] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a CDR3 region. Non-limiting examples of light chain CDR3 sequences are provided in Table 16.Attorney Docket No. 199830-739601Table 16. CD-20 Targeting Moiety Light Chain CDR3 Sequences.

[0193] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 66% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 77% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 88% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 193 to SEQ ID NO: 196.

[0194] In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196 In some embodiments, a CD-20 targeting moiety provided herein comprises a light chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196. In some embodiments, a CD-20 targetingAttorney Docket No. 199830-739601 moiety provided herein comprises a light chain CDR3 sequence that comprises six amino acid substitutions as compared to any one of SEQ ID NO: 193 to SEQ ID NO: 196.

[0195] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0196] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNR ATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 197).

[0197] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0198] QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLAS GVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 198).

[0199] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0200] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNR ATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 199).

[0201] In some embodiments, the CD-20 targeting moiety comprises a light chain comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:

[0202] DIVMTQTPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQ MSNLVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGGGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 200).Attorney Docket No. 199830-739601CD-20 targeting moiety structure and modi fications

[0203] Provided herein are compositions comprising a CD-20 targeting moiety that binds to CD- 20. In some embodiments, the CD-20 targeting moiety comprises an antibody or antigen binding fragment thereof that is an antagonistic anti-human CD-20 monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof, comprises a constant region of a human antibody, for example, an IgG constant region. In some embodiments, the constant region is a region that is deficient in complement activation, for example, a human IgGi constant region or a mutated human IgGi constant region.

[0204] In some embodiments, the CD-20 targeting moiety provided herein comprises one light chain. In some embodiments, the CD-20 targeting moiety comprises two light chains. In some embodiments, the CD-20 targeting moiety comprises one light chain and one heavy chain. In some embodiments, the CD-20 targeting moiety comprises two light chains and one heavy chain. In some embodiments, the CD-20 targeting moiety comprises one heavy chain. In some embodiments, the CD-20 targeting moiety comprises heavy light chains. In some embodiments, the CD-20 targeting moiety comprises one light chain and two heavy chains. In some embodiments, the CD-20 targeting moiety comprises two light chains and two heavy chains.

[0205] In some embodiments, the CD-20 targeting moiety comprises cysteine linked pairs of light and heavy chains. In some embodiments, the CD-20 targeting moiety comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 cysteine residues. In some embodiments, the CD-20 targeting moiety comprises about 32 cysteine residues. In some embodiments, the CD-20 targeting moiety comprises a constant domain, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0206] In some embodiments, the CD-20 targeting moiety comprises post-translational modifications. In some embodiments, the CD-20 targeting moiety comprises an N-linked glycan. In some embodiments, the N-linked glycan is present on a residue of a heavy chain constant region of the CD-20 targeting moiety.

[0207] In some embodiments, the CD-20 targeting moiety comprises a modification that enhances multimerization to another targeting moiety, delivery, and stability of the CD-20 target moiety. Non-limiting examples of such modifications include: half-life extending agents, fusing amphipathic helices or leucine zippers to the CD-20 targeting moiety; pegylation; introducing a positively charged amino acids (for example, a Glu345Arg mutation in the IgGl Fc can create multimeric IgGl that binds more strongly to a given target); adding an IgM tailpiece to create IgG hexamers; covalent modifications, e.g., isomerization, deamidation, and oxidation, glycation, orAttorney Docket No. 199830-739601 fragmentation, and conjugating multimeric cell-penetrating peptides. In some embodiments, the covalent modifications are in the CD-20 CDR regions. In some embodiments, at least one, e.g., 1, 2, 3, 4, 5, 6, CDR regions comprise at least one type of covalent modification, e.g., isomerization, deamidation, and oxidation, or combinations thereof. In some embodiments, the CD-20 targeting moiety comprises at least one, at least two, at least three, at least four, at least five, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.

[0208] In some embodiments, the CD-20 targeting moiety comprises a disulfide bridge that connect two cysteine residues of the CD-20 antibody. In some embodiments, the disulfide bridge is formed in a single-chain of the CD-20 variable fragment. In some embodiments, the disulfide bonds are formed by the oxidation of 2 thiol groups within the Cystine residues of the CD-20 variable fragment. In some embodiments, the disulfide bridge stabilizes the tertiary structures of the CD-20 antibody.

[0209] In some embodiments, the CD-20 targeting moiety comprises a knob and hole modification or amino acid substitution. In some embodiments, the knob and hole modification is in the constant region of the heavy chain or the constant region of the light chain. In some embodiments, the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. In some embodiments, the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). In some embodiments, the CD-20 targeting moiety comprises a knob in the heavy chain constant region. In some embodiments, the CD-20 targeting moiety comprises a Y to a W amino acid substitution. In some embodiments, the CD-20 targeting moiety comprises a hole mutation in the heavy chain constant region. In some embodiments, the CD-20 targeting moiety comprises a T to S amino acid substitution; an L to A amino acid substitution; a Y to V amino acid substation, or any combination thereof relative to the reference sequence of the CD-20 targeting moiety. In some embodiments, the knob modification and hole modification facilitate heterodimerization of an antibody fragment to another antibody fragment (e.g., an Fc region or a CH2 / CH3 region of an Fc). The Fc regions can be identical or different from each other.

[0210] In some embodiments, the CD-20 targeting moiety comprises an IgA fragment for multimerization of the CD-20 targeting moiety to another targeting moiety, antibody, or polypeptide.

[0211] In some embodiments, the CD-20 targeting moiety comprises a half-life extension agent. In some embodiments, the half-life extension agent is an albumin or a biotin.Attorney Docket No. 199830-739601(5) BAFF targeting moieties

[0212] Provided herein are B-cell activating factor (BAFF) targeting moieties and compositions thereof. Provided herein are B-cell activating factor receptor (BAFFR) targeting moieties and compositions thereof. BAFF is a protein encoded by the TNFSF13B gene (NCBI Gene ID: 10673). BAFF can be expressed as a membrane-bound type II transmembrane protein on various cell types including monocytes, dendritic cells, and bone marrow stromal cells; or BAFF can be a cytokine the is secreted in soluble form. BAFF belongs to the tumor necrosis factor (TNF) ligand family and is a ligand for receptors TNFRSF13B / TACI, TNFRSF17 / BCMA, and TNFRSF13C / BAFFR. BAFF binds to the BAFF receptor (BAFFR) and the Tumor Necrosis Factor Receptor-Like Molecule B Cell Maturation Antigen (BCMA). BAFF can act as a potent B cell activator and can modulate the proliferation and differentiation of B cells.

[0213] In some embodiments, the BAFF targeting moieties inhibit soluble membrane bound BAFF. In some embodiments, the BAFF targeting moieties inhibit BAFF binding to the BAFFR. In some embodiments, the BAFF targeting moieties inhibit BAFF binding to BCMA. In some embodiments, the BAFFR targeting moieties block BAFF from binding to the BAFFR.

[0214] In some embodiments, a BAFF targeting moiety provided herein binds to a BAFF molecule, epitope, or antigen on a cell. In some embodiments, the BAFF molecule is on the surface of a cell. In some embodiments, the cell is a leukocyte, a lymphocyte, a dendritic cell, a monocyte, a stromal cell, a B cell, a tumor cell, a stem cell, or an in vv / ra-differentiated cell. In some embodiments, the BAFF molecule comprises a sequence that is at least 90% identical to: NCBI Reference Sequence: NP 006564.1 tumor necrosis factor ligand superfamily member 13B isoform 1 [Homo sapiens MDDSTEREQSRLTSCLKKREEMKLKECVSILPRKESPSVRSSKDGKLLAATLLLALLSCC LTVVSFYQVAALQGDLASLRAELQGHHAEKLPAGAGAPKAGLEEAPAVTAGLKIFEPP APGEGNSSQNSRNKRAVQGPEETVTQDCLQLIADSETPTIQKGSYTFVPWLLSFKRGSAL EEKENKILVKETGYFFIYGQVLYTDKTYAMGHLIQRKKVHVFGDELSLVTLFRCIQNMP ETLPNNSCYSAGIAKLEEGDELQLAIPRENAQISLDGDVTFFGALKLL (SEQ ID NO: 201).

[0215] Provided herein are BAFF targeting moieties that comprise a fusion protein. In some embodiments, the BAFF targeting moieties are a TACLFC fusion protein or an Fc fusion protein. In some embodiments, the TACLFC fusion protein comprises (i) TACI extracellular region or fragments thereof that bind Blys and / or APRIL; and (ii) human immunoglobulin constant region. In some embodiments, the BAFF targeting moieties are a FC fusion protein or an Fc fusion protein. In some embodiments, the BAFF targeting moiety comprises a TACLFC fusion protein comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical,Attorney Docket No. 199830-739601 at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:SRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLS CRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELDKTHTCPPCPAP EAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 202)

[0216] In some embodiments, the BAFF targeting moiety comprises a TACI-FC fusion protein comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:AMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCIS CASICGQHPKQCAYFCENKLRSEPKSSDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 203).

[0217] In some embodiments, the BAFF targeting moiety comprises a FC fusion protein comprising a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:SLSCRKEQGEYYDHLLRDCISCASICGQHPKQCADFCENKLRSGSGGGGSEPKSSDKTHT CPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 204).

[0218] Provided herein are BAFF targeting moieties that comprise an antibody or an antibody fragment. In some embodiments, the BAFF targeting moiety comprises an antibody fragment that is selected from the group consisting of: a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. In some embodiments, the BAFF targeting moiety comprises a BAFF targeting antibody. In some embodiments, the BAFF targeting antibody comprises blisibimod, belimumab (BENLYSTA®), ianalumab, telitacicept (Tai'ai), atacicept,Attorney Docket No. 199830-739601AUR200, VT-109, APLN-303 (Povetacicept) or an antigen binding fragment thereof; derivatives, variants, or combinations thereof.

[0219] Provided herein are BAFF targeting moieties that comprise a fusion protein. In some embodiments, the BAFF targeting moieties are a TACI-FC fusion protein or an Fc fusion protein. In some embodiments, the TACI-FC fusion protein comprises (i) TACI extracellular region or fragments thereof that bind Blys and / or APRIL; and (ii) human immunoglobulin constant region. In some embodiments, the BAFF targeting moieties are a Fc fusion protein or an Fc fusion protein.

[0220] In some embodiments, the BAFF targeting moiety comprises an amino acid sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to at least one amino acid sequence listed in Table 17.Table 17. BAFF-targeting moiety sequences.Attorney Docket No. 199830-739601Attorney Docket No. 199830-739601BAFF Targeting Heavy Chain Compositions

[0221] Provided herein are compositions comprising a BAFF targeting moiety, wherein the BAFF targeting moiety comprises a heavy chain. In some embodiments, the heavy chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the heavy chain comprises a heavy chain variable region. In some embodiments, the heavy chain comprises a heavy chain constant region. In some embodiments, the heavy chain further comprises a signal sequence.Attorney Docket No. 199830-739601

[0222] In some embodiments, the BAFF targeting moiety comprises a heavy chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the BAFF targeting moiety comprises a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length. In some embodiments, the BAFF targeting moiety comprises a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 460 amino acids in length. In some embodiments, the BAFF targeting moiety comprises a heavy chain having an amino acid sequence that is between about 100 amino acids in length and 500 amino acids in length.

[0223] In some embodiments, the BAFF targeting moiety comprises a heavy chain comprising a CDR1 region. Non-limiting examples of heavy chain CDR1 sequences are provided in Table 18Table 18. BAFF Targeting Moiety Heavy Chain CDR1 Sequences.

[0224] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 225 to SEQ ID NO: 228. someAttorney Docket No. 199830-739601 embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that is 100% identical to any one SEQ ID NO: 225 to SEQ ID NO: 228.

[0225] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 225 to SEQ ID NO: 228. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 225 to SEQ ID NO: 228.

[0226] In some embodiments, the BAFF targeting moiety comprises a heavy chain comprising a CDR2 region. Non-limiting examples of heavy chain CDR2 sequences are provided in Table 19.Table 19. BAFF Targeting Moiety Heavy Chain CDR2 Sequences.

[0227] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 60% identical to any one of SEQ ID NO: 229 to SEQ ID NO: 232. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 75% identical to any one of SEQ ID NO: 229 to SEQ ID NO: 232. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 87% identical to any one of SEQ ID NO: 229 to SEQ ID NO: 232. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 229 to SEQ ID NO: 232.

[0228] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 229 to SEQ ID NO: 232. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises two amino acid substitutions as comparedAttorney Docket No. 199830-739601 to any one of SEQ ID NO: 229 to SEQ ID NO: 232. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 229 to SEQ ID NO: 232.

[0229] In some embodiments, the BAFF targeting moiety comprises a heavy chain comprising a CDR3 region. Non-limiting examples of heavy chain CDR3 sequences are provided in Table 20.Table 20. BAFF Targeting Moiety Heavy Chain CDR3 Sequences.

[0230] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 63% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 64% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 72% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 78% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 85% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 92% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236. InAttorney Docket No. 199830-739601 some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 233 to SEQ ID NO: 236.

[0231] In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236. In some embodiments, a BAFF targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises six amino acid substitutions as compared to any one of SEQ ID NO: 233 to SEQ ID NO: 236BAFF Targeting Light Chain Compositions

[0232] Provided herein are compositions comprising a BAFF targeting moiety, wherein the BAFF targeting moiety comprises a light chain. In some embodiments, the light chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the light chain comprises a light chain variable region. In some embodiments, the light chain comprises a light chain constant region. In some embodiments, the light chain further comprises a signal sequence.

[0233] In some embodiments, the BAFF targeting moiety comprises a light chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the BAFF targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 300 amino acids in length. In some embodiments, the BAFF targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.Attorney Docket No. 199830-739601

[0234] In some embodiments, the BAFF targeting moiety comprises a light chain comprising aCDR1 region. Non-limiting examples of light chain CDR1 sequences are provided in Table 21.Table 21. BAFF Targeting Moiety Light Chain CDR1 Sequences.

[0235] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that is 100% identical to any one SEQ ID NO: 237 to SEQ ID NO: 240.

[0236] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 237 to SEQ ID NO: 240 In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 237 to SEQ ID NO: 240. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR1 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 237 to SEQ ID NO: 240

[0237] In some embodiments, the BAFF targeting moiety comprises a light chain comprising a CDR2 region. Non-limiting examples of light chain CDR2 sequences are provided in Table 22.Attorney Docket No. 199830-739601Table 22. BAFF Targeting Moiety Light Chain CDR2 Sequences.

[0238] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 66% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 70% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 75% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 80% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 85% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 241 to SEQ ID NO: 244.

[0239] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 241 to SEQ ID NO: 244

[0240] In some embodiments, the BAFF targeting moiety comprises a light chain comprising a CDR3 region. Non-limiting examples of light chain CDR3 sequences are provided in Table 23.Table 23. BAFF Targeting Moiety Light Chain CDR3 Sequences.

[0241] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3Attorney Docket No. 199830-739601 sequence that is at least 66% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 77% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 88% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 245 to SEQ ID NO: 248.

[0242] In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 245 to SEQ ID NO: 248 In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 245 to SEQ ID NO: 248. In some embodiments, a BAFF targeting moiety provided herein comprises a light chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 245 to SEQ ID NO: 248BAFF tarsetins moiety structure and modifications

[0243] Provided herein are compositions comprising a BAFF targeting moiety that binds to BAFF. In some embodiments, the BAFF targeting moiety comprises an antibody or antigen binding fragment thereof that is an antagonistic anti-human BAFF monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof, comprises a constant region of a human antibody, for example, an IgG constant region. In some embodiments, the constant region is a region that is deficient in complement activation, for example, a human IgGi constant region or a mutated human IgGi constant region.Attorney Docket No. 199830-739601

[0244] In some embodiments, the BAFF targeting moiety provided herein comprises one light chain. In some embodiments, the BAFF targeting moiety comprises two light chains. In some embodiments, the BAFF targeting moiety comprises one light chain and one heavy chain. In some embodiments, the BAFF targeting moiety comprises two light chains and one heavy chain. In some embodiments, the BAFF targeting moiety comprises one heavy chain. In some embodiments, the BAFF targeting moiety comprises two heavy chains. In some embodiments, the BAFF targeting moiety comprises one light chain and two heavy chains. In some embodiments, the BAFF targeting moiety comprises two light chains and two heavy chains.

[0245] In some embodiments, the BAFF targeting moiety comprises cysteine linked pairs of light and heavy chains. In some embodiments, the BAFF targeting moiety comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 cysteine residues. In some embodiments, the BAFF targeting moiety comprises about 32 cysteine residues. In some embodiments, the BAFF targeting moiety comprises a constant domain, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0246] In some embodiments, the BAFF targeting moiety comprises post-translational modifications. In some embodiments, the BAFF targeting moiety comprises an N-linked glycan. In some embodiments, the N-linked glycan is present on a residue of a heavy chain constant region of the BAFF targeting moiety.

[0247] In some embodiments, the BAFF targeting moiety comprises a modification that enhances multimerization to another targeting moiety, delivery, and stability of the BAFF target moiety. Non-limiting examples of such modifications include: half-life extending agents, fusing amphipathic helices or leucine zippers to the BAFF targeting moiety; pegylation; introducing a positively charged amino acids (for example, a Glu345Arg mutation in the IgGl Fc can create multimeric IgGl that binds more strongly to a given target); adding an IgM tailpiece to create IgG hexamers; covalent modifications, e.g., isomerization, deamidation, and oxidation, glycation, or fragmentation, and conjugating multimeric cell-penetrating peptides. In some embodiments, the covalent modifications are in the BAFF CDR regions. In some embodiments, at least one, e.g., 1, 2, 3, 4, 5, 6, CDR regions comprise at least one type of covalent modification, e.g., isomerization, deamidation, and oxidation, or combinations thereof. In some embodiments, the BAFF targeting moiety comprises at least one, at least two, at least three, at least four, at least five, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.Attorney Docket No. 199830-739601

[0248] In some embodiments, the BAFF targeting moiety comprises a disulfide bridge that connect two cysteine residues of the BAFF antibody. In some embodiments, the disulfide bridge is formed in a single-chain of the CD-40 variable fragment. In some embodiments, the disulfide bonds are formed by the oxidation of 2 thiol groups within the Cystine residues of the BAFF variable fragment. In some embodiments, the disulfide bridge stabilizes the tertiary structures of the BAFF antibody.

[0249] In some embodiments, the BAFF targeting moiety comprises a knob and hole modification or amino acid substitution. In some embodiments, the knob and hole modification is in the constant region of the heavy chain or the constant region of the light chain. In some embodiments, the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. In some embodiments, the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). In some embodiments, the BAFF targeting moiety comprises a knob in the heavy chain constant region. In some embodiments, the BAFF targeting moiety comprises a Y to a W amino acid substitution. In some embodiments, the BAFF targeting moiety comprises a hole mutation in the heavy chain constant region. In some embodiments, the BAFF targeting moiety comprises a T to S amino acid substitution; an L to A amino acid substitution; a Y to V amino acid substation, or any combination thereof relative to the reference sequence of the BAFF targeting moiety. In some embodiments, the knob modification and hole modification facilitate heterodimerization of an antibody fragment to another antibody fragment (e.g., an Fc region or a CH2 / CH3 region of an Fc). The Fc regions can be identical or different from each other.

[0250] In some embodiments, the BAFF targeting moiety comprises an IgA fragment for multimerization of the BAFF targeting moiety to another targeting moiety, antibody, or polypeptide.In some embodiments, the BAFF targeting moiety comprises a half-life extension agent. In some embodiments, the half-life extension agent is an albumin or a biotin.(4) APRIL Targeting Moieties.

[0251] Provided herein are APRIL, a proliferation inducing ligand, targeting moieties and compositions thereof. In some embodiments, an APRIL targeting moiety binds to an APRIL molecule, epitope, or antigen on a cell. In some embodiments, the APRIL molecule is on the surface of a cell. In some embodiments, the cell is a B cell, a T cell, or a myeloid cell. In some embodiments, the APRIL molecule (also referred to as TNFSF13 or tumor necrosis factor ligandAttorney Docket No. 199830-739601 superfamily 13, TALL-2, or TRDL-1) comprises a sequence that is at least 90% identical to: GenBank Reference No.: AAL90442.1 APRIL [Homo sapiens] MPASSPFLLAPKGPPGNMGGPVREPALSVALWLSWGAALGAVACAMALLTQQTELQS LRREVSRLQGTGGPSQNGEGYPWQSLPEQSSDALEAWENGERSRKRRAVLTQKQKKQ HSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQVLF QDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVIIPR ARAKLNLSPHGTFLGFVKL (SEQ ID NO: 249).

[0252] Provided herein are APRIL targeting moieties that comprise a fusion protein. In some embodiments, the APRIL targeting moieties are a TACLFC fusion protein or an Fc fusion protein. In some embodiments, the TACLFC fusion protein comprises (i) TACI extracellular region or fragments thereof that bind Blys and / or APRIL; and (ii) human immunoglobulin constant region.

[0253] Provided herein are APRIL targeting moieties that comprises an antibody or an antibody fragment. In some embodiments, the APRIL targeting moiety comprises an antibody fragment that is selected from the group consisting of: a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. In some embodiments, the APRIL targeting moiety comprises a Fab region. In some embodiments, the APRIL targeting moiety comprises an ScFv region. In some embodiments, the APRIL targeting moiety comprises a APRIL binding Fc region. In some embodiments, the APRIL targeting moiety comprises an scFv-Fc region. In some embodiments, the APRIL targeting antibody comprises CLYM116 or an antigen binding fragment thereof; Zigakibart (BION-1301) or an antigen binding fragment thereof; Sibeprenlimab or an antigen binding fragment thereof; Telitacicept (Tai'ai) or an antigen binding fragment thereof; Atacicept or an antigen binding fragment thereof; AUR200 or an antigen binding fragment thereof; VT-109 or an antigen binding fragment thereof; APLN-303 (Povetacicept) or an antigen binding fragment thereof; derivatives, variants, or combinations thereof.

[0254] In some embodiments, the BAFF targeting moiety comprises an amino acid sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to at least one amino acid sequence listed in Table 24.Attorney Docket No. 199830-739601Table 24. APRIL-targeting moiety sequences.Attorney Docket No. 199830-739601APRIL Targeting Heavy Chain Compositions

[0255] Provided herein are compositions comprising an APRIL targeting moiety, wherein the APRIL targeting moiety comprises a heavy chain. In some embodiments, the heavy chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the heavy chain comprises a heavy chain variable region. In some embodiments, the heavy chain comprises a heavy chain constant region. In some embodiments, the heavy chain further comprises a signal sequence.

[0256] In some embodiments, the APRIL targeting moiety comprises a heavy chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the APRIL targeting moiety comprises aAttorney Docket No. 199830-739601 heavy chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0257] In some embodiments, the APRIL targeting moiety comprises a heavy chain comprising a CDR1 region. Non-limiting examples of heavy chain CDR1 sequences are provided in Table 25.Table 25. APRIL Targeting Moiety Heavy Chain CDR1 Sequences.

[0258] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262 some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that is 100% identical to any one of SEQ ID NO: 261 to SEQ ID NO: 262.

[0259] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 261 to SEQ ID NO: 262. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR1 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 261 to SEQ ID NO: 262

[0260] In some embodiments, the APRIL targeting moiety comprises a heavy chain comprising a CDR2 region. Non-limiting examples of heavy chain CDR2 sequences are provided in Table 26Attorney Docket No. 199830-739601Table 26. APRIL Targeting Moiety Heavy Chain CDR2 Sequences.

[0261] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 62% identical to any one of SEQ ID NO: 263 to SEQ ID NO: 264. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 75% identical to any one of SEQ ID NO: 263 to SEQ ID NO: 264. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that is at least 87% identical to any one of SEQ ID NO: 263 to SEQ ID NO: 264. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 263 to SEQ ID NO: 264.

[0262] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 263 to SEQ ID NO: 264. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 263 to SEQ ID NO: 264. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR2 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 263 to SEQ ID NO: 264

[0263] In some embodiments, the APRIL targeting moiety comprises a heavy chain comprising a CDR3 region. Non-limiting examples of heavy chain CDR3 sequences are provided in Table 27.Table 27. APRIL Targeting Moiety Heavy Chain CDR3 Sequences.

[0264] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 63% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 64% identical to any one of SEQ ID NO: 265 to SEQ IDAttorney Docket No. 199830-739601NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 72% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 78% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 85% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is at least 92% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 265 to SEQ ID NO: 266.

[0265] In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266 In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266. In some embodiments, an APRIL targeting moiety provided herein comprises a heavy chain CDR3 sequence that comprises six amino acid substitutions as compared to any one of SEQ ID NO: 265 to SEQ ID NO: 266APRIL Targeting Light Chain Compositions

[0266] Provided herein are compositions comprising an APRIL targeting moiety, wherein the APRIL targeting moiety comprises a light chain. In some embodiments, the light chain comprisesAttorney Docket No. 199830-7396013 complementarity determining regions (CDRs). In some embodiments, the light chain comprises a light chain variable region. In some embodiments, the light chain comprises a light chain constant region. In some embodiments, the light chain further comprises a signal sequence.

[0267] In some embodiments, the APRIL targeting moiety comprises a light chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the APRIL targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 300 amino acids in length. In some embodiments, the APRIL targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.

[0268] In some embodiments, the APRIL targeting moiety comprises a light chain comprising a CDR1 region. Non-limiting examples of light chain CDR1 sequences are provided in Table 28.Table 28. APRIL Targeting Moiety Light Chain CDR1 Sequences.

[0269] In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 60% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 66% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 70% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 80% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is at least 90% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that is 100% identical to any one of SEQ ID NO: 267 to SEQ ID NO: 268.Attorney Docket No. 199830-739601

[0270] In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 267 to SEQ ID NO: 268. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR1 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 267 to SEQ ID NO: 268

[0271] In some embodiments, the APRIL targeting moiety comprises a light chain comprising a CDR2 region. Non-limiting examples of light chain CDR2 sequences are provided in Table 29.Table 29. APRIL Targeting Moiety Light Chain CDR2 Sequences.

[0272] In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR2 sequence that is at least 66% identical to any one of SEQ ID NO: 269 to SEQ ID NO: 270. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR2 sequence that is 100% identical to any one of SEQ ID NO: 269 to SEQ ID NO: 270. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR2 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 269 to SEQ ID NO: 270

[0273] In some embodiments, the APRIL targeting moiety comprises a light chain comprising a CDR3 region. Non-limiting examples of light chain CDR3 sequences are provided in Table 30.Table 30. APRIL Targeting Moiety Light Chain CDR3 Sequences.

[0274] In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 60% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 66% identical to any one of SEQ ID NO: 271 to SEQ IDAttorney Docket No. 199830-739601NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 70% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 77% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 80% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 88% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is at least 90% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that is 100% identical to any one of SEQ ID NO: 271 to SEQ ID NO: 272.

[0275] In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises a single amino acid substitution as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises two amino acid substitutions as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises three amino acid substitutions as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises four amino acid substitutions as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises five amino acid substitutions as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272. In some embodiments, an APRIL targeting moiety provided herein comprises a light chain CDR3 sequence that comprises six amino acid substitutions as compared to any one of SEQ ID NO: 271 to SEQ ID NO: 272APRIL targeting moiety structure and modifications

[0276] Provided herein are compositions comprising an APRIL targeting moiety that binds to APRIL. In some embodiments, the APRIL targeting moiety comprises an antibody or antigen binding fragment thereof that is an antagonistic anti-human APRIL monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof, comprises a constant region of a human antibody, for example, an IgG constant region. In some embodiments, the constant regionAttorney Docket No. 199830-739601 is a region that is deficient in complement activation, for example, a human IgG4 constant region or a mutated human IgGi constant region.

[0277] In some embodiments, the APRIL targeting moiety provided herein comprises one light chain. In some embodiments, the APRIL targeting moiety comprises two light chains. In some embodiments, the APRIL targeting moiety comprises one light chain and one heavy chain. In some embodiments, the APRIL targeting moiety comprises two light chains and one heavy chain. In some embodiments, the APRIL targeting moiety comprises one heavy chain. In some embodiments, the APRIL targeting moiety comprises heavy light chains. In some embodiments, the APRIL targeting moiety comprises one light chain and two heavy chains. In some embodiments, the APRIL targeting moiety comprises two light chains and two heavy chains.

[0278] In some embodiments, the APRIL targeting moiety comprises cysteine linked pairs of light and heavy chains. In some embodiments, the APRIL targeting moiety comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 cysteine residues. In some embodiments, the APRIL targeting moiety comprises about 32 cysteine residues. In some embodiments, the APRIL targeting moiety comprises a constant domain, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0279] In some embodiments, the APRIL targeting moiety comprises post-translational modifications. In some embodiments, the APRIL targeting moiety comprises an N-linked glycan. In some embodiments, the N-linked glycan is present on a residue of a heavy chain constant region of the APRIL targeting moiety.

[0280] In some embodiments, the APRIL targeting moiety comprises a modification that enhances multimerization to another targeting moiety, delivery, and stability of the APRIL target moiety. Non-limiting examples of such modifications include: half-life extending agents, fusing amphipathic helices or leucine zippers to the APRIL targeting moiety; pegylation; introducing a positively charged amino acids (for example, a Glu345Arg mutation in the IgGl Fc can create multimeric IgGl that binds more strongly to a given target); adding an IgM tailpiece to create IgG hexamers; covalent modifications, e.g., isomerization, deamidation, and oxidation, glycation, or fragmentation, and conjugating multimeric cell-penetrating peptides. In some embodiments, the covalent modifications are in the APRIL CDR regions. In some embodiments, at least one, e.g., 1, 2, 3, 4, 5, 6, CDR regions comprise at least one type of covalent modification, e.g., isomerization, deamidation, and oxidation, or combinations thereof. In some embodiments, the APRIL targeting moiety comprises at least one, at least two, at least three, at least four, at least five, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at leastAttorney Docket No. 199830-739601 fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.

[0281] In some embodiments, the APRIL targeting moiety comprises a disulfide bridge that connect two cysteine residues of the APRIL antibody. In some embodiments, the disulfide bridge is formed in a single-chain of the APRIL variable fragment. In some embodiments, the disulfide bonds are formed by the oxidation of 2 thiol groups within the Cystine residues of the APRIL variable fragment. In some embodiments, the disulfide bridge stabilizes the tertiary structures of the APRIL antibody.

[0282] In some embodiments, the APRIL targeting moiety comprises a knob and hole modification or amino acid substitution. In some embodiments, the knob and hole modification is in the constant region of the heavy chain or the constant region of the light chain. In some embodiments, the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. In some embodiments, the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). In some embodiments, the APRIL targeting moiety comprises a knob in the heavy chain constant region. In some embodiments, the APRIL targeting moiety comprises a Y to a W amino acid substitution. In some embodiments, the APRIL targeting moiety comprises a hole mutation in the heavy chain constant region. In some embodiments, the APRIL targeting moiety comprises a T to S amino acid substitution; an L to A amino acid substitution; a Y to V amino acid substation, or any combination thereof relative to the reference sequence of the APRIL targeting moiety. In some embodiments, the knob modification and hole modification facilitate heterodimerization of an antibody fragment to another antibody fragment (e.g., an Fc region or a CH2 / CH3 region of an Fc). The Fc regions can be identical or different from each other.

[0283]

[0284] In some embodiments, the APRIL targeting moiety comprises an IgA fragment for multimerization of the APRIL targeting moiety to another targeting moiety, antibody, or polypeptide.In some embodiments, the APRIL targeting moiety comprises a half-life extension agent. In some embodiments, the half-life extension agent is an albumin or a biotin.(5) IFNR Targeting Moieties.

[0285] Provided herein are compositions comprising an interferon receptor (IFNR) targeting moiety, wherein the IFNR targeting moiety comprises a light chain. In some embodiments, the light chain comprises a light chain variable region. In some embodiments, the heavy chainAttorney Docket No. 199830-739601 comprises a light chain constant region. In some embodiments, the light chain further comprises a signal sequence. In some embodiments, the light chain comprises 3 complementarity determining regions (CDRs). In some embodiments, the IFNR targeting moiety comprises a light chain variable region comprising a CDR1 region. In some embodiments, the IFNR targeting moiety comprises a light chain comprising a CDR2 region. In some embodiments, the IFNR targeting moiety comprises a light chain comprising a CDR3 region. In some embodiments, the IFNR targeting moiety comprises a light chain constant region comprising a CHI region.

[0286] In some embodiments, the IFNR targeting moiety comprises a light chain having an amino acid sequence that is at least 100 amino acids in length at least 150 amino acids in length, at least 200 amino acids in length, at least 250 amino acids in length, at least 300 amino acids in length, at least 350 amino acids in length, at least 400 amino acids in length, at least 410 amino acids in length, at least 420 amino acids in length, at least 430 amino acids in length, at least 440 amino acids in length, at least 450 amino acids in length, at least 500 amino acids in length, or at least 600 amino acids in length. In some embodiments, the IFNR targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 300 amino acids in length. In some embodiments, the IFNR targeting moiety comprises a light chain having an amino acid sequence that is between about 100 amino acids in length and 450 amino acids in length.IFNR tarsetins moiety structure and modifications

[0287] Provided herein are compositions comprising a IFNR targeting moiety that binds to IFNR. In some embodiments, the IFNR-targeting moiety target a type 1 interferon receptor. In some embodiments, the IFNR-targeting moiety target a type 2 interferon receptor. In some embodiments, the IFNR targeting moiety comprises an antibody or antigen binding fragment thereof that is an antagonistic anti-human IFNR monoclonal antibody. In some embodiments, the antibody or antigen binding fragment thereof, comprises a constant region of a human antibody, for example, an IgG constant region. In some embodiments, the constant region is a region that is deficient in complement activation, for example, a human IgG4 constant region or a mutated human IgGl constant region.

[0288] In some embodiments, the IFNR targeting moiety provided herein comprises one light chain. In some embodiments, the IFNR targeting moiety comprises two light chains. In some embodiments, the IFNR targeting moiety comprises one light chain and one heavy chain. In some embodiments, the IFNR targeting moiety comprises two light chains and one heavy chain. In some embodiments, the IFNR targeting moiety comprises one heavy chain. In some embodiments, the IFNR targeting moiety comprises heavy light chains. In some embodiments, the IFNR targetingAttorney Docket No. 199830-739601 moiety comprises one light chain and two heavy chains. In some embodiments, the IFNR targeting moiety comprises two light chains and two heavy chains.

[0289] In some embodiments, the IFNR targeting moiety comprises cysteine linked pairs of light and heavy chains. In some embodiments, the IFNR targeting moiety comprises at least about 10, at least about 15, at least about 20, at least about 25, or at least about 30 cysteine residues. In some embodiments, the IFNR targeting moiety comprises about 32 cysteine residues. In some embodiments, the IFNR targeting moiety comprises a constant domain, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0290] In some embodiments, the IFNR targeting moiety comprises post-translational modifications. In some embodiments, the IFNR targeting moiety comprises an N-linked glycan. In some embodiments, the N-linked glycan is present on a residue of a heavy chain constant region of the IFNR targeting moiety.

[0291] In some embodiments, the IFNR targeting moiety comprises a modification that enhances multimerization to another targeting moiety, delivery, and stability of the IFNR target moiety. Non-limiting examples of such modifications include: half-life extending agents, fusing amphipathic helices or leucine zippers to the IFNR targeting moiety; pegylation; introducing a positively charged amino acids (for example, a Glu345Arg mutation in the IgGl Fc can create multimeric IgGl that binds more strongly to a given target); adding an IgM tailpiece to create IgG hexamers; covalent modifications, e.g., isomerization, deamidation, and oxidation, glycation, or fragmentation, and conjugating multimeric cell-penetrating peptides. In some embodiments, the covalent modifications are in the IFNR CDR regions. In some embodiments, the IFNR targeting moiety comprises at least one, at least two, at least three, at least four, at least five, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at nineteen, at least twenty, amino acids that are covalently modified.

[0292] In some embodiments, the IFNR targeting moiety comprises a disulfide bridge that connect two cysteine residues of the IFNR antibody. In some embodiments, the disulfide bridge is formed in a single-chain of the IFNR variable fragment. In some embodiments, the disulfide bonds are formed by the oxidation of 2 thiol groups within the Cystine residues of the IFNR variable fragment. In some embodiments, the disulfide bridge stabilizes the tertiary structures of the IFNR antibody.

[0293] In some embodiments, the IFNR targeting moiety comprises a knob and hole modification or amino acid substitution. In some embodiments, the knob and hole modification isAttorney Docket No. 199830-739601 in the constant region of the heavy chain or the constant region of the light chain. In some embodiments, the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. In some embodiments, the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). In some embodiments, the IFNR targeting moiety comprises a knob in the heavy chain constant region. In some embodiments, the IFNR targeting moiety comprises a Y to a W amino acid substitution. In some embodiments, the IFNR targeting moiety comprises a hole mutation in the heavy chain constant region. In some embodiments, the IFNR targeting moiety comprises a T to S amino acid substitution; an L to A amino acid substitution; a Y to V amino acid substation, or any combination thereof relative to the reference sequence of the IFNR targeting moiety. In some embodiments, the knob modification and hole modification facilitate heterodimerization of an antibody fragment to another antibody fragment (e.g., an Fc region or a CH2 / CH3 region of an Fc). The Fc regions can be identical or different from each other.

[0294] In some embodiments, the IFNR targeting moiety comprises an IgA fragment for multimerization of the IFNR targeting moiety to another targeting moiety, antibody, or polypeptide.

[0295] In some embodiments, the IFNR targeting moiety comprises a half-life extension agent. In some embodiments, the half-life extension agent is an albumin or a biotin.(6) Combination Compositions.

[0296] Provided herein are compositions comprising a polypeptide construct, antibody, or antibody fragment that targets CD-40 and / or CD-20, wherein the composition is formulated for subcutaneous administration to a subject. In some embodiments, the bispecific polypeptide construct comprises a CD-40 targeting moiety provided herein and a CD-20 targeting moiety provided herein.

[0297] Provided herein are compositions comprising a multimeric engineered polypeptide that targets CD-40 and CD-20. In some embodiments, the engineered polypeptide comprises a CD-40 targeting moiety provided herein and a CD-20 targeting moiety provided herein. In some embodiments, the engineered polypeptide comprises a first CD-40 targeting moiety; a second CD- 40 targeting moiety; and a CD-20 targeting moiety. In some embodiments, the engineered polypeptide comprises a BAFF-targeting moiety. In some embodiments, the engineered polypeptide comprises an APRIL-targeting moiety. In some embodiments, the engineered polypeptide comprises an IFNR targeting moiety.Attorney Docket No. 199830-739601

[0298] The compositions provided herein can be in various configurations. For example, the composition can comprise a Fab and an Scfv. In some embodiments, the polypeptide constructs provided herein comprise an antigen-binding moiety that binds to CD-20, CD-40, and / or an additional target protein. In some embodiments, the antigen-binding moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a fragment antigen-binding (e.g., Fab, Fab', Fab'-SH, F(ab')2) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment (e.g., scFv), single-chain antibody molecules, a minibody, an antibody, diabodies, or linear antibodies. In some embodiments, the antigen-binding moiety comprises an antibody, an antibody fragment, or antibody mimetic protein. In some embodiments, the antibody is a monoclonal antibody, a bispecific polypeptide construct, a polyclonal antibody, or an antibody fragment. In some embodiments, the antibody is an immunoglobulin. In some embodiments, the immunoglobulin comprises a heavy chain, including, but not limited to: a (IgA), 6 (IgD), 8 (IgE), y (IgG), or p (IgM), some of which may be further divided into subtypes, e.g., yl (IgGl), y2 (IgG2), y3 (IgG3), y4 (IgG4), al (IgAl) and a2 (IgA2). The light chain of an immunoglobulin may be assigned to one of two types, called kappa (K) and lambda (1), based on the amino acid sequence of its constant domain. In some embodiments, the immunoglobulin comprises two Fab molecules and an Fc domain, linked via an immunoglobulin hinge region.

[0299] In some embodiments, the antigen-binding moiety is a Fab or a portion thereof. In some embodiments, the antigen-binding moiety is on the N-terminus of a light chain of a Fab. In some embodiments, the antigen-binding moiety is on the N-terminus of a heavy chain of a Fab. In some embodiments, the antigen-binding moiety is on the C-terminus of a light chain of a Fab. In some embodiments, the antigen-binding moiety is on the C-terminus of a heavy chain of a Fab.

[0300] The compositions provided herein can further comprise a linker. In some embodiments, the antigen-binding moiety is directly linked to the first CD-40 targeting moiety, the second CD- 40 targeting moiety, and / or the CD-20 targeting moiety by a linker. In some embodiments, the first CD-40 targeting moiety and the CD-20 targeting moiety are linked through a linker sequence, a Fab region, Fc region, or an IgG region of an antibody. In some embodiments, the second CD-40 targeting moiety and the CD-20 targeting moiety are linked through a linker sequence, a Fab region, Fc region, or an IgG region of an antibody. In some embodiments, the first CD-40 targeting moiety and the second CD-40 targeting moiety are linked through a linker sequence, a Fab region, Fc region, or an IgG region of an antibody.

[0301] In some embodiments, the linker sequence is at least 5 amino acids, at least 10 amino acids, at least 15 amino acids, at least 20 amino acids, at least 25 amino acids, at least 30 amino acids, at least 35 amino acids, at least 40 amino acids, at least 45 amino acids, or at least 50 aminoAttorney Docket No. 199830-739601 acids. In some embodiments, the linker sequence is about 5 amino acids, about 10 amino acids, about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, about 45 amino acids, or about 50 amino acids. In some embodiments, the linker sequence is about 15 amino acids. In some embodiments, the linker is 15 amino acids. In some embodiments, the linker sequence is about 20 amino acids. In some embodiments, the linker sequence is 20 amino acids.

[0302] In some embodiments, the linker sequence is a non-immunogenic linker peptide. For example, Suitable, non-immunogenic linker peptides are, for example, (G4S)n, (SG4)n or G4(SG4)n peptide linkers, wherein "n" is generally a number between 1 and 10, typically between 2 and 4, in particular 2, / .< ., the peptides selected from the group consisting of GGGGS, GGGGSGGGGS, SGGGGSGGGG, GGGGSGGGGSGGGG (SEQ ID NO: 273), GSPGSSSSGS, (G4S), (G4S)2, (G4S)3, (G4S)4, GSGSGSGS, GSGSGNGS, GGSGSGSG, GGSGSG, GGSG, GGSGNGSG, GGNGSGSG, GGNGSG, GGGGS GGGGS GGGGS (SEQ ID NO: 274), and GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 275).

[0303] In some embodiments, the polypeptide constructs and bispecific antibodies provided herein comprise an antigen binding domain, a Fab region, an Fc region, an scFv, or an IgG region of an anti-TNF- alpha antibody, an anti- fibroblast activation protein (FAP) antibody, an antiinterleukin 6 receptor (IL6R) antibody, an anti-interleukin 6 (IL-6) antibody, an anti-interleukin 1 antibody, an anti-complement factor antibody, an anti- BLyS (B lymphocyte stimulator, also called BAFF) antibody, an anti-APRIL antibody, an anti-IL-17 antibody, an anti -IL-23 antibody, an anti- IL-5 antibody, an anti-IL-4 antibody, an anti-IL-13 antibody, an anti-IgE antibody, or an anti-a4p7 integrin antibody.

[0304] In some embodiments, the polypeptide constructs and bispecific antibodies provided herein comprise an antigen binding domain, Fab region, Fc region, scFv, or an IgG region of an antibody selected from the group consisting of: abagovomab, abciximab, abituzumab, abrilumab, actinium Ac-225 lintuzumab, actoxumab, adalimumab, adecatumumab, aducanumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, sevacizumab, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atinumab, atorolimumab, avelumab, bapineuzumab, basiliximab, bavituximab, bectumomab, begelomab, belimumab, benralizumab, bertilimumab, besilesomab, 177Lu-tetraxetan-tetulomab, bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, bivatuzumab mertansine, blinatumomab, blosozumab, bococizumab, brentuximab vedotin, BrevaRex, briakinumab, brodalumab, brolucizumab, brontictuzumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide, carlumab, catumaxomab, CBR96-doxorubicinAttorney Docket No. 199830-739601 immunoconjugate, cedelizumab, certolizumab pegol, cetuximab, citatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine, conatumumab, concizumab, cR6261, crenezumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab pegol, daratumumab, darleukin, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab, depatuxizumab mafodotin, derlotuximab biotin, detumomab, dinutuximab, diridavumab, dorlimomab aritox, drozitumab, duligotumab, dupilumab, durvalumab, dusigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emibetuzumab, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan, epratuzumab, erlizumab, ertumaxomab, etaracizumab, etrolizumab, evinacumab, evolocumab, exbivirumab, fanolesomab, faralimomab, farletuzumab, fasinumab, felvizumab, fezakinumab, FGFR2 Antibody -Drug Conjugate, Fibromun, ficlatuzumab, figitumumab, firivumab, flanvotumab, fletikumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulranumab, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab, gemtuzumab, gevokizumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab tiuxetan, icrucumab, idarucizumab, igovomab, imalumab, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, indusatumab vedotin, inebilizumab, infliximab, inolimomab, inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, isatuximab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, labetuzumab govitecan, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lenzilumab, lerdelimumab, leukotuximab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, lilotomab satetraxetan, lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, mapatumumab, margetuximab, maslimomab, matuzumab, mavrilimumab, mepolizumab, metelimumab, milatuzumab, milatuzumab-SN-38, minretumomab, mirvetuximab soravtansine, mitazalimab, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab pasudotox, MU1053, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, narnatumab, natalizumab, nebacumab, necitumumab, nemolizumab, nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab monatox, oregovomab, orticumab, otelixizumab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pankomab, PankoMab-GEX, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab,Attorney Docket No. 199830-739601 pinatuzumab vedotin, pintumomab, placulumab, polatuzumab vedotin, ponezumab, priliximab, pritoxaximab, pritumumab, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranibizumab, raxibacumab, refanezumab, regavirumab, reslizumab, rilotumumab, rinucumab, risankizumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, sacituzumab govitecan, samalizumab, sarilumab, satumomab pendetide, secukinumab, seribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, simtuzumab, siplizumab, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, tacatuzumab tetraxetan, tadocizumab, tafasitamab, talizumab, tanezumab, tanibirumab, taplitumomab paptox, tarextumab, tefibazumab, teleukin, telimomab aritox, tenatumomab, teneliximab, teplizumab, teprotumumab, tesidolumab, tetulomab, Thorium-227-Epratuzumab Conjugate, ticilimumab, tigatuzumab, tildrakizumab, tisotumab vedotin, tocilizumab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, trastuzumab deruxtecan, trastuzumab emtansine, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin, tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, utomilumab, ustekinumab, vadastuximab talirine, vandortuzumab vedotin, vantictumab, vanucizumab, vapaliximab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumumab, zanolimumab, zatuximab, ziralimumab, zolimomab aritox, any fragments thereof, or any biosimilars thereof.

[0305] In some embodiments, the polypeptide constructs and bispecific antibodies provided herein comprise a Fab region, Fc region, or an IgG region of an anti-CD40 antibody. In some embodiments, the anti-CD-40 antibody is PG102 or a functional variant thereof. In some embodiments, the anti-CD-40 antibody is a ch5D12 antibody or an antigen binding fragment thereof; a 2C10R4 antibody or an antigen binding fragment thereof; a BI 655064 antibody or an antigen binding fragment thereof; KPL-404 or an antigen binding fragment thereof; iscalimab or an antigen binding fragment thereof; bleselumab or an antigen binding fragment thereof; ravagalimab or an antigen binding fragment thereof; or mitazalimab or an antigen binding fragment thereof.

[0306] In some embodiments, the polypeptide constructs and bispecific antibodies provided herein comprise a Fab region, Fc region, or an IgG region of an anti-CD20 antibody. In some embodiments, the anti-CD-20 antibody is rituximab or a functional variant thereof, ocrelizumab or a functional variant thereof, ofatumumab or a functional variant thereof, obinutuzumab or a functional variant thereof, ibritumomab tiuxetan or a functional variant thereof, tositumomab or a functional variant thereof, ublituximab or a functional variant thereof, ocaratuzumab (or aAttorney Docket No. 199830-739601 functional variant thereof, TRU-015 or a functional variant thereof, veltuzumab (IMMU-106) or a functional variant thereof, or a combination of any of these.

[0307] Methods of generating a bispecific antibody can involve using CrossMab technology, which permits antibody light-chain association with their respective heavy chain in bispecific antibodies, together with methods enabling correct heavy-chain association using existing pairs of antibodies. Additional methods include knobs-into-holes technology (KiH), that enables the correct association of the different antibody light chains with their respective counterparts. This is achieved in different antibody formats and geometries by the exchange or crossover of antibody domains.

[0308] In some embodiments, a composition provided herein comprises a designed ankyrin repeat (DARPin) protein or an anticalin protein. In some embodiments, proteins provided herein comprise one or more DARPins. Designed ankyrin repeat proteins (DARPins) are antibody mimetics built from solenoid protein domains, which possess a modular architecture . The DARPin structure is generally derived by a consensus design approach, a stack of internal ankyrin repeats, each composed of short amino acid sequences, flanked by N- and C-terminal capping repeats (island C-Caps) that function to seal the hydrophobic core of the protein domain. Together, these structural units form an elongated ankyrin repeat domain. Amino acids present at defined positions at the surface of the internal repeats form a paratope, enabling the binding to target proteins with high specificity.

[0309] In some embodiments, proteins provided herein comprise one or more anticalins. Anticalin proteins are another type of antibody mimetic derived from human lipocalins. Anticalin proteins are capable of penetrating tissues and are stable at temperatures, e.g., up to 70 degrees Celsius. Anticalin proteins generally have a barrel structure formed by antiparallel P-strands pairwise connected by loops and an attached a-helix. Amino acids present at defined positions at the surface of the anticalin enable binding to target proteins.

[0310] In some embodiments, polypeptide constructs provided herein comprise one or more of a diabody, a tribody, or a tetrabody comprising a CD-40 targeting moiety and / or a CD-20 targeting moiety. The CD-40 targeting moieties provided herein can be combined with one or more additional targeting moieties provided herein, in any combination, to form bispecific, trispecific, tetraspecific, or multispecific constructs. Moreover, a polypeptide construct provided herein can comprise one or more CD-40 targeting moieties (e.g., two, three, four, etc.) that increase the engagement of CD-40 by the construct with a cell of interest in a subject. The constructs can comprise a light chain, heavy chain, or a combination of a heavy chain or light chain provided herein. Non-limiting examples of constructs that can be generated by the methods described herein are provided below.Attorney Docket No. 199830-739601Construct Type ExamplesBispecific • CD-40 targeting moiety and a CD-20-targeting moiety• Two CD-40 targeting moieties• CD-40 targeting moiety and a BAFF -targeting moiety• CD-40 targeting moiety and an APRIL-targeting moiety• CD-40 targeting moiety and an Interferon Receptor-targeting moietyTrispecific • Two CD-40 targeting moieties and a CD-20 targeting moiety• A CD-40 targeting moiety and two CD-20 targeting moieties• A CD-40 targeting moiety, a CD-20 targeting moiety, and a BAFF targeting moiety• A CD-40 targeting moiety, a CD-20 targeting moiety, and an APRIL targeting moiety• A CD-40 targeting moiety, a CD-20 targeting moiety, and an interferon receptor targeting moiety• A CD-40 targeting moiety, a BAFF targeting moiety, and an APRIL targeting moiety• A CD-20 targeting moiety, a BAFF targeting moiety, and an APRIL targeting moiety• A CD-20 targeting moiety, a BAFF targeting moiety, and an interferon receptor targeting moiety• A CD-20 targeting moiety, an APRIL targeting moiety, and an interferon receptor targeting moiety• A CD-40 targeting moiety, a BAFF targeting moiety, and an interferon receptor targeting moiety• A CD-40 targeting moiety, an APRIL targeting moiety, and an interferon receptor targeting moietyTetraspecific • Two CD-40 targeting moieties and two CD-20 targeting moieties• Two CD-40 targeting moieties, a CD-20 targeting moiety, and a BAFF targeting moiety• Two CD-40 targeting moieties, a CD-20 targeting moiety, and an APRIL targeting moietyAttorney Docket No. 199830-739601Construct Type Examples• Two CD-40 targeting moieties, a CD-20 targeting moiety, and an interferon receptor targeting moiety• One CD-40 targeting moieties, two CD-20 targeting moiety, and an interferon receptor targeting moiety• One CD-40 targeting moieties, two CD-20 targeting moiety, and a BAFF• One CD-40 targeting moieties, two CD-20 targeting moiety, and an APRIL• A CD-40 targeting moiety, a CD-20 targeting moiety, a BAFF targeting moiety, and an interferon receptor targeting moiety• A CD-40 targeting moiety, a CD-20 targeting moiety, a BAFF targeting moiety, and an APRIL targeting moiety• A CD-40 targeting moiety, a CD-20 targeting moiety, an interferon targeting moiety, and an APRIL targeting moiety

[0311] Provided herein are compositions, wherein the compositions comprise: a polypeptide construct comprising at least one sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 276 to SEQ ID NO: 327.

[0312] Provided herein are compositions, wherein the compositions comprise: a polypeptide construct comprising: a first antigen-binding moiety comprising: at least one sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 276 to SEQ ID NO: 327; and a second-antigen binding moiety comprising at least one sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 276 to SEQ ID NO: 327(7) Nucleic Acids and Vectors

[0313] The compositions provided herein can be made using recombinant DNA technology well known to a skilled person in the art. For example, one or more isolated polynucleotides encoding the compositions provided herein (e.g., a CD-40 targeting moiety, a CD-20 targeting moiety, aAttorney Docket No. 199830-739601 bispecific polypeptide construct, or an engineered polypeptide) can be ligated to other appropriate nucleotide sequences, including, for example, constant region coding sequences, and expression control sequences, to produce conventional gene expression constructs ( / .< ., expression vectors) encoding the desired polypeptide or antibody.

[0314] Nucleic acids encoding desired compositions provided herein can be incorporated (ligated) into expression vectors, which can be introduced into host cells through conventional transfection or transformation techniques. Exemplary host cells are / ■ / coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (EEK 293) cells, HeLa cells, baby hamster kidney (BEK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and myeloma cells that do not otherwise produce IgG protein. In some embodiments, the nucleic acids are expressed in a hybridoma cell, a Chinese hamster ovary cell, an NSO cell or a PER-C6TM cell. Transformed host cells can be grown under conditions that permit the host cells to express the genes that encode the desired polypeptide or antibody.

[0315] Specific expression and purification conditions will vary depending upon the expression system employed. For example, if a gene is to be expressed in E. coli, it is first cloned into an expression vector by positioning the engineered gene downstream from a suitable bacterial promoter, e.g., Trp or Tac, and a prokaryotic signal sequence. The expressed protein may be secreted. The expressed protein may accumulate in refractile or inclusion bodies, which can be harvested after disruption of the cells by French press or sonication. The refractile bodies then are solubilized, and the protein may be refolded and / or cleaved by methods known in the art.

[0316] If the engineered gene is to be expressed in eukaryotic host cells, e.g, CHO cells, it is first inserted into an expression vector containing a suitable eukaryotic promoter, a secretion signal, a poly A sequence, and a stop codon. Optionally, the vector or gene construct may contain enhancers and introns. In some embodiments, the vector comprises a nucleic acid encoding for one or more fusion proteins comprising the desired CD-40 and CD-20 targeting moieties, the expression vector optionally contains sequences encoding all or part of a constant region, enabling an entire, or a part of, a heavy or light chain to be expressed. The gene construct can be introduced into eukaryotic host cells using conventional techniques.

[0317] In some embodiments, an N-terminal signal sequence is included in the polypeptide construct. Exemplary N-terminal signal sequences include signal sequences from interleukin-2, CD-5, IgG kappa light chain, trypsinogen, serum albumin, and prolactin.

[0318] After transfection, single clones can be isolated for cell bank generation using methods known in the art, such as limited dilution, ELISA, FACS, microscopy, or Clonepix. Clones can be cultured under conditions suitable for bioreactor scale-up and maintained expression of the antibodies and polypeptides provided herein.Attorney Docket No. 199830-739601

[0319] The compositions provided herein can be isolated and purified using, for example, centrifugation, depth filtration, cell lysis, homogenization, freeze-thawing, affinity purification, gel filtration, ion exchange chromatography, hydrophobic interaction exchange chromatography, and mixed-mode chromatography.

[0320] Provided herein is a polynucleotide encoding one or more of the compositions provided herein (for example, the proteins, CD-40 targeting moieties, CD-20 targeting moieties, or bispecific antibodies provided herein). Further provided herein is a vector comprising: a polynucleotide encoding any composition provided herein. In some embodiments, the nucleic acid or polynucleotide encoding a composition provided herein is DNA. In some embodiments, the nucleic acid or polynucleotide encoding a composition provided herein is RNA. In some embodiments, the polynucleotide is chemically modified for stability.

[0321] In some embodiments, vectors provided herein are a viral vector. Exemplary viral vectors include, but are not limited to, lentiviral vectors, retroviral vectors, adeno-associated viral vectors (AAV), adenoviral vectors, herpes simplex viral vectors, alphaviral vectors, flaviviral vectors, rhabdoviral vectors, measles viral vectors, Newcastle disease viral vectors, poxviral vectors, and picomaviral vectors. In some embodiments, polynucleotides encoding a protein provided herein are contained in an AAV viral vector. In some embodiments, vectors provided herein are an oncolytic viral vector.(8) Pharmaceutical Compositions.

[0322] Provided herein are pharmaceutical compositions comprising a CD-40 targeting moiety, a polypeptide construct, a bispecific polypeptide construct, or a composition provided herein; and a pharmaceutically acceptable carrier, excipient, or diluent. The CD-40 targeting moieties, CD-20 targeting moieties, bispecific antibodies, and polypeptide constructs provided herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration. Routes for administration include, for example, intravenous, intra-arterial, subcutaneous, intramuscular, intraperitoneal, intravitreal, and other routes provided herein. Administration can also be achieved by nebulization. Administration forms are described elsewhere herein.

[0323] In some embodiments, compositions provided herein are combined with pharmaceutically acceptable salts, excipients, and / or carriers to form a pharmaceutical composition. Pharmaceutical salts, excipients, and carriers may be chosen based on the route of administration, the location of the target issue, and the time course of delivery of the drug. A pharmaceutically acceptable carrier or excipient may include solvents, dispersion media, coatings,Attorney Docket No. 199830-739601 antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., compatible with pharmaceutical administration.In some embodiments, the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas (aerosol). Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0324] In some embodiments, the solutions of the CD-40 targeting moieties, polypeptide constructs, or bispecific antibodies can for example be prepared in water or saline, and optionally mixed with a nontoxic surfactant. In some embodiments, the pharmaceutical compositions as described herein are formulated for intravenous or intra-arterial administration may include sterile aqueous solutions that may also contain buffers, liposomes, diluents, and other suitable additives. In some embodiments, the pharmaceutical composition can also comprise or include serum.

[0325] In some embodiments, the pharmaceutical composition is in a dosage form. In some embodiments, the dosage forms are suitable for injection or infusion can include sterile aqueous solutions or dispersions comprising the polypeptide constructs that are adapted for administration by encapsulation in liposomes. The ultimate dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage.

[0326] In some embodiments, a pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity (e.g., a viscosity reducer), clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. In such embodiments, suitable formulation materials include, but are not limited to, amino acids or salt thereof (such as glycine, glutamine, asparagine, arginine (e.g., arginine-HCl), histidine, or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA), pentetic acid (DTP A)); complexingAttorney Docket No. 199830-739601 agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta- cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrans); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as Pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapol); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants (see, Remington ’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).

[0327] Sterile injectable solutions are prepared by incorporating the polypeptide constructs in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington ’s Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0328] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0329] A polyol, which acts as a tonicifier and may stabilize the compositions and antibodies provided herein, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be alteredAttorney Docket No. 199830-739601 with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol is used in the formulation as a tonicity agent is mannitol.

[0330] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g, polysorbates 20, 80 etc.) or pol oxamers (e.g, pol oxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include a surfactant which is a polysorbate. In some embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitan monooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0331] In some embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative. In some embodiments, the proteins provided herein are formulated with a viscosity reducer. A viscosity reducer can include but is not limited to excipients such as: alanine, arginine, methionine, lysine, histidine, glutamine, valine, serine, glycine, niacinamide, caffeine, ethyleneimine, carnitine, camphorsulfonic acid, ornithine, imidazole, aspartate, sodium chloride, sucrose, polysorbate, a derivative, or a salt of any of these. The pharmaceutical compositions and dosing regimens can comprise one or more viscosity reducers.

[0332] In some embodiments, the pH of the liquid formulation is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide. In some embodiments, the pH of the liquid formulation is from about to about 3.5 to 9, 5.5 to 6.5, for example 6.0. In some embodiments, the pH of the liquid formulation is about 6. Provided herein are pharmaceutical compositions for subcutaneous administration, wherein the pharmaceutical compositions comprise: a pH of 5.8.

[0333] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water forAttorney Docket No. 199830-739601 injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.

[0334] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.

[0335] The compositions and antibodies provided herein may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0336] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1 :2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1 :2 to 1 :5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0337] Provided herein are sustained release formulations comprising a pharmaceutical composition provided herein. In some embodiments, the sustained release formulation comprises a carrier. In some embodiments, the carrier is a polymer matrix. In some embodiments, the polymer matrix comprises acetylated pullulan, alginate, chitosan, collagen, gelatin, glycerin, hyaluronic acid, poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA) polycaprolactone (PCL), polyethylene glycol (PEG), poly D, L-lactide-polyethylene glycol (PELA), or a combination thereof. In some embodiments, the carrier is a liposome, an extracellular vesicle, a nanoparticle, or a lipid. In some embodiments, the carrier is a hydrogel.

[0338] Provided herein are hydrogels comprising a polypeptide construct provided herein. In some embodiments, the hydrogel is formulated for subcutaneous administration. In some embodiments, the hydrogel comprises: pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise one or more of: poly-s-caprolactone (PCL); polyethylene glycol (PEG); polyethylene oxide (PEO); alginate; chitosan; or polyglutamic acid.Subcutaneous Pharmaceutical Compositions

[0339] Sterile injectable solutions are prepared by incorporating the polypeptide constructs provided herein in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington ’sAttorney Docket No. 199830-739601Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Formulation components suitable for parenteral administration include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as EDTA; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. In some embodiments, the formulation for parenteral administration is citrate-free.

[0340] For intravenous or subcutaneous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). The carrier should be stable under the conditions of manufacture and storage, and should be preserved against microorganisms. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0341] A polyol, which acts as a tonicifier and may stabilize the compositions and antibodies provided herein, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In some embodiments, the aqueous formulation is isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g., mannitol) is added, compared to a disaccharide (such as trehalose). In some embodiments, the polyol which is used in the formulation as a tonicity agent is mannitol.

[0342] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates (e.g., polysorbates 20, 80 etc.) or pol oxamers (e.g., pol oxamer 188). The amount of detergent added is such that it reduces aggregation of the formulated antibody and / or minimizes the formation of particulates in the formulation and / or reduces adsorption. In some embodiments, the formulation may include a surfactant which is a polysorbate. In some embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80. Tween 80 is a term used to describe polyoxyethylene (20) sorbitan monooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th edi., 1996).

[0343] In some embodiments, the protein product of the present disclosure is formulated as a liquid formulation. In some embodiments, the liquid formulation is prepared in combination with a sugar at stabilizing levels. In some embodiments, the liquid formulation is prepared in an aqueous carrier. In some embodiments, a stabilizer is added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In some embodiments, the sugar is disaccharides, e.g., sucrose. In some embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative. InAttorney Docket No. 199830-739601 some embodiments, the proteins provided herein are formulated with a viscosity reducer. A viscosity reducer can include but is not limited to excipients such as: alanine, arginine, methionine, lysine, histidine, glutamine, valine, serine, glycine, niacinamide, caffeine, ethyleneimine, carnitine, camphorsulfonic acid, ornithine, imidazole, aspartate, sodium chloride, sucrose, polysorbate, a derivative, or a salt of any of these. The pharmaceutical compositions and dosing regiments can comprise one or more viscosity reducers.

[0344] In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 40 millimolar (mM) arginine-hydrochloride (Arg HCl) up to 300 mM Arg HCl. In some embodiments, a pharmaceutical composition provided herein comprises about 50 mM Arg HCl up to 150 mM Arg HCl. In some embodiments, a pharmaceutical composition provided herein comprises at least 50 mM Arg HCl. In some embodiments, a pharmaceutical composition provided herein comprises at least 100 mM Arg HCl. In some embodiments, a pharmaceutical composition provided herein comprises about 50 mM Arg HCl. In some embodiments, a pharmaceutical composition provided herein comprises about 100 mM Arg HCl.

[0345] In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 40 mM glycine up to 300 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 50 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 60 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 70 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 80 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 90 mM glycine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 100 mM glycine.

[0346] In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 10 mM methionine up to 200 mM methionine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 20 mM methionine. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 80 mM methionine.

[0347] In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 40 mM niacinamide up to 300 mM niacinamide. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 100 mM niacinamide. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 140 mM niacinamide.Attorney Docket No. 199830-739601

[0348] In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 0.01 mM EDTA up to 0.1 mM EDTA. In some embodiments, a pharmaceutical composition provided herein is formulated to comprise about 0.05 mM EDTA.

[0349] In some embodiments, a pharmaceutical composition provided herein comprises a buffer. In some embodiments, the buffer comprises histidine. In some embodiments, a pharmaceutical composition provided herein comprises a buffer. In some embodiments, the buffer comprises histidine and glutamate. In some embodiments, the buffer comprises about 10 mM histidine up to 200 mM histidine. In some embodiments, the buffer comprises about 20 mM histidine. In some embodiments, the buffer comprises about 10 mM glutamate up to 200 mM glutamate. In some embodiments, the buffer comprises about 20 mM glutamate. In some embodiments, the buffer comprises 20 mM histidine and a pH of 5.5. some embodiments, the buffer comprises 20 mM histidine and a pH of 6.0. In some embodiments, the buffer comprises 20 mM histidine-glutamate (1 : 1) at a pH of 5.5. In some embodiments, a protein provided herein is admixed into a buffer provided herein at a concentration of about 200 mg / mL. In some embodiments, a protein provided herein is admixed into the buffer prior to being combined with additional excipients or surfactants provided herein. Provided herein are pharmaceutical compositions for subcutaneous administration, wherein the pharmaceutical compositions comprise: 20 mM Histidine buffer and a pH of 5.8.

[0350] In some embodiments, the pH of the liquid formulation is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the base is sodium hydroxide. In some embodiments, the pH of the liquid formulation is from about 3.5 to 9. In some embodiments, the pH of a liquid formulation is from about 5.0 to 6.5. In some embodiments, the pH of a liquid formulation is from about 5.5 to 6.5. In some embodiments, the pH of a pharmaceutical composition provided herein is between about 5.5 to 6.0. In some embodiments, a pharmaceutical composition provided herein comprises a pH of at least 5.5. In some embodiments, a pharmaceutical composition provided herein comprises a pH of about 5.6 up to 6.5. In some embodiments, a pharmaceutical composition provided herein comprises a pH of 5.5, 5.6, 5.7, or 5.8. In some embodiments, a pharmaceutical composition provided herein comprises a pH of In some embodiments, a pharmaceutical composition provided herein comprises a pH of 5.6. In some embodiments, a pharmaceutical composition provided herein comprises a pH of 5.8.

[0351] The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water forAttorney Docket No. 199830-739601 injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.

[0352] A preservative may be optionally added to the formulations herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.

[0353] The compositions and antibodies provided herein may be lyophilized to produce a lyophilized formulation including the proteins and a lyoprotectant. The lyoprotectant may be sugar, e.g., disaccharides. In some embodiments, the lyoprotectant is sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and / or a preservative.

[0354] The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1 :2 protein to sucrose or maltose. In some embodiments, the protein to sucrose or maltose weight ratio is of from 1 :2 to 1 :5. In some embodiments, the pH of the formulation, prior to lyophilization, is set by addition of a pharmaceutically acceptable acid and / or base. In some embodiments, the pharmaceutically acceptable acid is hydrochloric acid. In some embodiments, the pharmaceutically acceptable base is sodium hydroxide.

[0355] In some embodiments, the pharmaceutical compositions comprising a CD-40 targeting moiety provided herein are injectable liquid formulations. In some embodiments, the injectable liquid formulation comprises a viscosity reducer. In some embodiments, the injectable liquid formulation comprises one or more excipients selected from the group consisting of: arginine or a salt thereof, a sugar, glycine or a salt thereof, a surfactant, methionine or a salt thereof, niacinamide or a salt thereof, an emulsifier, a solubilizer, a polyethoxylated sorbitan, an oleic acid, a chelating agent, histidine or a salt thereof, a poloxamer, and any combinations thereof.

[0356] In some embodiments, the sugar comprises sucrose, glucose, fructose, or any combination thereof. In some embodiments, the sugar is sucrose. In some embodiments, the pharmaceutical composition comprises at least 1% sucrose, at least 2% sucrose, at least 3% sucrose, at least 4% sucrose, at least 5% sucrose, at least 6% sucrose, at least 7% sucrose, at least 8% sucrose, at least 9% sucrose, at least 10% sucrose, up to about 20% sucrose (weight to total volume, w / v). In some embodiments, the pharmaceutical composition comprises an amount of 1% sucrose (w / v) up to 5% sucrose (w / v). In some embodiments, the pharmaceutical composition comprises an amount of 2% sucrose (w / v). In some embodiments, the pharmaceutical composition comprises an amount of 4% sucrose (w / v).

[0357] In some embodiments, the surfactant is a hydrophobic surfactant. In some embodiments, the surfactant is a hydrophilic surfactant. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant comprises polysorbate 20, polysorbate 40,Attorney Docket No. 199830-739601 polysorbate 60, polysorbate 80 (TWEEN® 80). In some embodiments, the pharmaceutical composition comprises at least 0.01% polysorbate 80, at least 0.02% polysorbate 80, at least 0.03% polysorbate 80, at least 0.04% polysorbate 80, at least 0.05% polysorbate 80, at least 0.06% polysorbate 80, at least 0.07% polysorbate 80, at least 0.08% polysorbate 80, at least 0.09% polysorbate 80, at least 0.10% polysorbate 80, up to about 0.20% polysorbate 80 (weight to total volume, w / v). In some embodiments, the pharmaceutical composition comprises about 0.01% up to 0.5% polysorbate 80.

[0358] In some embodiments, the pharmaceutical composition comprises about 0.01% up to 0.5% (weight to total volume, w / v) pol oxamer 188 (Pl 88). Pl 88 is a copolymer of repeating unites of polyethylene oxide (PEO) and polypropylene oxide (PPO). In some embodiments, the pharmaceutical composition comprises about 0.1% (w / v) P188.

[0359] In some embodiments, the pharmaceutical composition comprises at least 20 millimolar (mM) arginine hydrochloride, at least 30 mM arginine hydrochloride, at least 40 mM arginine hydrochloride, at least 50 mM arginine hydrochloride, at least 60 mM arginine hydrochloride, at least 70 mM arginine hydrochloride, at least 80 mM arginine hydrochloride, at least 90 mM arginine hydrochloride, at least 100 mM arginine hydrochloride, at least 110 mM arginine hydrochloride, at least 120 mM arginine hydrochloride, at least 130 mM arginine hydrochloride, at least 140 mM arginine hydrochloride, at least 150 mM arginine hydrochloride, at least 160 mM arginine hydrochloride, at least 170 mM arginine hydrochloride, at least 180 mM arginine hydrochloride, at least 190 mM arginine hydrochloride, at least 200 mM arginine hydrochloride, up to about 500 mM arginine hydrochloride.

[0360] In some embodiments, a pharmaceutical composition provided herein comprises a CD- 40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 140mM arginine hydrochloride; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM arginine hydrochloride; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 4% w / v sucrose; 50mM arginine hydrochloride; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM glycine; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided hereinAttorney Docket No. 199830-739601 comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM arginine hydrochloride; 100 mM niacinamide, and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; 80mM methionine; 140mM niacinamide; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; 20 mM methionine; lOOmM arginine hydrochloride; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; 0.05 mM EDTA; lOOmM arginine hydrochloride; and / or 0.02% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM arginine hydrochloride; and / or 0.1% w / v poloxamer 188. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM arginine hydrochloride; and / or 0.04% w / v polysorbate 80. In some embodiments, a pharmaceutical composition provided herein comprises a CD-40 targeting moiety provided herein; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: 2% w / v sucrose; lOOmM arginine hydrochloride; and / or 0.02% w / v polysorbate 80.

[0361] Provided herein are hydrogels comprising a polypeptide construct provided herein. In some embodiments, the hydrogel is formulated for subcutaneous administration. In some embodiments, the hydrogel comprises: pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise one or more of: poly-s-caprolactone (PCL); polyethylene glycol (PEG); polyethylene oxide (PEO); alginate; chitosan; or polyglutamic acid.(9) Drug Delivery Devices.

[0362] Provided herein are drug delivery devices for administering a composition provided herein. In some embodiments, the drug delivery device comprises a pre-fillable reservoir comprising the pharmaceutical composition provided herein. In some embodiments, the drug delivery device comprises a body comprising an injection opening, a drive mechanism that isAttorney Docket No. 199830-739601 actuated to move the reservoir through the injection opening. In some embodiments, the drug delivery device comprises a needle assembly for injection of the pharmaceutical composition into the skin of a subject. In some embodiments, the drug delivery device comprises a hub portion attachable to the pre-fillable reservoir and support the needle. In some embodiments, the pre- fillable reservoir is a syringe.

[0363] In some embodiments, the drug delivery device is an autoinjector. Autoinjector devices aim to make self-inj ection easier for patients. A conventional autoinjector may provide the force for administering the injection by a spring, a trigger button, or other mechanisms used to activate the injection. Autoinjectors may be single-use or reusable devices.

[0364] An intravenous or subcutaneous drug delivery formulation comprising any of the compositions or polypeptide construct provided herein, may be contained in a syringe, a pen, or a bag. In some embodiments, the bag is connected to a channel comprising a tube and / or a needle. In some embodiments, the formulation is a lyophilized formulation or a liquid formulation. In some embodiments, the formulation is a liquid formulation. Various devices can be used to deliver liquid formulations by subcutaneous route of administration, including on-body infusion devices, autoinjector devices, prefilled syringes, and syringes. Generally, administration time depends on volume and device, and can range from seconds to minutes.

[0365] These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.(10) Dosing, Administration, and Efficacy.

[0366] Compositions provided herein may be formulated in dosage unit form for ease of administration and uniformity of dosage. A dosage unit form is a physically discrete unit of a composition provided herein appropriate for a subject to be treated. It will be understood, however, that the total usage of compositions provided herein will be decided by the attending physician within the scope of sound medical judgment. For any composition provided herein the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, such as mice, rabbits, dogs, pigs, or non-human primates. Subjects include, without limitation, domesticate or farmed animals (including without limitation pigs, cows, horses, buffalo, pigs, ducks, geese, chicken, turkey, fish) as well as humans. Dosing may be for veterinary or human therapeutic uses. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity of compositions provided herein can be determined by standard pharmaceutical procedures in cell cultures or experimentalAttorney Docket No. 199830-739601 animals, e.g., ED50 (the dose is therapeutically effective in 50% of the population) and LDso (the dose is lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions which exhibit large therapeutic indices may be useful in some embodiments. The data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use.

[0367] In some embodiments, the compositions provided herein are administered at a dose of about 1 mg to about 2000 mg. In some embodiments, the compositions provided herein are administered at a dose of about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, about 20 mg / kg, about 24 mg / kg, 25 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, or about 500 mg / kg. In some embodiments, the compositions provided herein are administered at a dose of about 30 mg / kg. In some embodiments, the compositions provided herein are administered at a dose of about 50 mg / kg. In some embodiments, the compositions provided herein are administered at a dose of about 100 mg / kg. In some embodiments, the compositions provided herein are administered at a dose of about 300 mg / kg.

[0368] n some embodiments, the compositions provided herein are administered at a dose of about 300 mg. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be about 250 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0369] The specific dose can be a uniform dose for each patient of about 150 mg, of about 200 mg, of about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg or more of the composition provided herein. Alternatively, a patient’s dose can be tailored to the approximate body weight or surface area of the patient. Other factors in determining the appropriate dosage can include the disease or condition to be treated or prevented, the severity of the disease, the route of administration, and the age, sex and medical condition of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those skilled in the art, especially in light of the dosage information and assays disclosed herein. TheAttorney Docket No. 199830-739601 dosage can also be determined through the use of known assays for determining dosages used in conjunction with appropriate dose-response data. An individual patient's dosage can be adjusted as the progress of the disease is monitored. Blood levels of the targetable construct or complex in a patient can be measured to see if the dosage needs to be adjusted to reach or maintain an effective concentration. Pharmacogenomics may be used to determine which targetable constructs and / or complexes, and dosages thereof, are most likely to be effective for a given individual.

[0370] Provided herein are compositions and pharmaceutical compositions for administering to a subject in need thereof. In some embodiments, the administering is local administration or systemic administration. In some embodiments, a composition provided herein is formulated for administration / for use in administration via a subcutaneous, intradermal, intramuscular, inhalation, intravenous, intraperitoneal, intracranial, intranasal, or intrathecal route, the administering comprises intravenous administration, intra-arterial administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, vaginal administration, intravitreal administration, intratumoral administration, intraocular administration, nasal administration, or intrathecal administration. In some embodiments, a dosing regimen provided herein comprises different modes of administration, for example intravenous administration and subcutaneous administration.

[0371] In some embodiments, the administering is every 1, 2, 4, 6, 8, 12, 24, 36, or 48 hours. In some embodiments, the administering is daily, weekly, or monthly. In some embodiments, the administering is repeated at least about every 28 days or 56 days.

[0372] In some embodiments, a single dose of a composition provided herein is administered to a subject. In some embodiments, a composition or pharmaceutical composition provided herein is administered to the subject by two doses. In some embodiments, a second dose of a composition or pharmaceutical composition provided herein is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, or about 56 days after the first dose. In some embodiments, a first dose is administered, and a second dose is administered about 14 days later, or about 21 days later, or about 28 days later, or about 35 days later, or about 42 days later, or about 49 days later, or about 56 days later, or about 63 days later, or about 70 days later, or about 77 days later, or about 84 days later. In some embodiments, the second dose is administered about 10-90 days following administration of the first dose, or about 15-85 days following administration of the first dose, or about 20-80 days following administration of the first dose, or about 25-75 days following administration of the first dose, or about 30-70 days following administration of the first dose, or about 35-65 days following administration of the first dose, or about 40-60 days following administration of the first dose.Attorney Docket No. 199830-739601

[0373] In some embodiments, an additional, for example third or more, dose of a composition or pharmaceutical composition provided herein is administered to a subject. In some embodiments, the additional dose is administered about 1 month following administration of the second dose, about 2 months following administration of the second dose, about 3 months following administration of the second dose, about 4 months following administration of the second dose, about 5 months following administration of the second dose, about 6 months following administration of the second dose, about 7 months following administration of the second dose, about 8 months following administration of the second dose, about 9 months following administration of the second dose, about 10 months following administration of the second dose, about 11 months following administration of the second dose, about 12 months following administration of the second dose, about 13 months following administration of the second dose, about 14 months following administration of the second dose, about 15 months following administration of the second dose, about 16 months following administration of the second dose, about 17 months following administration of the second dose, or about 18 months following administration of the second dose.

[0374] Provided herein are dosing regimens for use in the treatment of a disease in a subject in need thereof, the dosing regimen comprising: (a) a first liquid formulation comprising a dose of at least about 30 mg / kg of a CD-40 targeting moiety; and (b) a second liquid formulation comprising a dose of at least about 150 mg / kg of a CD-40 targeting moiety, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation, thereby treating the disease in the subject, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43

[0375] In some embodiments, the first liquid formulation is for subcutaneous administration. In some embodiments, the first liquid formulation is for intravenous administration. In some embodiments, the second liquid formulation is for subcutaneous administration. In some embodiments, the second liquid formulation is for intravenous administration. In some embodiments, the first liquid formulation is suitable for administration as a single injection or multiple injections. In some embodiments, the second liquid formulation is suitable forAttorney Docket No. 199830-739601 administration as a single injection or multiple injections. In some embodiments, the first liquid formulation comprises a dose of 30 mg / kg up to about 150 mg / kg of a CD-40 targeting moiety. In some embodiments, the second liquid formulation comprises a dose of 150 mg / kg up to about 800 mg / kg of a CD-40 targeting moiety. In some embodiments, the second liquid formulation comprises a dose of 180 mg / kg. In some embodiments, the second liquid formulation comprises a dose of 200 mg / kg.

[0376] Provided herein are dosing regimens further comprising one or more additional injectable formulations that serve as a maintenance dose to keep the plasma concentration of the CD-40 targeting moiety and compositions thereof within a certain level at steady state. In some embodiments, the dosing regimens for use in the treatment of a disease in a subject in need thereof. In some embodiments, the dosing regimens comprise: a first liquid formulation comprising a dose of at least about 30 mg / kg of a CD-40 targeting moiety provided herein. In some embodiments, the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43. Further provided herein are dosing regimens further comprising: (b) a second liquid formulation comprising a dose of at least about 150 mg / kg of a CD-40 targeting moiety, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation. Further provided herein are dosing regimens, wherein the first liquid formulation is for subcutaneous administration Further provided herein are dosing regimens, wherein the first liquid formulation is for intravenous administration. Further provided herein are dosing regimens, wherein the second liquid formulation is for subcutaneous administration. Further provided herein are dosing regimens, wherein the second liquid formulation is for intravenous administration. Further provided herein are dosing regimens, wherein the first liquid formulation is suitable for administration as a single injection or multiple injections. Further provided herein are dosing regimens, wherein the second liquid formulation is suitable for administration as a single injection or multiple injections. Further provided herein are dosing regimens, wherein the first liquid formulation comprises a dose of 30 mg / kg up to about 150 mg / kg of a CD-40 targeting moiety. Further provided herein are dosing regimens, wherein the second liquid formulation comprises a dose of 150 mg / kg up to about 800 mg / kg of a CD-40 targeting moiety. Further provided hereinAttorney Docket No. 199830-739601 are dosing regimens, wherein the first liquid formulation further comprises one or more of a sugar; a polysorbate; an arginine or a salt thereof; or a histidine or a salt thereof. Further provided herein are dosing regimens, wherein the second liquid formulation further comprises one or more of a sugar; a polysorbate; an arginine or a salt thereof; or a histidine or a salt thereof. Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a heavy chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to SEQ ID NO: 45; SEQ ID NO: 46; or SEQ ID NO: 47. Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a heavy chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 62. Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 56, SEQ ID NO: 63 to SEQ ID NO: 68 Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises: (a) a CDR1 comprising RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88; (b) a CDR2 comprising KVSNRFS (SEQ ID NO: 96), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96; and (c) a CDR3 comprising SQSTHVPWT (SEQ ID NO: 110) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110. Further provided herein are dosing regimens, wherein the light chain comprises a light chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 126 to SEQ ID NO: 131. Further provided herein are dosing regimens, wherein the light chain comprises a light chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 138. Further providedAttorney Docket No. 199830-739601 herein are dosing regimens, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 139 to SEQ ID NO: 143, SEQ ID NO: 148 to SEQ ID NO: 153 Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region. Further provided herein are dosing regimens, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region. Further provided herein are dosing regimens, wherein the CD-40 targeting moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. Further provided herein are dosing regimens, wherein the CD-40 targeting moiety is linked directly or indirectly to a CD-20 targeting moiety. Further provided herein are dosing regimens, wherein the dosing regimen comprises sucrose. Further provided herein are dosing regimens, wherein the sucrose is present in an amount of about 2% weight to total volume of the dosing regimen. Further provided herein are dosing regimens, wherein dosing regimen comprises sucrose, and wherein the sucrose is present in an amount of about 4% weight to total volume of the pharmaceutical composition. Further provided herein are dosing regimens, wherein the dosing regimen comprises a surfactant. Further provided herein are dosing regimens, wherein the surfactant comprises polysorbate 188 or polysorbate 80. Further provided herein are dosing regimens, further comprising a chelating agent. Further provided herein are dosing regimens, wherein the chelating agent comprises ethylenediaminetetraacetic acid (EDTA). Further provided herein are dosing regimens, further comprising an enzyme. Further provided herein are dosing regimens, wherein the enzyme comprises hyaluronidase (rHuPH20).(11) Methods of Treating a Disease.

[0377] Provided herein are methods of treating a disease in a subject in need thereof by administering to the subject a composition, a dosing regimen, or a pharmaceutical composition provided herein, optionally wherein the administering is subcutaneous administration.. Further provided herein are methods of modulating an immune response in a subject in need thereof. The compositions provided herein can be used for both in vivo and in vitro methods as well as medical and non-medical procedures. In some embodiments, the compositions provided herein are provided for use as a medicament. In certain embodiments, the CD-40 targeting moieties, polypeptide constructs, bispecific antibodies, and / or compositions provided herein are provided orAttorney Docket No. 199830-739601 administered for treatment of a disease, condition, or a disorder, a clinical or physiological condition associated with CD-40 activity, a CD-20 activity, a BAFF activity, an APRIL activity, and / or an IFNR activity. In some embodiments, the CD-40 activity is increased in the subject relative to a healthy subject. In some embodiments, the CD-20 activity is increased in the subject relative to a healthy subject. The compositions can also be applied for use in the preparation of a medicament, for example for the treatment of a disease or a disorder, a clinical or physiological condition associated with a CD-40 or , a CD-20 activity, a BAFF activity, an APRIL activity, and / or an IFNR activity. The compositions as disclosed herein bind to a target protein or proteins implicated in a disease or a condition, for example CD-40, CD-20, BAFF, APRIL, IFNR, and any combination thereof. In some embodiments, the disease is a cancer, an inflammatory disease, an autoimmune disease, an infectious disease, a cardiac disease, diabetes, a genetic disease, or a neurological disease. In some embodiments, the disease is an autoimmune disease.

[0378] In certain embodiments, the polypeptide constructs as disclosed herein comprise an antigen-binding moiety that binds to a target protein implicated in a cancer. The term “cancer” as used herein refers to proliferative diseases, such as lymphomas, carcinoma, lymphoma, blastoma, sarcoma, leukemia, lymphocytic leukemias, lung cancer, non-small cell lung (NSCL) cancer, bone cancer, bronchioloalveolar cell lung cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colorectal cancer (CRC), pancreatic cancer, breast cancer, triple-negative breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwanomas, ependymonas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenoma and Ewings sarcoma, melanoma, multiple myeloma, B-cell cancer (lymphoma), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers. In some embodiments, the cancer is a breast cancer, a colorectal cancer, a lung cancer, a leukemia, a bladder cancer, a lymphoma, a melanoma, a carcinoma, a kidney cancer, a prostate cancer, a bone cancer, a brain tumor, an adenocarcinoma, an adrenal cancer, a bile duct cancer, a cervical cancer, a pancreatic cancer, a thyroid cancer, anAttorney Docket No. 199830-739601 appendix cancer, a myeloma, a sarcoma, a cancer that primarily affects minors or children, or any combination thereof. In some embodiments, the composition provided herein are used in the treatment of CD40 positive cancers, autoimmune and / or inflammatory disorders. In some embodiments, the compositions provided herein comprise an CD-40 targeting moiety that binds to a CD-40 protein implicated in an inflammatory disease that is an autoimmune disease.

[0379] In some embodiments, the inflammatory disease or disorder provided herein can include but is not limited to fatty liver disease, endometriosis, type 1 diabetes mellitus, type 2 diabetes mellitus, asthma, obesity, inflammatory bowel disease, rheumatoid arthritis, colitis, gout, sinusitis, vasculitis, ankylosing spondylitis, myalgic encephalomyelitis, fibromyalgia, migraines, or an autoimmune disease. In some embodiments, the compositions provided herein comprise an CD- 20 targeting moiety that binds to a CD-20 protein implicated in an inflammatory disease that is an autoimmune disease. The term “autoimmune disease” as used herein refers to a disease that results when a subject’s immune system is overactive causing it to attack and damage tissues in the subject’s body. In some embodiments, the autoimmune disease can include but is not limited to rheumatoid arthritis, type 1 diabetes, type 2 diabetes, multiple sclerosis, psoriasis, Grave’s disease, inflammatory bowel disease, Hashimoto thyroiditis, Sjogren syndrome, Celiac disease, Myasthenia gravis, Addison's disease, alopecia areata, autoimmune angioedema, vitiligo, Crohn’s Disease, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, vasculitis, pemphigus vulgaris, atopic dermatitis, allergy, asthma, urticaria, psoriatic arthritis, dermatomyositis, pernicious anemia, or lupus nephritis.

[0380] Provided herein are methods for treating a disease in a human subject, the methods comprising: administering to the human subject a therapeutically effective amount of the pharmaceutical composition provided herein, thereby treating the disease in the human subject.

[0381] Provided herein are methods for inducing immune tolerance in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition provided herein, thereby inducing immune tolerance in the subject.

[0382] Provided herein are methods for reducing inflammation in a subject, the methods comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of provided herein, thereby reducing inflammation in the subject relative to a level of inflammation in the subject prior to administering the pharmaceutical composition.

[0383] In some embodiments, the disease comprises an autoimmune disease, a bowel disease, a cancer, diabetes, a gastrointestinal disease, a heart disease, an inflammatory disease, a kidney disease, a liver disease, a metabolic disease, a muscular disease, a neurodegenerative disease, a neurological disease, a neuromuscular disease, an ocular disease, pain, a psychiatric disease, a respiratory disease, a skin disease, or a urinary disease. In some embodiments, the diseaseAttorney Docket No. 199830-739601 comprises Crohn’s Disease or inflammatory bowel disease. In some embodiments, the disease comprises multiple sclerosis. In some embodiments, the disease comprises systemic lupus erythematosus. In some embodiments, the disease comprises pemphigus vulgaris. In some embodiments, the disease comprises vasculitis. In some embodiments, the disease comprises scleroderma. In some embodiments, the disease comprises rheumatoid arthritis. In some embodiments, the disease comprises lupus nephritis. In some embodiments, the disease comprises amyloidosis. In some embodiments, the disease comprises Sjogren’s Disease. In some embodiments, the disease comprises psoriasis. In some embodiments, the disease comprises bullous pemphigoides. In some embodiments, the disease comprises atopic dermatitis.

[0384] Provided herein are methods of alleviating at least one symptom of a disease or a disorder by administering the polypeptide constructs to a subject in need thereof. Provided herein are methods of alleviating at least one symptom of a disease or a disorder by subcutaneously administering the polypeptide constructs to a subject in need thereof. In some embodiments, the polypeptide constructs upon contact with a cell or a population of cells: (a) depletes a number of memory B cells as assessed by measuring memory B cell markers; (b) reduces an amount of innate pro-inflammatory cytokines; (c) increases a number of T regulatory cells; (d) increases a number of exhausted effector T cells; (e) reduces a number of CD3+, CD20+ T cells; (f) reduces a number of CD 19+ CD20+ B cells; (g) reduces a number of tissue resident activated B cells in a tissue; (h) reduces a population of cancer cells; or (i) any combination of (a)-(h).(12) Kits.

[0385] Provided herein is a kit for treating a disease in a subject in need thereof comprising: (a) an injectable liquid formulation comprising a CD-40 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 19, or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 34 to SEQ ID NO: 44; and (b) a needle, (c) a pre-fillable reservoir, and (d) instructions to administer the injectable liquid formulation of the CD-40 targeting moiety or the composition provided herein. In some embodiments, the injectable liquid formulation is allocated into separateAttorney Docket No. 199830-739601 units. In some embodiments, the kit comprises an injectable liquid formulation that is allocated into separate units. In some embodiments, the kit comprises an autoinjector.

[0386] Provided herein is a kit for treating a disease in a subject in need thereof comprising: a first container comprising: an injectable liquid formulation comprising a CD-40 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 19, or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 34 to SEQ ID NO: 44; and a second container comprising an immunosuppressive agent.

[0387] Provided herein is a kit for treating a disease in a subject in need thereof comprising: (a) an injectable liquid formulation comprising a CD-40 targeting moiety and a CD-20 targeting moiety, wherein the CD-40 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 19, or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 34 to SEQ ID NO: 44; and wherein the CD- 20 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 164 to SEQ ID NO: 169 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 164 to SEQ ID NO: 169; (ii) a CDR2 comprising any one of SEQ ID NO: 170 to SEQ ID NO: 174 a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 170 to SEQ ID NO: 174; and (iii) a CDR3 comprising any one of SEQ ID NO: 175 to SEQ ID NO: 178 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 175 to SEQ ID NO: 178; and (b) a needle, (c) a pre-fillable reservoir, and (d) instructions to administer the injectable liquid formulation of the CD-40 targeting moiety or the composition provided herein. In someAttorney Docket No. 199830-739601 embodiments, the kit comprises an injectable liquid formulation that is allocated into separate units. In some embodiments, the kit comprises an autoinjector.

[0388] Provided herein is a kit for treating a disease in a subject in need thereof comprising: (a) an injectable liquid formulation comprising a CD-40 targeting moiety and a CD-20 targeting moiety, wherein the CD-40 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 19, or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 1 to SEQ ID NO: 19; (ii) a CDR2 comprising any one of SEQ ID NO: 20 to SEQ ID NO: 33 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 20 to SEQ ID NO: 33; and (iii) a CDR3 comprising SEQ ID NO: 34 to SEQ ID NO: 44 or a functional variant thereof, wherein the functional variant comprises a single amino acid substitution as compared to any one of SEQ ID NO: 34 to SEQ ID NO: 44; and wherein the CD- 20 targeting moiety or a composition provided herein that comprises a heavy chain variable region that comprises: (i) a CDR1 comprising any one of SEQ ID NO: 164 to SEQ ID NO: 169 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 164 to SEQ ID NO: 169; (ii) a CDR2 comprising any one of SEQ ID NO: 170 to SEQ ID NO: 174 a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 170 to SEQ ID NO: 174; and (iii) a CDR3 comprising any one of SEQ ID NO: 175 to SEQ ID NO: 178 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 175 to SEQ ID NO: 178 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 175 to SEQ ID NO: 178; and a second container comprising an immunosuppressive agent.Exemplary Embodiments:

[0389] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising RYSVY (SEQ ID NO: 1), GFSLSRY (SEQ ID NO: 2), GFSISRY (SEQ ID NO: 3), GFSVSRY (SEQ ID NO: 4), GFSLSRYSVY (SEQ ID NO: 5), GFSISRYSVY (SEQ ID NO: 6), or GFSVSRYSVY (SEQ ID NO: 7) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7; (ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein theAttorney Docket No. 199830-739601 functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and (iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34.

[0390] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43.

[0391] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 61

[0392] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a light chain variable region, wherein the light chain variable region comprises: (a) a CD-40 targeting moiety comprising an anti-CD-40 antibody or antibody fragment, wherein the anti-CD-40 antibody or antibody fragment comprises a light chain variable region, wherein the light chain variable region comprises: (i) a CDR1 comprising any one of SEQ ID NO: 87 to SEQ ID NO: 95 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 87 to SEQ ID NO: 95; (ii) a CDR2 comprising any one of SEQ ID NO: 96 to SEQ ID NO: 109 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96 to SEQ ID NO: 109; and (iii) a CDR3 comprising any one of SEQ ID NO: 110 to SEQ ID NO: 125 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 to SEQ ID NO: 125

[0393] Provided herein are polypeptide constructs, wherein the polypeptide constructs comprise: a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a light chain, whereinAttorney Docket No. 199830-739601 the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to SEQ ID NO: 137

[0394] Provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide constructs comprise: (a) a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising: : (i) a CDR1 comprising a sequence of any one of SEQ ID NOS: 1 to 19, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 19; (ii) a CDR2 comprising a sequence of any one of SEQ ID NOS: 20 to 33, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 20 to 33; and (iii) a CDR3 comprising a sequence of any one of SEQ ID NOS: 34 to 43, or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 34 to 43; and (b) a CD-20 targeting moiety. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a heavy chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 45, SEQ ID NO: 46, or SEQ ID NO: 47. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a heavy chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 47. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 48, SEQ ID NO: 49, or SEQ ID NO: 50. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 81 or SEQ ID NO: 86. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety further comprises a light chain. Further provided herein are bispecific polypeptide constructs, wherein the light chainAttorney Docket No. 199830-739601 comprises: (a) a CDR1 comprising RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88; (b) a CDR2 comprising KVSNRFS (SEQ ID NO: 96), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96; and (c) a CDR3 comprising SQSTHVPWT (SEQ ID NO: 110) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 110 Further provided herein are bispecific polypeptide constructs, wherein the light chain comprises a light chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 126 to SEQ ID NO: 131. Further provided herein are bispecific polypeptide constructs, wherein the light chain comprises a light chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to: SEQ ID NO: 138 Further provided herein are bispecific polypeptide constructs, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 139 to SEQ ID NO: 143, SEQ ID NO: 148 to SEQ ID NO: 153 Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region. Further provided herein are bispecific polypeptide constructs, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigenbinding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR1 comprising any one of SEQ ID NO: 164 to SEQ ID NO: 169 orAttorney Docket No. 199830-739601 a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 164 to SEQ ID NO: 169. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR2 comprising any one of SEQ ID NO: 170 to SEQ ID NO: 174 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 170 to SEQ ID NO: 174. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a CDR3 comprising any one of SEQ ID NO: 175 to SEQ ID NO: 181 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 175 to SEQ ID NO: 181. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 182 to SEQ ID NO: 185, SEQ ID NO: 328, or SEQ ID NO: 329 Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR1 comprising any one of SEQ ID NO: 186 to SEQ ID NO: 188 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 186 to SEQ ID NO: 188. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR2 comprising any one SEQ ID NO: 189 to SEQ ID NO: 192 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 189 to SEQ ID NO: 192. Further provided herein are bispecific polypeptide constructs, wherein the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a CDR3 comprising any one of SEQ ID NO: 193 to SEQ ID NO: 196 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions relative to any one of SEQ ID NO: 193 to SEQ ID NO: 196. Further provided herein are bispecific polypeptide constructs, the CD-20 targeting moiety comprises a light chain, wherein the light chain comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 197 to SEQ ID NO: 200 Further provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide construct does not bind to CD-40 ligand (CD40L). Further provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide construct further comprises a half-life extension moiety. Further provided herein are bispecific polypeptideAttorney Docket No. 199830-739601 constructs, wherein the half-life extension moiety is an albumin. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an N-linked glycan. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises two light chains. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises two heavy chains. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises one heavy chain and one light chain. Further provided herein are bispecific polypeptide constructs, wherein the CD-40 targeting moiety comprises two light chains and two heavy chains. Further provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide construct comprises an IgA fragment. Further provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide constructs further comprise a constant domain comprising one or more amino acid substitutions that increase multimerization of the CD-40 targeting moiety and / or the CD-20 targeting moiety. Further provided herein are bispecific polypeptide constructs, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise an import amino acid residue having a larger side chain volume than the original amino acid residue. Further provided herein are bispecific polypeptide constructs, wherein the import amino acid residue comprises a phenylalanine (F), a tyrosine (Y), or a tryptophan (W). Further provided herein are bispecific polypeptide constructs, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitutions comprise a Y to a W amino acid substitution, a T to S amino acid substitution, an L to A amino acid substitution, a Y to V amino acid substation, or any combination thereof. Further provided herein are bispecific polypeptide constructs, wherein the constant domain comprises the one or more amino acid substitutions, wherein the one or more amino acid substitution comprises an import amino acid residue comprises a cysteine (C) relative to the original amino acid residue.

[0395] Provided herein are bispecific polypeptide constructs, wherein the bispecific polypeptide constructs comprise: (a) a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a light chain variable region, wherein the light chain variable region comprises: (i) a CDR1 comprising any one of SEQ ID NO: 87 to SEQ ID NO: 88 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NO: 87 to SEQ ID NO: 88; (ii) a CDR2 comprising any one of SEQ ID NO: 96 to SEQ ID NO: 109 or a functional variant thereof, wherein the functional variant comprises one or two amino acid su...

Claims

Attorney Docket No. 199830-739601CLAIMSWHAT IS CLAIMED IS:

1. A dosing regimen for use in the treatment of a disease in a subject in need thereof, the dosing regimen comprising:(a) a first liquid formulation comprising a dose of at least about 30 mg / kg of a CD- 40 targeting moiety; and(b) a second liquid formulation comprising a dose of at least about 150 mg / kg of the CD-40 targeting moiety, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34.

2. The dosing regimen of claim 1, wherein the first liquid formulation is for subcutaneous administration.

3. The dosing regimen of claim 1, wherein the first liquid formulation is for intravenous administration.

4. The dosing regimen of claim 1, wherein the second liquid formulation is for subcutaneous administration.

5. The dosing regimen of claim 1, wherein the second liquid formulation is for intravenous administration.

6. The dosing regimen of claim 1, wherein the first liquid formulation is suitable for administration as a single injection or multiple injections.

7. The dosing regimen of claim 1, wherein the second liquid formulation is suitable for administration as a single injection or multiple injections.

8. The dosing regimen of claim 1, wherein the first liquid formulation comprises a dose of 30 mg / kg up to about 150 mg / kg of a CD-40 targeting moiety.Attorney Docket No. 199830-7396019. The dosing regimen of claim 1, wherein the second liquid formulation comprises a dose of 150 mg / kg up to about 800 mg / kg of a CD-40 targeting moiety.

10. The dosing regimen of claim 1, wherein the first liquid formulation further comprises one or more of: a sugar; a polysorbate; a citrate; an arginine or a salt thereof; or a histidine or a salt thereof.

11. The dosing regimen of claim 1, wherein the second liquid formulation further comprises one or more of: a sugar; a polysorbate; a citrate; an arginine or a salt thereof; or a histidine or a salt thereof.

12. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a heavy chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 45);QVQLQESGPGLVKPSETLSITCTVSGFSISRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 46); orQVQLQESGPGLVKPSETLSITCTVSGFSVSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 47)13. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a heavy chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:Attorney Docket No. 199830-739601ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 62).

14. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 64);QVQLQESGPGLVKPSETLSITCTVSGFSISRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 65); orQVQLQESGPGLVKPSETLSITCTVSGFSVSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 66).Attorney Docket No. 199830-73960115. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 81, SEQ ID NO: 8616. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a light chain, wherein the light chain comprises:(a) a CDR1 comprising RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88;(b) a CDR2 comprising KVSNRFS (SEQ ID NO: 50), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96; and(c) a CDR3 comprising SQSTHVPWT (SEQ ID NO: 58) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 11017. The dosing regimen of claim 16, wherein the light chain comprises a light chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to 137.

18. The dosing regimen of claim 16, wherein the light chain comprises a light chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13819. The dosing regimen of claim 16, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to SEQ ID NO: 153.

20. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region.Attorney Docket No. 199830-73960121. The dosing regimen of claim 20, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

22. The dosing regimen of claim 20, wherein the IgG comprises a modification that facilitates heterodimerization of the CD-40 targeting moiety with an additional polypeptide construct.

23. The dosing regimen of claim 1, wherein the CD-40 targeting moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof.

24. The dosing regimen of claim 1, wherein the CD-40 targeting moiety is linked directly or indirectly to a CD-20 targeting moiety.

25. The dosing regimen of claim 24, wherein the CD-40 targeting moiety heterodimerizes with the CD-20-targeting moiety.

26. A dosing regimen for use in the treatment of a disease in a subject in need thereof, the dosing regimen comprising:(a) a first liquid formulation comprising a dose of at least about 30 mg / kg of a bispecific polypeptide construct; and(b) a second liquid formulation comprising a dose of at least about 150 mg / kg of the bispecific polypeptide construct, wherein the second liquid formulation is administered at least 1 day after the first liquid formulation, wherein the bispecific polypeptide construct comprises:(i) a CD-40 targeting moiety; and(ii) a CD-20 targeting moiety.

27. The dosing regimen of claim 26, wherein the CD-40 targeting moiety comprises a region that binds to CD-40 and an IgG region.

28. The dosing regimen of claim 26, wherein the CD-20 targeting moiety comprises a region that binds to CD-40 and an IgG region.

29. The dosing regimen of claim 26, wherein the CD-40 targeting moiety and the CD- 20 targeting moiety are directly linked to each other by a linker region.

30. The dosing regimen of claim 26, wherein the CD-40 targeting moiety and the CD- 20 targeting moiety each comprise an IgG region, wherein each IgG region comprises a modification that facilitates heterodimerization of the CD-40 targeting moiety and the CD-20 targeting moiety.

31. A pharmaceutical composition comprising: nAttorney Docket No. 199830-739601 a subcutaneous liquid formulation comprising a protein that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: a sugar; a polysorbate; and arginine or a salt thereof.

32. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of at least 100 milligrams per milliliter (mg / mL) of the injectable liquid formulation.

33. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of at least 150 mg / mL of the injectable liquid formulation.

34. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of at least 180 mg / mL of the injectable liquid formulation.

35. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of at least 200 mg / mL of the injectable liquid formulation.

36. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of at least 220 mg / mL of the injectable liquid formulation.

37. The pharmaceutical composition of claim 31, wherein the protein is present in an amount of about 180 up to 220 milligrams per milliliter (mg / mL) of the injectable liquid formulation.

38. The pharmaceutical composition of any one of claims 31 to 37, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a heavy chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:Attorney Docket No. 199830-739601QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 45);QVQLQESGPGLVKPSETLSITCTVSGFSISRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 46); orQVQLQESGPGLVKPSETLSITCTVSGFSVSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 47)39. The pharmaceutical composition of any one of claims 31 to 38, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a heavy chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 62).

40. The pharmaceutical composition of any one of claims 31 to 38, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 64);QVQLQESGPGLVKPSETLSITCTVSGFSISRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTVAttorney Docket No. 199830-739601SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 65); orQVQLQESGPGLVKPSETLSITCTVSGFSVSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ S SGL YSLS S VVTVPS S SLGTKT YTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFN STYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 66).

41. The pharmaceutical composition of any one of claims 31 to 38, wherein the CD-40 targeting moiety comprises the heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 81, or SEQ ID NO: 86.

42. The pharmaceutical composition of any one of claims 31 to 38, wherein the CD-40 targeting moiety further comprises a light chain.

43. The pharmaceutical composition of claim 42, wherein the light chain comprises:(a) a CDR1 comprising RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88;(b) a CDR2 comprising KVSNRFS (SEQ ID NO: 96), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96; and(c) a CDR3 comprising SQSTHVPWT (SEQ ID NO: 110) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 11044. The pharmaceutical composition of claim 42, wherein the light chain comprises a light chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97%Attorney Docket No. 199830-739601 identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to SEQ ID NO: 13745. The pharmaceutical composition of claim 42, wherein the light chain comprises a light chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138)46. The pharmaceutical composition of claim 42, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 139 to SEQ ID NO: 153.

47. The pharmaceutical composition of any one of claims 31 to 46, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region.

48. The pharmaceutical composition of claim 47, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

49. The pharmaceutical composition of any one of claims 31 to 48, wherein the CD-40 targeting moiety comprises a single domain antibody, a heavy-chain only antibody (HCAb), a single chain antigen-binding fragment (ScFab), a scFV-Fc, a fragment antigen-binding (Fab) domain, a fragment crystallizable (Fc) domain, a single chain variable fragment, a minibody, a nanobody (VHH), and any combination thereof.

50. The pharmaceutical composition of any one of claims 31 to 49, wherein the protein further comprises a CD-20 targeting moiety.

51. The pharmaceutical composition of any one of claims 31 to 50, wherein the protein further comprises an APRIL-targeting moiety.

52. The pharmaceutical composition of any one of claims 31 to 51, wherein the protein further comprises a BAFF-targeting moiety.

53. The pharmaceutical composition of any one of claims 31 to 52, wherein the protein further comprises an interferon receptor-targeting moiety.

54. A pharmaceutical composition comprising:(a) an anti-CD-40 antibody comprising a heavy chain variable region that comprises:Attorney Docket No. 199830-739601(i) a CDR1 comprising RYSVY (SEQ ID NO: 1), GFSLSRY (SEQ ID NO: 2), GFSISRY (SEQ ID NO: 3), GFSVSRY (SEQ ID NO: 4), GFSLSRYSVY (SEQ ID NO: 5), GFSISRYSVY (SEQ ID NO: 6), or GFSVSRYSVY (SEQ ID NO: 7) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and(b) a pharmaceutically acceptable excipient, wherein the anti-CD-40 antibody is present in an amount of at least 150 milligrams per milliliter (mg / mL) of the pharmaceutical composition, and wherein the pharmaceutical composition is an injectable liquid formulation.

55. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 160 mg / mL of the pharmaceutical composition.

56. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 170 mg / mL of the pharmaceutical composition.

57. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 180 mg / mL of the pharmaceutical composition.

58. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 190 mg / mL of the pharmaceutical composition.

59. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 200 mg / mL of the pharmaceutical composition.

60. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 210 mg / mL of the pharmaceutical composition.

61. The pharmaceutical composition of claim 54, wherein the anti-CD-40 antibody is present in an amount of at least 220 mg / mL of the pharmaceutical composition.

62. The pharmaceutical composition of any one of claims 54 to 61, wherein the heavy chain variable region comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:Attorney Docket No. 199830-739601QVQLQESGPGLVKPSETLSITCTVSGFSLSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 45);QVQLQESGPGLVKPSETLSITCTVSGFSISRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 46); orQVQLQESGPGLVKPSETLSITCTVSGFSVSRYSVYWVRQPPGKGLEWMGMMWG GGSTDYSTSLKSRLTISKDTSKSQVSLKMSSLTAADTAVYYCVRTDGDYWGQGTLVTV SS (SEQ ID NO: 47)63. The pharmaceutical composition of claim 62, wherein the anti-CD-40 antibody comprises a heavy chain, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 6164. The pharmaceutical composition of claim 54, wherein the heavy chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 45 to SEQ ID NO: 81, or SEQ ID NO: 8665. The pharmaceutical composition of claim 48, wherein the anti-CD-40 antibody further comprises a light chain.

66. The pharmaceutical composition of claim 65, wherein the light chain comprises:(a) a CDR1 comprising RSSQSLASSQGNTYLH (SEQ ID NO: 87), RSSQSLASSSGNTYLH (SEQ ID NO: 88), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 87 or SEQ ID NO: 88;(b) a CDR2 comprising KVSNRFS (SEQ ID NO: 96), or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 96; and(c) a CDR3 comprising SQSTHVPWT (SEQ ID NO: 110) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 11067. The pharmaceutical composition of claim 65, wherein the light chain comprises a light chain variable region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97%Attorney Docket No. 199830-739601 identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to SEQ ID NO: 13768. The pharmaceutical composition of claim 65, wherein the light chain comprises a light chain constant region that comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to:RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138)69. The pharmaceutical composition of claim 65, wherein the light chain comprises a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, at least 99% identical, or 100% identical to any one of SEQ ID NO: 126 to SEQ ID NO: 153.

70. The pharmaceutical composition of any one of claims 54 to 69, wherein the CD-40 targeting moiety comprises a heavy chain constant region, wherein the heavy chain constant region comprises an Immunoglobulin G (IgG) heavy chain constant region.

71. The pharmaceutical composition of claim 70, wherein the IgG comprises an IgGl, and IgG2, and IgG3, or an IgG4 heavy chain constant region.

72. A pharmaceutical composition comprising: a subcutaneous liquid formulation comprising a protein that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: a sugar; a polysorbate;Attorney Docket No. 199830-739601 a citrate; and arginine or a salt thereof.

73. A pharmaceutical composition comprising: a subcutaneous liquid formulation comprising a protein that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: a sugar; a polysorbate; and arginine or a salt thereof, wherein the pharmaceutical composition does not comprise a citrate.

74. A pharmaceutical composition comprising: a subcutaneous liquid formulation comprising a protein that comprises:(a) a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34;Attorney Docket No. 199830-739601(b) a CD-20 targeting moiety; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise: a sugar; a polysorbate; a citrate; and arginine or a salt thereof.

75. The pharmaceutical composition of any one of claims 72 to 74, further comprising a viscosity reducer.

76. The pharmaceutical composition of claim 75, wherein the viscosity reducer comprises one or more of: alanine, arginine, methionine, lysine, histidine, glutamine, valine, serine, glycine, niacinamide, caffeine, ethyleneimine, carnitine, camphorsulfonic acid, ornithine, imidazole, aspartate, sodium chloride, sucrose, polysorbate, a derivative, or a salt of any of these.

77. The pharmaceutical composition of any one of claims 72 to 74, wherein the pharmaceutical composition comprises a pH of at least about 5.5.

78. The pharmaceutical composition of any one of claims 72 to 74, wherein the pharmaceutical composition comprises a pH of about 5.6 up to 6.5.

79. The pharmaceutical composition of any one of claims 72 to 74, wherein the pharmaceutical composition comprises a pH of 5.8.

80. The pharmaceutical composition of any one of claims 72 to 74, wherein the sugar comprises sucrose, and wherein the sucrose is present in an amount of about 2% weight to total volume of the pharmaceutical composition.

81. The pharmaceutical composition of any one of claims 72 to 74, wherein the sugar comprises sucrose, and wherein the sucrose is present in an amount of about 4% weight to total volume of the pharmaceutical composition.

82. The pharmaceutical composition of any one of claims 72 to 74, wherein the pharmaceutical composition comprises a surfactant.

83. The pharmaceutical composition of claim 82, wherein the surfactant comprises polysorbate 188 or polysorbate 80.

84. The pharmaceutical composition of any one of claims 72 to 74, further comprising a chelating agent.

85. The pharmaceutical composition of claim 84, wherein the chelating agent comprises ethylenediaminetetraacetic acid (EDTA).

86. The pharmaceutical composition of any one of claims 72 to 74, further comprising an enzyme.Attorney Docket No. 199830-73960187. The pharmaceutical composition of claim 86, wherein the enzyme comprises hyaluronidase (rHuPH20).

88. A hydrogel comprising: a protein that comprises a CD-40 targeting moiety, wherein the CD-40 targeting moiety comprises a heavy chain comprising:(i) a CDR1 comprising any one of SEQ ID NO: 1 to SEQ ID NO: 7 or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to any one of SEQ ID NOS: 1 to 7;(ii) a CDR2 comprising WGGGSTD (SEQ ID NO: 20) or MMWGGGSTDYSTSLKS (SEQ ID NO: 21) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 20 or SEQ ID NO: 21; and(iii) a CDR3 comprising TDGDY (SEQ ID NO: 34) or a functional variant thereof, wherein the functional variant comprises one or two amino acid substitutions as compared to SEQ ID NO: 34; and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise one or more of: poly-s-caprolactone (PCL); polyethylene glycol (PEG); polyethylene oxide (PEO); alginate; chitosan; or polyglutamic acid.

89. A drug delivery device, wherein the drug delivery device comprises a reservoir comprising the pharmaceutical composition of any one of claims 25 to 87; or the hydrogel of claim 88.

90. A method of treating a disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 25 to 87; or the hydrogel of claim 88, thereby treating the disease in the subject.

91. A method of reducing inflammation in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 25 to 87; or the hydrogel of claim 88, thereby reducing inflammation in the subject relative to a level of inflammation in the subject prior to administering the pharmaceutical composition.

92. The method of claim 90 or claim 91, wherein the administering is subcutaneous administration.

93. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 10 mg / kg of the pharmaceutical composition.Attorney Docket No. 199830-73960194. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 30 mg / kg of the pharmaceutical composition.

95. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 70 mg / kg of the pharmaceutical composition.

96. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 100 mg / kg of the pharmaceutical composition.

97. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 150 mg / kg of the pharmaceutical composition.

98. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 180 mg / kg of the pharmaceutical composition.

99. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 200 mg / kg of the pharmaceutical composition.

100. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 220 mg / kg of the pharmaceutical composition.

101. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 240 mg / kg of the pharmaceutical composition.

102. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 300 mg / kg of the pharmaceutical composition.

103. The method of claim 90 or claim 91, wherein the subject is administered a dose of about 30 mg / kg up to about 300 mg / kg of the pharmaceutical composition.

104. The method of claim 90 or claim 91, wherein the subject is administered the pharmaceutical composition every 24 hours.

105. The method of claim 90 or claim 91, wherein the subject is administered the pharmaceutical composition every 5 days.

106. The method of any one of claims 90 to 105, wherein the subject is administered the pharmaceutical composition every 7 days.

107. The method of any one of claims 90 to 105, wherein the subject is administered the pharmaceutical composition every 10 days.

108. The dosing regimen or the method of any preceding claim, wherein the disease comprises an autoimmune disease.

109. The dosing regimen or the method of any preceding claim, wherein the disease comprises an inflammatory disease.

110. The dosing regimen or the method of any preceding claim, wherein the disease comprises multiple sclerosis.Attorney Docket No. 199830-739601111. The dosing regimen or the method of any preceding claim, wherein the disease comprises systemic lupus erythematosus.

112. The dosing regimen or the method of any preceding claim, wherein the disease comprises scleroderma.

113. The dosing regimen or the method of any preceding claim, wherein the disease comprises vasculitis.

114. The dosing regimen or the method of any preceding claim, wherein the disease comprises pemphigus vulgaris.

115. The dosing regimen or the method of any preceding claim, wherein the disease comprises multiple sclerosis.

116. The dosing regimen or the method of any preceding claim, wherein the disease comprises rheumatoid arthritis.

117. The dosing regimen or the method of any preceding claim, wherein the disease comprises amyloidosis.

118. The dosing regimen or the method of any preceding claim, wherein the disease comprises Sjogren’s Disease.

119. The dosing regimen or the method of any preceding claim, wherein the disease comprises lupus nephritis.

120. The dosing regimen or the method of any preceding claim, wherein the disease comprises diabetes.

121. A nucleic acid encoding for a polypeptide construct of any preceding claim.

122. A pharmaceutical composition comprising: a polypeptide construct or a nucleic acid encoding for the polypeptide construct, wherein the polypeptide construct comprises an amino acid sequence that is at least 80% identical to any one of the sequences listed in Table 35.

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